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.3887A>T | E1296V 2D  AIThe SynGAP1 missense variant E1296V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. High‑accuracy predictions therefore indicate a benign outcome: AlphaMissense‑Optimized is benign, the SGM Consensus is benign, and no Foldetta data are available. 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. | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -3.384 | Likely Benign | 0.443 | Ambiguous | Likely Benign | 0.229 | Likely Benign | -4.24 | Deleterious | 0.992 | Probably Damaging | 0.902 | Possibly Damaging | 2.62 | Benign | 0.01 | Affected | 0.0678 | 0.6040 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||||
| c.3888G>C | E1296D 2D  AIThe SynGAP1 missense variant E1296D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -3.566 | Likely Benign | 0.276 | Likely Benign | Likely Benign | 0.299 | Likely Benign | -2.15 | Neutral | 0.980 | Probably Damaging | 0.812 | Possibly Damaging | 2.59 | Benign | 0.04 | Affected | 0.1906 | 0.3443 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3888G>T | E1296D 2D AIThe SynGAP1 missense variant E1296D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -3.566 | Likely Benign | 0.276 | Likely Benign | Likely Benign | 0.493 | Likely Benign | -2.15 | Neutral | 0.980 | Probably Damaging | 0.812 | Possibly Damaging | 2.59 | Benign | 0.04 | Affected | 0.1906 | 0.3443 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3913A>C | T1305P 2D  AIThe SynGAP1 missense variant T1305P is not 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 | 0.791621 | Disordered | 0.894658 | Binding | 0.390 | 0.873 | 0.875 | -1.882 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.204 | Likely Benign | -1.41 | Neutral | 0.027 | Benign | 0.114 | Benign | 2.86 | Benign | 0.03 | Affected | 0.2157 | 0.5386 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3913A>G | T1305A 2D  AIThe SynGAP1 missense variant T1305A is listed in ClinVar (ID 411587.0) with an “Uncertain” clinical significance and is present in the gnomAD database (variant ID 6‑33451787‑A‑G). All evaluated in‑silico predictors classify the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic or likely pathogenic outcome. High‑accuracy assessments reinforce this benign prediction: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Overall, the computational evidence overwhelmingly supports a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.894658 | Binding | 0.390 | 0.873 | 0.875 | Conflicting | 4 | 6-33451787-A-G | 30 | 1.86e-5 | -2.692 | Likely Benign | 0.055 | Likely Benign | Likely Benign | 0.069 | Likely Benign | 1.74 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.24 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.4533 | 0.4746 | 1 | 0 | 2.5 | -30.03 | ||||||||||||||||||||||||||||||||
| c.3913A>T | T1305S 2D  AIThe SynGAP1 missense variant T1305S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.894658 | Binding | 0.390 | 0.873 | 0.875 | -2.813 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.053 | Likely Benign | 0.20 | Neutral | 0.003 | Benign | 0.026 | Benign | 2.83 | Benign | 0.08 | Tolerated | 0.3683 | 0.4988 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3914C>A | T1305K 2D  AIThe SynGAP1 missense variant T1305K 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 reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also 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 preponderance of evidence points to a benign impact for T1305K, 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 | 0.791621 | Disordered | 0.894658 | Binding | 0.390 | 0.873 | 0.875 | -4.289 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.164 | Likely Benign | -1.33 | Neutral | 0.027 | Benign | 0.042 | Benign | 2.77 | Benign | 0.01 | Affected | 0.1290 | 0.3532 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||||
| c.3914C>G | T1305R 2D  AIThe SynGAP1 missense variant T1305R 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 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 | 0.791621 | Disordered | 0.894658 | Binding | 0.390 | 0.873 | 0.875 | -2.945 | Likely Benign | 0.194 | Likely Benign | Likely Benign | 0.220 | Likely Benign | -1.33 | Neutral | 0.027 | Benign | 0.114 | Benign | 2.75 | Benign | 0.01 | Affected | 0.1115 | 0.3214 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||||||||||||
| 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.3034C>A | P1012T 2D  AIThe SynGAP1 missense variant P1012T is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.894674 | Binding | 0.319 | 0.866 | 0.625 | -4.788 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.052 | Likely Benign | -0.56 | Neutral | 0.369 | Benign | 0.171 | Benign | 2.84 | Benign | 0.14 | Tolerated | 0.1399 | 0.5730 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3034C>G | P1012A 2D  AIThe SynGAP1 missense variant P1012A 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 | 0.834292 | Disordered | 0.894674 | Binding | 0.319 | 0.866 | 0.625 | -4.038 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -0.55 | Neutral | 0.112 | Benign | 0.084 | Benign | 2.81 | Benign | 0.26 | Tolerated | 0.3272 | 0.4900 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3034C>T | P1012S 2D  AIThe SynGAP1 missense variant P1012S is catalogued in gnomAD (ID 6‑33443586‑C‑T) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Overall, the evidence strongly supports a benign classification, and this conclusion is consistent with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.894674 | Binding | 0.319 | 0.866 | 0.625 | 6-33443586-C-T | 2 | 1.24e-6 | -3.342 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.23 | Neutral | 0.224 | Benign | 0.131 | Benign | 2.81 | Benign | 0.22 | Tolerated | 3.77 | 5 | 0.3217 | 0.5300 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3035C>A | P1012H 2D  AIThe SynGAP1 missense variant P1012H is 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for P1012H, 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 | 0.834292 | Disordered | 0.894674 | Binding | 0.319 | 0.866 | 0.625 | -4.877 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.024 | Likely Benign | -0.38 | Neutral | 0.832 | Possibly Damaging | 0.600 | Possibly Damaging | 2.75 | Benign | 0.08 | Tolerated | 0.1553 | 0.4635 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3035C>G | P1012R 2D  AIThe SynGAP1 missense variant P1012R 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 benign prediction: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the consensus of all available predictions strongly supports a benign classification, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.894674 | Binding | 0.319 | 0.866 | 0.625 | -4.413 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.034 | Likely Benign | 1.24 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.89 | Benign | 0.88 | Tolerated | 0.1339 | 0.3083 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3035C>T | P1012L 2D  AIThe SynGAP1 missense variant P1012L 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 the ClinVar status, which contains no pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.894674 | Binding | 0.319 | 0.866 | 0.625 | -4.363 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.014 | Likely Benign | -0.90 | Neutral | 0.224 | Benign | 0.131 | Benign | 2.76 | Benign | 0.12 | Tolerated | 0.2155 | 0.6388 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3880G>A | A1294T 2D  AIThe SynGAP1 missense variant A1294T is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33447928‑G‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs two pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy predictions show AlphaMissense‑Optimized as benign, while SGM Consensus and Foldetta remain unavailable. Overall, five tools predict pathogenicity versus four predicting benign, and the lack of ClinVar evidence does not contradict these findings. Thus, the variant is most likely pathogenic based on the current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.784345 | Disordered | 0.895011 | Binding | 0.565 | 0.806 | 0.625 | 6-33447928-G-A | -3.966 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.290 | Likely Benign | -3.04 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 2.18 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1244 | 0.5479 | 0 | 1 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||
| c.3880G>C | A1294P 2D  AIThe SynGAP1 missense variant A1294P is catalogued in gnomAD (6‑33447928‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a 2‑to‑2 split and is therefore inconclusive; Foldetta results are not available. Overall, the balance of evidence leans toward a pathogenic effect, though the single high‑accuracy benign call and the inconclusive consensus temper certainty. This assessment does not conflict with ClinVar, which currently contains no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.784345 | Disordered | 0.895011 | Binding | 0.565 | 0.806 | 0.625 | 6-33447928-G-C | 1 | 6.45e-7 | -2.688 | Likely Benign | 0.220 | Likely Benign | Likely Benign | 0.367 | Likely Benign | -3.79 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.14 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1682 | 0.3207 | -1 | 1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||
| c.3880G>T | A1294S 2D  AIThe SynGAP1 missense variant A1294S is reported in ClinVar as not yet classified (no ClinVar ID) and is present in gnomAD (variant ID 6-33447928‑G‑T). Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign. No Foldetta stability analysis is available. Overall, the majority of evidence points to a benign effect for A1294S, and this conclusion does not contradict the current ClinVar status, which remains unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.895011 | Binding | 0.565 | 0.806 | 0.625 | 6-33447928-G-T | -3.229 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.276 | Likely Benign | -2.21 | Neutral | 0.997 | Probably Damaging | 0.991 | Probably Damaging | 2.19 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2302 | 0.3990 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.3881C>A | A1294D 2D  AIThe SynGAP1 missense variant A1294D is listed in gnomAD (ID 6‑33447929‑C‑A) but has no ClinVar entry. Functional prediction tools show mixed results: benign calls come from REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessment further clarifies the picture: AlphaMissense‑Optimized predicts a benign effect, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward pathogenicity. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a pathogenic effect, which is consistent with the lack of a benign ClinVar classification and the presence of the variant in a general population database. Thus, the variant is most likely pathogenic, and this prediction does not contradict any ClinVar status because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.784345 | Disordered | 0.895011 | Binding | 0.565 | 0.806 | 0.625 | 6-33447929-C-A | -4.179 | Likely Benign | 0.369 | Ambiguous | Likely Benign | 0.224 | Likely Benign | -4.17 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.14 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1893 | 0.2262 | -2 | 0 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||
| c.3881C>G | A1294G 2D  AIThe SynGAP1 missense variant A1294G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). 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 (AlphaMissense‑Optimized) indicate a benign outcome, while the consensus of other tools is split. Thus, the variant is most likely benign based on current predictions, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.784345 | Disordered | 0.895011 | Binding | 0.565 | 0.806 | 0.625 | -3.242 | Likely Benign | 0.132 | Likely Benign | Likely Benign | 0.201 | Likely Benign | -3.06 | Deleterious | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 2.15 | Pathogenic | 0.00 | Affected | 0.1980 | 0.2695 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3881C>T | A1294V 2D  AIThe SynGAP1 missense variant A1294V is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33447929‑C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it yields a 2‑benign/2‑pathogenic split. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools specifically show AlphaMissense‑Optimized as benign, SGM Consensus as inconclusive, and Foldetta as unavailable. Overall, the predictions are mixed, with one more pathogenic than benign calls. Thus, the variant is most likely pathogenic based on the current computational 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. | 0.784345 | Disordered | 0.895011 | Binding | 0.565 | 0.806 | 0.625 | 6-33447929-C-T | 1 | 6.45e-7 | -3.842 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.164 | Likely Benign | -3.16 | Deleterious | 0.997 | Probably Damaging | 0.983 | Probably Damaging | 2.22 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1033 | 0.4413 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||
| c.3340A>C | S1114R 2D  AIThe SynGAP1 missense variant S1114R is 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, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a likely benign outcome. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence supports a benign classification, 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 | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | -5.718 | Likely Benign | 0.696 | Likely Pathogenic | Likely Benign | 0.037 | Likely Benign | -1.52 | Neutral | 0.157 | Benign | 0.153 | Benign | 2.68 | Benign | 0.03 | Affected | 0.0999 | 0.3649 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3340A>G | S1114G 2D  AIThe SynGAP1 missense variant S1114G is reported in gnomAD (ID 6‑33443892‑A‑G) but has no ClinVar entry. 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. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as none is assigned. 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 | 6-33443892-A-G | -3.894 | Likely Benign | 0.064 | Likely Benign | Likely Benign | 0.080 | Likely Benign | -1.33 | Neutral | 0.000 | Benign | 0.000 | Benign | 2.75 | Benign | 0.08 | Tolerated | 4.32 | 2 | 0.2414 | 0.4914 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||||
| c.3340A>T | S1114C 2D  AIThe SynGAP1 missense variant S1114C is reported in gnomAD (ID 6‑33443892‑A‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict 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 | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | 6-33443892-A-T | -8.600 | Likely Pathogenic | 0.091 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -1.77 | Neutral | 0.938 | Possibly Damaging | 0.552 | Possibly Damaging | 2.63 | Benign | 0.01 | Affected | 4.32 | 2 | 0.1101 | 0.5675 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||
| c.3341G>A | S1114N 2D  AIThe SynGAP1 missense variant S1114N 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. The high‑accuracy consensus, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), also reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports 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 | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | -6.089 | Likely Benign | 0.106 | Likely Benign | Likely Benign | 0.047 | Likely Benign | -0.51 | Neutral | 0.071 | Benign | 0.058 | Benign | 2.71 | Benign | 0.06 | Tolerated | 0.1416 | 0.4610 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| 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.3341G>T | S1114I 2D  AIThe SynGAP1 missense variant S1114I is reported in gnomAD (ID 6‑33443893‑G‑T) but has no ClinVar entry. Functional 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, 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 from both general and high‑accuracy predictors indicates that the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | 6-33443893-G-T | -6.718 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.023 | Likely Benign | -1.86 | Neutral | 0.570 | Possibly Damaging | 0.292 | Benign | 2.65 | Benign | 0.02 | Affected | 4.32 | 2 | 0.1159 | 0.5276 | -2 | -1 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||
| c.3342C>A | S1114R 2D AIThe SynGAP1 missense variant S1114R is not reported in ClinVar and has no entry in gnomAD. Prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. Only two tools predict pathogenicity: SIFT and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of 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 predictions, including the high‑accuracy tools, suggest 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 | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | -5.718 | Likely Benign | 0.696 | Likely Pathogenic | Likely Benign | 0.035 | Likely Benign | -1.52 | Neutral | 0.157 | Benign | 0.153 | Benign | 2.68 | Benign | 0.03 | Affected | 0.0999 | 0.3649 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3342C>G | S1114R 2D AIThe SynGAP1 missense variant S1114R is not reported in ClinVar and has no entry in gnomAD. Prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. Only two tools predict pathogenicity: SIFT and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of 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 predictions, including the high‑accuracy tools, suggest 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 | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | -5.718 | Likely Benign | 0.696 | Likely Pathogenic | Likely Benign | 0.035 | Likely Benign | -1.52 | Neutral | 0.157 | Benign | 0.153 | Benign | 2.68 | Benign | 0.03 | Affected | 0.0999 | 0.3649 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3889A>G | R1297G 2D  AIThe SynGAP1 missense variant R1297G is reported in gnomAD (ID 6‑33451763‑A‑G) but has no ClinVar entry. Functional 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, 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 preponderance of evidence from both general and high‑accuracy predictors indicates that R1297G 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 | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | 6-33451763-A-G | 3 | 1.86e-6 | -2.833 | Likely Benign | 0.168 | Likely Benign | Likely Benign | 0.215 | Likely Benign | -3.65 | Deleterious | 0.224 | Benign | 0.171 | Benign | 2.56 | Benign | 0.01 | Affected | 3.77 | 5 | 0.3089 | 0.2400 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||
| c.3889A>T | R1297W 2D  AIThe SynGAP1 missense variant R1297W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of evaluated predictors (five pathogenic vs. three benign) indicate a pathogenic impact. This conclusion is consistent with the lack of ClinVar reporting; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | -6.039 | Likely Benign | 0.358 | Ambiguous | Likely Benign | 0.262 | Likely Benign | -4.45 | Deleterious | 0.983 | Probably Damaging | 0.868 | Possibly Damaging | 2.44 | Pathogenic | 0.01 | Affected | 0.1260 | 0.2587 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3890G>A | R1297K 2D  AIThe SynGAP1 missense variant R1297K is catalogued in gnomAD (ID 6‑33451764‑G‑A) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as tolerated or benign. Grouping by consensus, all listed predictors fall into the benign category, with no tool reporting a pathogenic outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign classification. Foldetta stability analysis is unavailable for this variant. Consequently, the aggregate evidence strongly supports a benign interpretation, and this assessment does not conflict with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | 6-33451764-G-A | 1 | 6.20e-7 | -3.780 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.074 | Likely Benign | 0.55 | Neutral | 0.000 | Benign | 0.004 | Benign | 2.80 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.4109 | 0.2801 | 2 | 3 | 0.6 | -28.01 | ||||||||||||||||||||||||||||||||||
| c.3890G>C | R1297T 2D  AIThe SynGAP1 missense variant R1297T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Functional prediction tools cluster into two groups: seven tools (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a benign effect, while two tools (PROVEAN, FATHMM) predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | -3.941 | Likely Benign | 0.287 | Likely Benign | Likely Benign | 0.151 | Likely Benign | -2.95 | Deleterious | 0.224 | Benign | 0.171 | Benign | 2.49 | Pathogenic | 0.08 | Tolerated | 0.1634 | 0.2972 | -1 | -1 | 3.8 | -55.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3890G>T | R1297M 2D  AIThe SynGAP1 missense variant R1297M is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | -4.286 | Likely Benign | 0.383 | Ambiguous | Likely Benign | 0.139 | Likely Benign | -3.00 | Deleterious | 0.938 | Possibly Damaging | 0.690 | Possibly Damaging | 2.45 | Pathogenic | 0.02 | Affected | 0.1294 | 0.2449 | 0 | -1 | 6.4 | -24.99 | ||||||||||||||||||||||||||||||||||||||||
| c.3891G>C | R1297S 2D  AIThe SynGAP1 missense variant R1297S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the consensus of available predictions indicates that R1297S is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | -3.468 | Likely Benign | 0.401 | Ambiguous | Likely Benign | 0.139 | Likely Benign | -2.39 | Neutral | 0.224 | Benign | 0.096 | Benign | 2.50 | Benign | 0.07 | Tolerated | 0.2863 | 0.2347 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3891G>T | R1297S 2D AIThe SynGAP1 missense variant R1297S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign classification. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions strongly suggests that R1297S is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | -3.468 | Likely Benign | 0.401 | Ambiguous | Likely Benign | 0.139 | Likely Benign | -2.39 | Neutral | 0.224 | Benign | 0.096 | Benign | 2.50 | Benign | 0.07 | Tolerated | 0.2863 | 0.2347 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3892C>A | Q1298K 2D  AIThe SynGAP1 missense variant Q1298K is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is not contradicted by any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -3.415 | Likely Benign | 0.228 | Likely Benign | Likely Benign | 0.138 | Likely Benign | -0.27 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.86 | Benign | 0.24 | Tolerated | 0.1360 | 0.2903 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3892C>G | Q1298E 2D  AIThe SynGAP1 missense variant Q1298E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is benign, and this conclusion does not contradict any ClinVar annotation (none present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -3.530 | Likely Benign | 0.156 | Likely Benign | Likely Benign | 0.098 | Likely Benign | -1.14 | Neutral | 0.026 | Benign | 0.018 | Benign | 2.83 | Benign | 0.06 | Tolerated | 0.1235 | 0.1330 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3893A>C | Q1298P 2D  AIThe SynGAP1 missense variant Q1298P is not 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, 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 unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -1.819 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.196 | Likely Benign | -2.93 | Deleterious | 0.586 | Possibly Damaging | 0.105 | Benign | 2.76 | Benign | 0.03 | Affected | 0.2237 | 0.4025 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3893A>G | Q1298R 2D  AIThe SynGAP1 missense variant Q1298R is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -2.643 | Likely Benign | 0.174 | Likely Benign | Likely Benign | 0.112 | Likely Benign | 1.38 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.15 | Benign | 1.00 | Tolerated | 0.1142 | 0.1628 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.3893A>T | Q1298L 2D  AIThe SynGAP1 missense variant Q1298L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, PROVEAN and SIFT predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -2.251 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 0.221 | Likely Benign | -3.04 | Deleterious | 0.224 | Benign | 0.078 | Benign | 2.79 | Benign | 0.04 | Affected | 0.0667 | 0.4164 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| 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.2323C>G | R775G 2D AIThe SynGAP1 missense variant R775G is not 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 of 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 R775G, 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 | 0.444081 | Structured | 0.895337 | Binding | 0.320 | 0.896 | 0.250 | -4.186 | Likely Benign | 0.359 | Ambiguous | Likely Benign | 0.118 | Likely Benign | -1.23 | Neutral | 0.933 | Possibly Damaging | 0.871 | Possibly Damaging | 4.12 | Benign | 0.07 | Tolerated | 0.3194 | 0.3761 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2324G>A | R775Q 2D  AIThe SynGAP1 missense variant R775Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33442482‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (derived from the same set of high‑confidence predictors) 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, 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 | 0.444081 | Structured | 0.895337 | Binding | 0.320 | 0.896 | 0.250 | Conflicting | 3 | 6-33442482-G-A | 11 | 1.41e-5 | -4.476 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -0.63 | Neutral | 0.969 | Probably Damaging | 0.863 | Possibly Damaging | 4.17 | Benign | 0.16 | Tolerated | 3.64 | 6 | 0.2844 | 0.2863 | 1 | 1 | 1.0 | -28.06 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.2324G>C | R775P 2D  AIThe SynGAP1 missense variant R775P is listed in ClinVar (ID 2959355) as Benign and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Two tools (polyPhen‑2 HumDiv and HumVar) predict a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus also indicating a likely benign status, and Foldetta’s protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, which is consistent with the ClinVar classification and does not contradict the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.444081 | Structured | 0.895337 | Binding | 0.320 | 0.896 | 0.250 | Benign | 2 | -5.072 | Likely Benign | 0.452 | Ambiguous | Likely Benign | 0.168 | Likely Benign | -0.79 | Neutral | 0.971 | Probably Damaging | 0.944 | Probably Damaging | 4.13 | Benign | 0.07 | Tolerated | 3.64 | 6 | 0.1891 | 0.4834 | -2 | 0 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||
| c.2324G>T | R775L 2D  AIThe SynGAP1 missense variant R775L (ClinVar ID 4327035) is present in gnomAD (ID 6‑33442482‑G‑T). Prediction tools that agree on benign include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those predicting pathogenic are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus also indicates likely benign; Foldetta results are unavailable. Overall, the consensus of computational evidence points to a benign effect, consistent with the ClinVar annotation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.444081 | Structured | 0.895337 | Binding | 0.320 | 0.896 | 0.250 | 1 | 6-33442482-G-T | -5.951 | Likely Benign | 0.598 | Likely Pathogenic | Likely Benign | 0.124 | Likely Benign | -1.86 | Neutral | 0.933 | Possibly Damaging | 0.871 | Possibly Damaging | 4.13 | Benign | 0.06 | Tolerated | 3.64 | 6 | 0.1665 | 0.5089 | -2 | -3 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||
| c.3895C>A | L1299I 2D  AIThe SynGAP1 missense variant L1299I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.896323 | Binding | 0.398 | 0.832 | 0.750 | -5.264 | Likely Benign | 0.116 | Likely Benign | Likely Benign | 0.396 | Likely Benign | 0.71 | Neutral | 0.003 | Benign | 0.004 | Benign | 3.20 | Benign | 1.00 | Tolerated | 0.1014 | 0.3893 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3895C>G | L1299V 2D  AIThe SynGAP1 missense variant L1299V is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification—there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.896323 | Binding | 0.398 | 0.832 | 0.750 | -4.502 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.385 | Likely Benign | -0.02 | Neutral | 0.124 | Benign | 0.025 | Benign | 2.89 | Benign | 0.09 | Tolerated | 0.1726 | 0.3544 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3895C>T | L1299F 2D  AIThe SynGAP1 missense variant L1299F is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.896323 | Binding | 0.398 | 0.832 | 0.750 | -5.618 | Likely Benign | 0.171 | Likely Benign | Likely Benign | 0.138 | Likely Benign | -1.80 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.69 | Benign | 0.42 | Tolerated | 0.0707 | 0.3342 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3896T>A | L1299H 2D  AIThe SynGAP1 missense variant L1299H 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 because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.896323 | Binding | 0.398 | 0.832 | 0.750 | -4.586 | Likely Benign | 0.300 | Likely Benign | Likely Benign | 0.317 | Likely Benign | -3.83 | Deleterious | 0.992 | Probably Damaging | 0.750 | Possibly Damaging | 2.67 | Benign | 0.00 | Affected | 0.1293 | 0.1273 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||||||
| c.3896T>C | L1299P 2D  AIThe SynGAP1 missense variant L1299P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Grouping by consensus, the majority of predictors (five out of nine) favor a benign effect, and the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is likely benign; Foldetta data are unavailable. Consequently, the variant is most likely benign according to the available 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 Benign | 0.771762 | Disordered | 0.896323 | Binding | 0.398 | 0.832 | 0.750 | -2.589 | Likely Benign | 0.222 | Likely Benign | Likely Benign | 0.322 | Likely Benign | -4.06 | Deleterious | 0.971 | Probably Damaging | 0.690 | Possibly Damaging | 2.67 | Benign | 0.01 | Affected | 0.3552 | 0.1309 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3896T>G | L1299R 2D  AIThe SynGAP1 missense variant L1299R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.896323 | Binding | 0.398 | 0.832 | 0.750 | -3.080 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.293 | Likely Benign | -3.75 | Deleterious | 0.971 | Probably Damaging | 0.597 | Possibly Damaging | 2.68 | Benign | 0.01 | Affected | 0.1366 | 0.1147 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3031G>A | G1011R 2D  AIThe SynGAP1 missense variant G1011R is reported in gnomAD (variant ID 6‑33443583‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign, reflecting the majority of benign calls. High‑accuracy assessments further support a benign outcome: 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 effect for G1011R, 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 | 0.834292 | Disordered | 0.898380 | Binding | 0.332 | 0.869 | 0.625 | 6-33443583-G-A | -4.650 | Likely Benign | 0.609 | Likely Pathogenic | Likely Benign | 0.118 | Likely Benign | -0.79 | Neutral | 0.642 | Possibly Damaging | 0.494 | Possibly Damaging | 2.72 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1041 | 0.4415 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||
| c.3031G>C | G1011R 2D AIThe SynGAP1 missense variant G1011R is not reported in ClinVar and is absent from gnomAD, so no population frequency or clinical assertion data are available. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, and FATHMM, while pathogenic predictions arise 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. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to 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. | Likely Benign | 0.834292 | Disordered | 0.898380 | Binding | 0.332 | 0.869 | 0.625 | -4.650 | Likely Benign | 0.609 | Likely Pathogenic | Likely Benign | 0.118 | Likely Benign | -0.79 | Neutral | 0.642 | Possibly Damaging | 0.494 | Possibly Damaging | 2.72 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1041 | 0.4415 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.3032G>A | G1011E 2D  AIThe SynGAP1 missense variant G1011E is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM, while those predicting a pathogenic outcome are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the collective predictions point to a benign effect, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.898380 | Binding | 0.332 | 0.869 | 0.625 | -3.870 | Likely Benign | 0.617 | Likely Pathogenic | Likely Benign | 0.091 | Likely Benign | -1.10 | Neutral | 0.642 | Possibly Damaging | 0.252 | Benign | 2.78 | Benign | 0.01 | Affected | 0.1692 | 0.4521 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| 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.3032G>T | G1011V 2D  AIThe SynGAP1 missense variant G1011V is not 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 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 is present). 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 | -4.883 | Likely Benign | 0.129 | Likely Benign | Likely Benign | 0.133 | Likely Benign | -1.21 | Neutral | 0.473 | Possibly Damaging | 0.192 | Benign | 2.71 | Benign | 0.01 | Affected | 0.1352 | 0.3434 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3175G>A | G1059R 2D AIThe SynGAP1 missense variant G1059R is listed in ClinVar with an uncertain significance and is present in the gnomAD database (ID 6‑33443727‑G‑A). Consensus among most in silico predictors leans toward a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized all report benign. In contrast, SIFT and ESM1b predict pathogenicity, while AlphaMissense‑Default remains uncertain. High‑accuracy assessment consolidates this view: AlphaMissense‑Optimized is benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a benign classification. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its influence is unavailable. Overall, the preponderance of computational evidence 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. | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | Conflicting | 2 | 6-33443727-G-A | 68 | 4.23e-5 | -8.452 | Likely Pathogenic | 0.376 | Ambiguous | Likely Benign | 0.333 | Likely Benign | -0.55 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.53 | Benign | 0.00 | Affected | 4.32 | 2 | 0.1052 | 0.4342 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||
| c.3175G>C | G1059R 2D AIThe SynGAP1 missense variant G1059R is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors shows a predominance of benign calls: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized all predict a benign effect, whereas SIFT and ESM1b predict pathogenicity; AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized is benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also returns a benign prediction. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence points to a benign impact for G1059R, and this conclusion is consistent with the absence of any ClinVar annotation or gnomAD observation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | -8.452 | Likely Pathogenic | 0.376 | Ambiguous | Likely Benign | 0.333 | Likely Benign | -0.55 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.53 | Benign | 0.00 | Affected | 4.32 | 2 | 0.1052 | 0.4342 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3175G>T | G1059W 2D  AIThe SynGAP1 missense variant G1059W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | -11.549 | Likely Pathogenic | 0.312 | Likely Benign | Likely Benign | 0.446 | Likely Benign | -1.18 | Neutral | 0.983 | Probably Damaging | 0.813 | Possibly Damaging | 2.53 | Benign | 0.00 | Affected | 0.0925 | 0.4046 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3176G>A | G1059E 2D AIThe SynGAP1 missense variant G1059E is reported in gnomAD (variant ID 6‑33443728‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only two tools—SIFT and ESM1b—predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | 6-33443728-G-A | 1 | 6.22e-7 | -10.459 | Likely Pathogenic | 0.297 | Likely Benign | Likely Benign | 0.390 | Likely Benign | -0.71 | Neutral | 0.126 | Benign | 0.066 | Benign | 2.53 | Benign | 0.00 | Affected | 4.32 | 2 | 0.1464 | 0.4069 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| c.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.3176G>T | G1059V 2D AIThe SynGAP1 missense variant G1059V is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score benign, while the majority‑vote SGM‑Consensus also classifies it as likely benign. Only SIFT predicts a pathogenic outcome, and ESM1b remains uncertain. High‑accuracy tools corroborate the benign prediction: AlphaMissense‑Optimized is benign and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely benign; Foldetta results are not available. Overall, the preponderance of evidence supports a benign classification for G1059V, and this assessment does not conflict with ClinVar, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | -7.242 | In-Between | 0.106 | Likely Benign | Likely Benign | 0.478 | Likely Benign | -0.82 | Neutral | 0.259 | Benign | 0.066 | Benign | 2.54 | Benign | 0.00 | Affected | 0.1462 | 0.3494 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3970C>A | P1324T 2D AIThe SynGAP1 missense variant P1324T is listed in gnomAD (ID 6‑33451844‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv and SIFT. 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 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 the available predictions points to a benign effect, and this conclusion does not contradict any ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.899181 | Binding | 0.432 | 0.793 | 0.875 | 6-33451844-C-A | -5.289 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.072 | Likely Benign | 0.95 | Neutral | 0.588 | Possibly Damaging | 0.175 | Benign | 4.43 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1863 | 0.4761 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3970C>G | P1324A 2D AIThe SynGAP1 missense variant P1324A 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 | 0.891961 | Disordered | 0.899181 | Binding | 0.432 | 0.793 | 0.875 | -4.416 | Likely Benign | 0.056 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -0.57 | Neutral | 0.011 | Benign | 0.017 | Benign | 4.30 | Benign | 0.00 | Affected | 0.3489 | 0.3776 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3970C>T | P1324S 2D AIThe SynGAP1 missense variant P1324S is listed in ClinVar as Benign (ClinVar ID 1137951.0) and is present in gnomAD (ID 6‑33451844‑C‑T). 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, and PROVEAN). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) also benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, which is consistent with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.899181 | Binding | 0.432 | 0.793 | 0.875 | Likely Benign | 1 | 6-33451844-C-T | 5 | 3.26e-6 | -5.451 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.049 | Likely Benign | 0.35 | Neutral | 0.225 | Benign | 0.092 | Benign | 4.33 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3505 | 0.4450 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||
| c.3971C>A | P1324Q 2D  AIThe SynGAP1 missense variant P1324Q is reported in gnomAD (ID 6‑33451845‑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 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 is likely benign; Foldetta results are unavailable. Overall, the consensus of the majority of tools, including the high‑accuracy predictors, points to a benign effect. This prediction 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 | 0.891961 | Disordered | 0.899181 | Binding | 0.432 | 0.793 | 0.875 | 6-33451845-C-A | -5.577 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.028 | Likely Benign | -0.69 | Neutral | 0.027 | Benign | 0.010 | Benign | 4.27 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1744 | 0.4736 | -1 | 0 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||
| c.3971C>G | P1324R 2D AIThe SynGAP1 missense variant P1324R is not 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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.899181 | Binding | 0.432 | 0.793 | 0.875 | -5.718 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -0.80 | Neutral | 0.414 | Benign | 0.133 | Benign | 4.28 | Benign | 0.00 | Affected | 0.1723 | 0.3613 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3971C>T | P1324L 2D AIThe SynGAP1 missense variant P1324L is reported in gnomAD (ID 6‑33451845‑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. 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 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 | 0.891961 | Disordered | 0.899181 | Binding | 0.432 | 0.793 | 0.875 | 6-33451845-C-T | -5.549 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -1.17 | Neutral | 0.414 | Benign | 0.175 | Benign | 4.26 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2507 | 0.5864 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||
| 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.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.3037T>G | S1013A 2D  AIThe SynGAP1 missense variant S1013A 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, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.899570 | Binding | 0.308 | 0.846 | 0.625 | -3.400 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -0.89 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.71 | Benign | 0.30 | Tolerated | 0.4728 | 0.5131 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3038C>A | S1013Y 2D  AIThe SynGAP1 missense variant S1013Y is not 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. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.899570 | Binding | 0.308 | 0.846 | 0.625 | -4.882 | Likely Benign | 0.338 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -1.78 | Neutral | 0.290 | Benign | 0.124 | Benign | 2.66 | Benign | 0.03 | Affected | 0.0954 | 0.5629 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.3038C>G | S1013C 2D AIThe SynGAP1 missense variant S1013C is listed in ClinVar with an uncertain significance (ClinVar ID 934570.0) and is present in gnomAD (ID 6‑33443590‑C‑G). 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 results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.899570 | Binding | 0.308 | 0.846 | 0.625 | Uncertain | 1 | 6-33443590-C-G | 4 | 2.48e-6 | -6.745 | Likely Benign | 0.110 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -2.06 | Neutral | 0.898 | Possibly Damaging | 0.579 | Possibly Damaging | 2.64 | Benign | 0.05 | Affected | 3.77 | 5 | 0.1345 | 0.5817 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||
| c.3038C>T | S1013F 2D  AIThe SynGAP1 missense variant S1013F is catalogued in gnomAD (ID 6‑33443590‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen2_HumVar, ESM1b, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen2_HumDiv, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign; the SGM Consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive due to mixed signals, and Foldetta results are unavailable. Overall, the balance of evidence, including the benign call from AlphaMissense‑Optimized, points to a likely benign effect. 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. | 0.823549 | Disordered | 0.899570 | Binding | 0.308 | 0.846 | 0.625 | 6-33443590-C-T | 1 | 6.20e-7 | -5.370 | Likely Benign | 0.353 | Ambiguous | Likely Benign | 0.057 | Likely Benign | -2.54 | Deleterious | 0.453 | Possibly Damaging | 0.272 | Benign | 2.65 | Benign | 0.03 | Affected | 3.77 | 5 | 0.0922 | 0.5803 | -2 | -3 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||
| c.3151G>A | G1051S 2D  AIThe SynGAP1 missense variant G1051S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only FATHMM predicts a pathogenic outcome. When the predictions are grouped, the benign consensus includes eight tools, whereas the pathogenic consensus contains a single tool. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign effect, and the SGM‑Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a likely benign outcome. Foldetta data are unavailable, so no stability inference can be drawn. Overall, the computational evidence overwhelmingly supports a benign classification for G1051S, and this conclusion is consistent with the absence of any ClinVar annotation. Thus, the variant is most likely benign, and this assessment does not contradict ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.987317 | Disordered | 0.900141 | Binding | 0.358 | 0.936 | 0.875 | -4.742 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.445 | Likely Benign | 0.10 | Neutral | 0.245 | Benign | 0.096 | Benign | -0.74 | Pathogenic | 0.61 | Tolerated | 0.2446 | 0.4911 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3151G>C | G1051R 2D AIThe SynGAP1 missense variant G1051R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. Two tools (ESM1b and AlphaMissense‑Default) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it contains one pathogenic, one benign, and two uncertain calls, and Foldetta results are unavailable. Overall, the balance of evidence favors a benign classification. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.900141 | Binding | 0.358 | 0.936 | 0.875 | -7.907 | In-Between | 0.346 | Ambiguous | Likely Benign | 0.438 | Likely Benign | 0.20 | Neutral | 0.761 | Possibly Damaging | 0.305 | Benign | -0.74 | Pathogenic | 0.20 | Tolerated | 0.0956 | 0.4342 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3151G>T | G1051C 2D  AIThe SynGAP1 missense variant G1051C is listed in ClinVar as Pathogenic and is not reported in gnomAD. Functional prediction tools show a split assessment: benign calls come from REVEL, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic calls come from polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. High‑accuracy methods give a benign result from AlphaMissense‑Optimized; the SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is tied (2 benign vs. 2 pathogenic) and therefore inconclusive, and Foldetta’s stability prediction is unavailable. Overall, the majority of predictions lean toward a benign effect, which contradicts the ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.900141 | Binding | 0.358 | 0.936 | 0.875 | Likely Pathogenic | 1 | -9.050 | Likely Pathogenic | 0.122 | Likely Benign | Likely Benign | 0.497 | Likely Benign | -0.90 | Neutral | 0.971 | Probably Damaging | 0.750 | Possibly Damaging | -0.74 | Pathogenic | 0.10 | Tolerated | 3.77 | 5 | 0.1322 | 0.4612 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||
| c.3152G>A | G1051D 2D  AISynGAP1 missense variant G1051D is listed in ClinVar as Benign and is present in gnomAD (variant ID 6‑33443704‑G‑A). Prediction tools that classify the variant as benign include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are polyPhen‑2 HumDiv, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign versus two pathogenic votes), and Foldetta stability analysis is unavailable. Overall, the balance of evidence favors a benign effect, consistent with the ClinVar annotation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.900141 | Binding | 0.358 | 0.936 | 0.875 | Benign | 1 | 6-33443704-G-A | 2 | 1.24e-6 | -9.379 | Likely Pathogenic | 0.311 | Likely Benign | Likely Benign | 0.445 | Likely Benign | -0.31 | Neutral | 0.761 | Possibly Damaging | 0.239 | Benign | -0.74 | Pathogenic | 0.39 | Tolerated | 3.77 | 5 | 0.1872 | 0.2235 | -1 | 1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||
| c.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.3152G>T | G1051V 2D AIThe SynGAP1 missense variant G1051V is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443704‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign prediction (2 benign vs. 1 pathogenic, 1 uncertain). Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for G1051V, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.900141 | Binding | 0.358 | 0.936 | 0.875 | 6-33443704-G-T | 1 | 6.20e-7 | -7.098 | In-Between | 0.102 | Likely Benign | Likely Benign | 0.460 | Likely Benign | -0.62 | Neutral | 0.245 | Benign | 0.096 | Benign | -0.74 | Pathogenic | 0.17 | Tolerated | 3.77 | 5 | 0.1274 | 0.3680 | -3 | -1 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||
| c.3979C>A | P1327T 2D AIThe SynGAP1 missense variant P1327T is reported in gnomAD (ID 6‑33451853‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are not available. Taken together, the majority of evidence points to a benign impact. There is no ClinVar classification to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | 6-33451853-C-A | -5.263 | Likely Benign | 0.150 | Likely Benign | Likely Benign | 0.144 | Likely Benign | 1.20 | Neutral | 0.994 | Probably Damaging | 0.908 | Possibly Damaging | 4.51 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.1386 | 0.4779 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3979C>G | P1327A 2D AIThe SynGAP1 missense variant P1327A is reported in gnomAD (ID 6‑33451853‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict the variant to be pathogenic. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a pathogenic ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | 6-33451853-C-G | 2 | 1.28e-6 | -4.661 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -0.37 | Neutral | 0.980 | Probably Damaging | 0.811 | Possibly Damaging | 4.24 | Benign | 0.42 | Tolerated | 3.77 | 5 | 0.3152 | 0.3645 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.3979C>T | P1327S 2D AIThe SynGAP1 missense variant P1327S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33451853‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | Uncertain | 1 | 6-33451853-C-T | -4.744 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.092 | Likely Benign | 0.28 | Neutral | 0.980 | Probably Damaging | 0.857 | Possibly Damaging | 4.25 | Benign | 0.71 | Tolerated | 3.77 | 5 | 0.3098 | 0.4025 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3980C>A | P1327H 2D AIThe SynGAP1 missense variant P1327H is reported in gnomAD (ID 6‑33451854‑C‑A) and 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, SGM‑Consensus is Likely Benign, and Foldetta results are unavailable. 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 annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | 6-33451854-C-A | -5.496 | Likely Benign | 0.263 | Likely Benign | Likely Benign | 0.144 | Likely Benign | -0.49 | Neutral | 0.998 | Probably Damaging | 0.953 | Probably Damaging | 4.09 | Benign | 0.04 | Affected | 3.77 | 5 | 0.1559 | 0.3932 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||
| c.3980C>G | P1327R 2D AIThe SynGAP1 missense variant P1327R is reported in gnomAD (variant ID 6‑33451854‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict the variant to be pathogenic. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a likely benign outcome. No Foldetta stability analysis is available, so it does not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | 6-33451854-C-G | -4.724 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.137 | Likely Benign | -0.95 | Neutral | 0.994 | Probably Damaging | 0.937 | Probably Damaging | 4.12 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.1442 | 0.2798 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||
| c.3980C>T | P1327L 2D AIThe SynGAP1 missense variant P1327L is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33451854‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a benign outcome. Foldetta results are not available for this variant. Overall, the majority of computational evidence supports a benign classification, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | Uncertain | 1 | 6-33451854-C-T | 2 | 1.28e-6 | -5.264 | Likely Benign | 0.242 | Likely Benign | Likely Benign | 0.142 | Likely Benign | -1.24 | Neutral | 0.994 | Probably Damaging | 0.908 | Possibly Damaging | 4.12 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.2123 | 0.5538 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||
| c.3337G>A | G1113S 2D AIThe SynGAP1 missense variant G1113S is not 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 | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | -3.601 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -0.51 | Neutral | 0.905 | Possibly Damaging | 0.538 | Possibly Damaging | 2.58 | Benign | 0.35 | Tolerated | 0.2499 | 0.5309 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3337G>C | G1113R 2D AIThe SynGAP1 missense variant G1113R is not 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, 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 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 exists). Thus, the variant is most likely benign based on current predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | -4.765 | Likely Benign | 0.618 | Likely Pathogenic | Likely Benign | 0.063 | Likely Benign | -1.54 | Neutral | 0.986 | Probably Damaging | 0.848 | Possibly Damaging | 2.65 | Benign | 0.64 | Tolerated | 0.0939 | 0.4426 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3337G>T | G1113C 2D AIThe SynGAP1 missense variant G1113C is not 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, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. 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 | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | -7.917 | In-Between | 0.128 | Likely Benign | Likely Benign | 0.130 | Likely Benign | -1.64 | Neutral | 0.999 | Probably Damaging | 0.917 | Probably Damaging | 2.50 | Benign | 0.06 | Tolerated | 0.1325 | 0.4956 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.3338G>A | G1113D 2D AIThe SynGAP1 missense variant G1113D is listed in ClinVar with an uncertain significance (ClinVar ID 2766136.0) and is present in gnomAD (variant ID 6‑33443890‑G‑A). Functional prediction tools that agree on a benign outcome include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—all of which classify the substitution as benign. AlphaMissense‑Optimized also predicts a benign effect, whereas AlphaMissense‑Default remains uncertain. No tool predicts a pathogenic effect. The high‑accuracy consensus methods reinforce this benign assessment: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” and AlphaMissense‑Optimized also indicates benign. Foldetta, a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the collective evidence strongly supports a benign impact, and this conclusion does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | Uncertain | 1 | 6-33443890-G-A | -4.638 | Likely Benign | 0.354 | Ambiguous | Likely Benign | 0.061 | Likely Benign | -0.72 | Neutral | 0.029 | Benign | 0.017 | Benign | 2.58 | Benign | 0.34 | Tolerated | 4.32 | 2 | 0.1872 | 0.2452 | -1 | 1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||
| 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.3338G>T | G1113V 2D AIThe SynGAP1 missense variant G1113V is not 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 | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | -5.708 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -1.98 | Neutral | 0.827 | Possibly Damaging | 0.456 | Possibly Damaging | 2.53 | Benign | 0.11 | Tolerated | 0.1333 | 0.4224 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.2281C>G | R761G 2D AIThe SynGAP1 missense variant R761G is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors indicates a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all score it as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also classifies it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default tool remains uncertain, and no Foldetta stability assessment is available. High‑accuracy methods reinforce the benign prediction: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign, with no contradictory Foldetta data. Overall, the majority of evidence supports a benign classification, and this is consistent with the lack of ClinVar annotation; there is no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.538167 | Disordered | 0.900613 | Binding | 0.353 | 0.865 | 0.250 | -4.453 | Likely Benign | 0.427 | Ambiguous | Likely Benign | 0.220 | Likely Benign | -2.07 | Neutral | 0.992 | Probably Damaging | 0.900 | Possibly Damaging | 2.70 | Benign | 0.83 | Tolerated | 0.3333 | 0.3217 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2281C>T | R761W 2D AIThe SynGAP1 missense variant R761W is listed in gnomAD (ID 6‑33441746‑C‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains Likely Pathogenic; Foldetta results are unavailable. Overall, the majority of tools (six pathogenic vs. four benign) suggest a pathogenic 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. | Likely Pathogenic | 0.538167 | Disordered | 0.900613 | Binding | 0.353 | 0.865 | 0.250 | 6-33441746-C-T | 1 | 6.20e-7 | -9.248 | Likely Pathogenic | 0.665 | Likely Pathogenic | Likely Benign | 0.193 | Likely Benign | -3.52 | Deleterious | 1.000 | Probably Damaging | 0.987 | Probably Damaging | 2.66 | Benign | 0.06 | Tolerated | 3.99 | 5 | 0.1018 | 0.3668 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.2282G>A | R761Q 2D AIThe SynGAP1 missense variant R761Q is listed in ClinVar (ID 2882770.0) with an “Uncertain” status and is present in gnomAD (6‑33441747‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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 the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.538167 | Disordered | 0.900613 | Binding | 0.353 | 0.865 | 0.250 | Uncertain | 1 | 6-33441747-G-A | 11 | 6.81e-6 | -4.187 | Likely Benign | 0.202 | Likely Benign | Likely Benign | 0.191 | Likely Benign | -0.63 | Neutral | 0.996 | Probably Damaging | 0.878 | Possibly Damaging | 2.75 | Benign | 0.40 | Tolerated | 3.99 | 5 | 0.2640 | 0.2329 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.2282G>C | R761P 2D AIThe SynGAP1 missense variant R761P is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33441747‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions point to a benign impact, 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 | 0.538167 | Disordered | 0.900613 | Binding | 0.353 | 0.865 | 0.250 | Uncertain | 3 | 6-33441747-G-C | 1 | 6.20e-7 | -5.091 | Likely Benign | 0.640 | Likely Pathogenic | Likely Benign | 0.201 | Likely Benign | -1.89 | Neutral | 0.999 | Probably Damaging | 0.968 | Probably Damaging | 2.69 | Benign | 0.38 | Tolerated | 3.99 | 5 | 0.1998 | 0.4449 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||
| c.2282G>T | R761L 2D AIThe SynGAP1 missense variant R761L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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 predictions lean toward a benign impact. This consensus does not contradict any ClinVar annotation, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.538167 | Disordered | 0.900613 | Binding | 0.353 | 0.865 | 0.250 | -5.653 | Likely Benign | 0.718 | Likely Pathogenic | Likely Benign | 0.171 | Likely Benign | -2.51 | Deleterious | 0.992 | Probably Damaging | 0.900 | Possibly Damaging | 2.70 | Benign | 0.24 | Tolerated | 0.1786 | 0.4326 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2821C>A | P941T 2D AIThe SynGAP1 missense variant P941T is listed in gnomAD (ID 6‑33443373‑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, while only SIFT predicts it to be 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 results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.900790 | Binding | 0.403 | 0.906 | 0.625 | 6-33443373-C-A | 2 | 1.24e-6 | -6.193 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.19 | Neutral | 0.144 | Benign | 0.085 | Benign | 2.77 | Benign | 0.05 | Affected | 4.32 | 4 | 0.1612 | 0.5607 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||
| c.2821C>G | P941A 2D AIThe SynGAP1 missense variant P941A is reported in gnomAD (variant ID 6-33443373-C-G) but has no ClinVar entry. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign effect. No tool predicts pathogenicity. The high‑accuracy consensus, SGM‑Consensus, also reports the variant as Likely Benign, and AlphaMissense‑Optimized concurs with a benign prediction. Foldetta, a protein‑folding stability method, did not provide a result for this variant, so its status remains unavailable. Overall, the collective 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 | 0.874069 | Disordered | 0.900790 | Binding | 0.403 | 0.906 | 0.625 | 6-33443373-C-G | 2 | 1.24e-6 | -4.313 | Likely Benign | 0.054 | Likely Benign | Likely Benign | 0.046 | Likely Benign | 0.10 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.80 | Benign | 0.10 | Tolerated | 4.32 | 4 | 0.2844 | 0.5190 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.2821C>T | P941S 2D AIThe SynGAP1 missense variant P941S is reported in gnomAD (ID 6‑33443373‑C‑T) but has no ClinVar entry. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. 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, which evaluates protein‑folding stability via FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of all available predictions indicates that P941S 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 | 0.874069 | Disordered | 0.900790 | Binding | 0.403 | 0.906 | 0.625 | 6-33443373-C-T | 1 | 6.20e-7 | -5.099 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.039 | Likely Benign | 0.58 | Neutral | 0.036 | Benign | 0.039 | Benign | 3.05 | Benign | 0.95 | Tolerated | 4.32 | 4 | 0.2759 | 0.5576 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.2822C>A | P941H 2D AIThe SynGAP1 missense variant P941H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. In contrast, two tools—polyPhen‑2 HumDiv and SIFT—classify the change as pathogenic. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; no Foldetta stability data are available. Overall, the majority of evidence points to a benign effect, and this 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 | 0.874069 | Disordered | 0.900790 | Binding | 0.403 | 0.906 | 0.625 | -4.439 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.09 | Neutral | 0.589 | Possibly Damaging | 0.309 | Benign | 2.71 | Benign | 0.00 | Affected | 0.1621 | 0.4826 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2822C>G | P941R 2D AIThe SynGAP1 missense variant P941R 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 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 for P941R, 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 | 0.874069 | Disordered | 0.900790 | Binding | 0.403 | 0.906 | 0.625 | -5.463 | Likely Benign | 0.181 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -0.34 | Neutral | 0.144 | Benign | 0.062 | Benign | 2.75 | Benign | 0.01 | Affected | 0.1487 | 0.3775 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2822C>T | P941L 2D AIThe SynGAP1 missense variant P941L is listed in ClinVar (ID 3451960.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). The only tool that predicts a pathogenic outcome is SIFT. High‑accuracy assessments further support a benign classification: 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 assessment. Overall, the majority of predictions, including the high‑accuracy tools, point to a benign effect, which is consistent with the ClinVar “Uncertain” designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.900790 | Binding | 0.403 | 0.906 | 0.625 | Uncertain | 2 | -5.692 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.44 | Neutral | 0.144 | Benign | 0.039 | Benign | 2.76 | Benign | 0.01 | Affected | 0.2196 | 0.5931 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||
| c.2851C>A | H951N 2D  AIThe SynGAP1 missense variant H951N 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 | 0.988291 | Disordered | 0.901477 | Binding | 0.415 | 0.925 | 0.750 | -5.833 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -0.41 | Neutral | 0.011 | Benign | 0.018 | Benign | 5.43 | Benign | 0.16 | Tolerated | 0.2590 | 0.3197 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.2851C>G | H951D 2D  AIThe SynGAP1 missense variant H951D 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 assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988291 | Disordered | 0.901477 | Binding | 0.415 | 0.925 | 0.750 | -5.901 | Likely Benign | 0.188 | Likely Benign | Likely Benign | 0.186 | Likely Benign | -0.33 | Neutral | 0.000 | Benign | 0.001 | Benign | 5.43 | Benign | 0.46 | Tolerated | 0.2851 | 0.2475 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2851C>T | H951Y 2D  AIThe SynGAP1 missense variant H951Y 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. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the consensus of high‑accuracy predictors (AlphaMissense‑Optimized and SGM‑Consensus) supports a benign interpretation. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988291 | Disordered | 0.901477 | Binding | 0.415 | 0.925 | 0.750 | -5.165 | Likely Benign | 0.113 | Likely Benign | Likely Benign | 0.142 | Likely Benign | -1.03 | Neutral | 0.000 | Benign | 0.001 | Benign | 5.61 | Benign | 0.10 | Tolerated | 0.2247 | 0.4112 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.2852A>C | H951P 2D  AIThe SynGAP1 missense variant H951P 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 collective evidence strongly supports a benign classification, and this conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988291 | Disordered | 0.901477 | Binding | 0.415 | 0.925 | 0.750 | -2.798 | Likely Benign | 0.051 | Likely Benign | Likely Benign | 0.312 | Likely Benign | -0.06 | Neutral | 0.000 | Benign | 0.001 | Benign | 5.43 | Benign | 0.14 | Tolerated | 0.2745 | 0.3707 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2852A>G | H951R 2D  AIThe SynGAP1 missense variant H951R is listed in ClinVar as Pathogenic (ClinVar ID 1003739.0) and is not reported in 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 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 is benign, and the SGM‑Consensus is likely benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Based on the collective predictions, the variant is most likely benign, which contradicts its ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988291 | Disordered | 0.901477 | Binding | 0.415 | 0.925 | 0.750 | Likely Pathogenic | 1 | -4.964 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.185 | Likely Benign | -1.08 | Neutral | 0.048 | Benign | 0.029 | Benign | 5.46 | Benign | 0.24 | Tolerated | 3.77 | 5 | 0.2808 | 0.3220 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||
| c.2852A>T | H951L 2D  AIThe SynGAP1 missense variant H951L 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 lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988291 | Disordered | 0.901477 | Binding | 0.415 | 0.925 | 0.750 | -4.822 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.192 | Likely Benign | -0.99 | Neutral | 0.022 | Benign | 0.018 | Benign | 5.47 | Benign | 0.43 | Tolerated | 0.2224 | 0.4526 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||||||
| c.2853T>A | H951Q 2D  AIThe SynGAP1 missense variant H951Q 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 | 0.988291 | Disordered | 0.901477 | Binding | 0.415 | 0.925 | 0.750 | -4.755 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.172 | Likely Benign | -0.51 | Neutral | 0.001 | Benign | 0.002 | Benign | 5.43 | Benign | 0.29 | Tolerated | 0.2757 | 0.3328 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2853T>G | H951Q 2D AIThe SynGAP1 missense variant H951Q 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 | 0.988291 | Disordered | 0.901477 | Binding | 0.415 | 0.925 | 0.750 | -4.755 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.171 | Likely Benign | -0.51 | Neutral | 0.001 | Benign | 0.002 | Benign | 5.43 | Benign | 0.29 | Tolerated | 0.2757 | 0.3328 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3916A>C | N1306H 2D  AIThe SynGAP1 missense variant N1306H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is labeled “Likely Benign”). In contrast, tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for this variant, 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 | 0.795062 | Disordered | 0.902190 | Binding | 0.367 | 0.888 | 0.875 | -2.949 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.240 | Likely Benign | -3.42 | Deleterious | 0.961 | Probably Damaging | 0.825 | Possibly Damaging | 2.54 | Benign | 0.00 | Affected | 0.1705 | 0.7846 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3916A>G | N1306D 2D  AIThe SynGAP1 missense variant N1306D is not 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, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign 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 | 0.795062 | Disordered | 0.902190 | Binding | 0.367 | 0.888 | 0.875 | -2.089 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -3.43 | Deleterious | 0.001 | Benign | 0.010 | Benign | 2.58 | Benign | 0.00 | Affected | 0.2018 | 0.4992 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3916A>T | N1306Y 2D  AIThe SynGAP1 missense variant N1306Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) as benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the preponderance 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 | 0.795062 | Disordered | 0.902190 | Binding | 0.367 | 0.888 | 0.875 | -4.193 | Likely Benign | 0.298 | Likely Benign | Likely Benign | 0.273 | Likely Benign | -5.59 | Deleterious | 0.961 | Probably Damaging | 0.825 | Possibly Damaging | 2.54 | Benign | 0.00 | Affected | 0.0732 | 0.6658 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||||||||||||
| c.3917A>C | N1306T 2D  AIThe SynGAP1 missense variant N1306T is reported in gnomAD (ID 6‑33451791‑A‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, while pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.902190 | Binding | 0.367 | 0.888 | 0.875 | 6-33451791-A-C | -1.863 | Likely Benign | 0.156 | Likely Benign | Likely Benign | 0.240 | Likely Benign | -4.17 | Deleterious | 0.697 | Possibly Damaging | 0.399 | Benign | 2.59 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1588 | 0.8327 | 0 | 0 | 2.8 | -13.00 | ||||||||||||||||||||||||||||||||||||
| c.3917A>G | N1306S 2D  AIThe SynGAP1 missense variant N1306S is not 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, SGM‑Consensus as likely benign, while Foldetta results are unavailable. 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 | 0.795062 | Disordered | 0.902190 | Binding | 0.367 | 0.888 | 0.875 | -1.344 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.233 | Likely Benign | -3.49 | Deleterious | 0.319 | Benign | 0.242 | Benign | 2.69 | Benign | 0.00 | Affected | 0.4120 | 0.7826 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||||||||||
| c.3917A>T | N1306I 2D  AIThe SynGAP1 missense variant N1306I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict 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 | 0.795062 | Disordered | 0.902190 | Binding | 0.367 | 0.888 | 0.875 | -3.234 | Likely Benign | 0.296 | Likely Benign | Likely Benign | 0.188 | Likely Benign | -6.15 | Deleterious | 0.890 | Possibly Damaging | 0.761 | Possibly Damaging | 2.56 | Benign | 0.00 | Affected | 0.0837 | 0.6672 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| 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.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.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.2968T>G | S990A 2D AIThe SynGAP1 missense variant S990A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. 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 | -3.554 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.020 | Likely Benign | -0.51 | Neutral | 0.001 | Benign | 0.004 | Benign | 2.91 | Benign | 0.03 | Affected | 0.4537 | 0.4509 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2969C>A | S990Y 2D AIThe SynGAP1 missense variant S990Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, 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, and Foldetta results are unavailable. Taken together, the majority of evidence points to a benign impact. The predictions do not contradict the ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.816150 | Disordered | 0.902387 | Binding | 0.301 | 0.919 | 0.750 | -4.272 | Likely Benign | 0.314 | Likely Benign | Likely Benign | 0.131 | Likely Benign | -2.52 | Deleterious | 0.832 | Possibly Damaging | 0.500 | Possibly Damaging | 2.74 | Benign | 0.00 | Affected | 0.0893 | 0.5832 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2969C>G | S990C 2D AIThe SynGAP1 missense variant S990C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for S990C, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.816150 | Disordered | 0.902387 | Binding | 0.301 | 0.919 | 0.750 | -5.753 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.112 | Likely Benign | -1.91 | Neutral | 0.938 | Possibly Damaging | 0.690 | Possibly Damaging | 2.73 | Benign | 0.01 | Affected | 0.1041 | 0.5823 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2969C>T | S990F 2D AIThe SynGAP1 missense variant S990F is not 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, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; no Foldetta stability result is available. Overall, the majority of evidence points to a benign impact for S990F. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.816150 | Disordered | 0.902387 | Binding | 0.301 | 0.919 | 0.750 | -4.253 | Likely Benign | 0.290 | Likely Benign | Likely Benign | 0.107 | Likely Benign | -2.65 | Deleterious | 0.710 | Possibly Damaging | 0.272 | Benign | 2.75 | Benign | 0.00 | Affected | 0.0814 | 0.6021 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.2320G>A | A774T 2D AIThe SynGAP1 missense variant A774T is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is 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 | 0.450668 | Structured | 0.905168 | Binding | 0.336 | 0.897 | 0.250 | -3.238 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.46 | Neutral | 0.037 | Benign | 0.063 | Benign | 4.20 | Benign | 0.39 | Tolerated | 0.1436 | 0.7578 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2320G>C | A774P 2D AIThe SynGAP1 missense variant A774P is not 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 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 status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.905168 | Binding | 0.336 | 0.897 | 0.250 | -3.869 | Likely Benign | 0.192 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -0.94 | Neutral | 0.801 | Possibly Damaging | 0.481 | Possibly Damaging | 4.15 | Benign | 0.18 | Tolerated | 0.1902 | 0.5749 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2320G>T | A774S 2D AIThe SynGAP1 missense variant A774S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.905168 | Binding | 0.336 | 0.897 | 0.250 | -2.780 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.090 | Likely Benign | -0.09 | Neutral | 0.071 | Benign | 0.115 | Benign | 4.27 | Benign | 0.43 | Tolerated | 0.2711 | 0.6399 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2321C>A | A774D 2D AIThe SynGAP1 missense variant A774D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; the Foldetta protein‑folding stability analysis is unavailable. 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 | 0.450668 | Structured | 0.905168 | Binding | 0.336 | 0.897 | 0.250 | -4.455 | Likely Benign | 0.603 | Likely Pathogenic | Likely Benign | 0.123 | Likely Benign | -0.46 | Neutral | 0.570 | Possibly Damaging | 0.386 | Benign | 4.21 | Benign | 0.06 | Tolerated | 0.1645 | 0.1793 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2321C>G | A774G 2D AIThe SynGAP1 missense variant A774G 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 does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.905168 | Binding | 0.336 | 0.897 | 0.250 | -3.129 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -0.68 | Neutral | 0.135 | Benign | 0.152 | Benign | 4.16 | Benign | 0.22 | Tolerated | 0.2392 | 0.5436 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2321C>T | A774V 2D AIThe SynGAP1 missense variant A774V is catalogued in gnomAD (ID 6‑33442479‑C‑T) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool listed—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently scores the variant as benign. No pathogenic predictions are reported. Grouping by agreement, the benign‑predicting tools comprise the entire set, while the pathogenic group is empty. High‑accuracy assessments further support a benign interpretation: 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, has no available result for this variant. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.905168 | Binding | 0.336 | 0.897 | 0.250 | 6-33442479-C-T | 1 | 1.28e-6 | -3.075 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.73 | Neutral | 0.000 | Benign | 0.003 | Benign | 4.20 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1070 | 0.6659 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||
| c.3148G>A | G1050R 2D AIThe SynGAP1 missense variant G1050R is catalogued in gnomAD (ID 6‑33443700‑G‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Only FATHMM predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. 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) also yields a benign verdict, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.906802 | Binding | 0.370 | 0.928 | 0.875 | 6-33443700-G-A | 3 | 1.86e-6 | -6.637 | Likely Benign | 0.349 | Ambiguous | Likely Benign | 0.045 | Likely Benign | -0.68 | Neutral | 0.009 | Benign | 0.008 | Benign | 2.48 | Pathogenic | 0.06 | Tolerated | 3.77 | 5 | 0.0939 | 0.4532 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.3148G>C | G1050R 2D AIThe SynGAP1 missense variant G1050R is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. Only FATHMM predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority vote. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact; this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.906802 | Binding | 0.370 | 0.928 | 0.875 | -6.637 | Likely Benign | 0.349 | Ambiguous | Likely Benign | 0.045 | Likely Benign | -0.68 | Neutral | 0.009 | Benign | 0.008 | Benign | 2.48 | Pathogenic | 0.06 | Tolerated | 3.77 | 5 | 0.0939 | 0.4532 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3149G>A | G1050E 2D AIThe SynGAP1 missense variant G1050E is not 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only ESM1b 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. There is no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.987317 | Disordered | 0.906802 | Binding | 0.370 | 0.928 | 0.875 | -8.175 | Likely Pathogenic | 0.266 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -0.28 | Neutral | 0.411 | Benign | 0.171 | Benign | 2.50 | Benign | 0.08 | Tolerated | 0.1418 | 0.4258 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| 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.3149G>T | G1050V 2D AIThe SynGAP1 missense variant G1050V is not 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, 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 as Likely Benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently contains no classification for G1050V. 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 | -6.450 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -0.83 | Neutral | 0.126 | Benign | 0.096 | Benign | 2.49 | Pathogenic | 0.13 | Tolerated | 0.1260 | 0.3684 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3967C>A | P1323T 2D AIThe SynGAP1 missense variant P1323T is reported in gnomAD (ID 6‑33451841‑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, and AlphaMissense‑Optimized all classify the change as tolerated or benign. Only two algorithms—polyPhen‑2 HumDiv and SIFT—suggest a damaging impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not conflict with any ClinVar classification, as none is present. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.901269 | Disordered | 0.907659 | Binding | 0.489 | 0.814 | 0.875 | 6-33451841-C-A | -6.296 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.064 | Likely Benign | -0.37 | Neutral | 0.588 | Possibly Damaging | 0.227 | Benign | 3.95 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1988 | 0.5161 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3967C>G | P1323A 2D AIThe SynGAP1 missense variant P1323A is catalogued in gnomAD (ID 6‑33451841‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated outcomes, while the single pathogenic signal comes from SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign classification. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is likely benign; Foldetta results are not available. Overall, the consensus of available predictions points to a benign impact for P1323A, 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 Benign | 0.901269 | Disordered | 0.907659 | Binding | 0.489 | 0.814 | 0.875 | 6-33451841-C-G | -4.802 | Likely Benign | 0.053 | Likely Benign | Likely Benign | 0.040 | Likely Benign | -0.73 | Neutral | 0.011 | Benign | 0.017 | Benign | 3.92 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3743 | 0.3976 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||
| c.3967C>T | P1323S 2D AIThe SynGAP1 missense variant P1323S is not reported in ClinVar and is absent from gnomAD. 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 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). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.901269 | Disordered | 0.907659 | Binding | 0.489 | 0.814 | 0.875 | -6.007 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -0.52 | Neutral | 0.588 | Possibly Damaging | 0.122 | Benign | 3.88 | Benign | 0.00 | Affected | 0.3758 | 0.4371 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3968C>A | P1323Q 2D AIThe SynGAP1 missense variant P1323Q is reported in gnomAD (ID 6‑33451842‑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, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 HumDiv and SIFT predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that P1323Q 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 | 0.901269 | Disordered | 0.907659 | Binding | 0.489 | 0.814 | 0.875 | 6-33451842-C-A | -6.134 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.033 | Likely Benign | -0.85 | Neutral | 0.712 | Possibly Damaging | 0.328 | Benign | 3.82 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1791 | 0.4657 | -1 | 0 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||
| c.3968C>G | P1323R 2D AIThe SynGAP1 missense variant P1323R 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 P1323R 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 | 0.901269 | Disordered | 0.907659 | Binding | 0.489 | 0.814 | 0.875 | -5.785 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -0.67 | Neutral | 0.002 | Benign | 0.003 | Benign | 3.82 | Benign | 0.00 | Affected | 0.1725 | 0.3015 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3968C>T | P1323L 2D AIThe SynGAP1 missense variant P1323L is reported in gnomAD (variant ID 6‑33451842‑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. 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 (majority‑vote) is 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 | 0.901269 | Disordered | 0.907659 | Binding | 0.489 | 0.814 | 0.875 | 6-33451842-C-T | 3 | 1.95e-6 | -6.005 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -1.04 | Neutral | 0.414 | Benign | 0.175 | Benign | 3.82 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2650 | 0.6052 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| 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.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.2965T>G | S989A 2D AIThe SynGAP1 missense variant S989A is not reported in ClinVar and is absent from gnomAD. 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 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 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 | 0.795062 | Disordered | 0.908835 | Binding | 0.296 | 0.911 | 0.750 | -3.495 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -1.15 | Neutral | 0.580 | Possibly Damaging | 0.253 | Benign | 2.68 | Benign | 0.00 | Affected | 0.4580 | 0.4221 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2966C>A | S989Y 2D AIThe SynGAP1 missense variant S989Y is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy predictions therefore indicate a benign outcome: AlphaMissense‑Optimized is benign, the SGM Consensus is benign, and Foldetta data are unavailable. Consequently, the variant is most likely benign 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. | 0.795062 | Disordered | 0.908835 | Binding | 0.296 | 0.911 | 0.750 | -4.774 | Likely Benign | 0.471 | Ambiguous | Likely Benign | 0.103 | Likely Benign | -3.32 | Deleterious | 0.986 | Probably Damaging | 0.876 | Possibly Damaging | 2.60 | Benign | 0.00 | Affected | 0.0611 | 0.4815 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||||||
| c.2966C>G | S989C 2D AIThe SynGAP1 missense variant S989C 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 a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, while 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 | 0.795062 | Disordered | 0.908835 | Binding | 0.296 | 0.911 | 0.750 | -5.889 | Likely Benign | 0.160 | Likely Benign | Likely Benign | 0.080 | Likely Benign | -2.88 | Deleterious | 0.996 | Probably Damaging | 0.905 | Possibly Damaging | 2.59 | Benign | 0.00 | Affected | 0.0828 | 0.5202 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2966C>T | S989F 2D AIThe SynGAP1 missense variant S989F is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, and Foldetta results are unavailable. Overall, the majority of reliable predictors and the consensus high‑accuracy tools indicate a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.795062 | Disordered | 0.908835 | Binding | 0.296 | 0.911 | 0.750 | -4.115 | Likely Benign | 0.435 | Ambiguous | Likely Benign | 0.109 | Likely Benign | -3.35 | Deleterious | 0.986 | Probably Damaging | 0.876 | Possibly Damaging | 2.60 | Benign | 0.00 | Affected | 0.0598 | 0.5103 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||||
| c.3334G>A | E1112K 2D  AIThe SynGAP1 missense variant E1112K is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign. Only two tools predict pathogenicity: SIFT and AlphaMissense‑Default. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the conclusion. Overall, the majority of predictions, including the high‑accuracy tools, suggest the variant is most likely benign, and this is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.909381 | Binding | 0.335 | 0.902 | 0.875 | -3.772 | Likely Benign | 0.684 | Likely Pathogenic | Likely Benign | 0.210 | Likely Benign | 0.15 | Neutral | 0.245 | Benign | 0.096 | Benign | 2.82 | Benign | 0.02 | Affected | 0.3002 | 0.7704 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3334G>C | E1112Q 2D  AIThe SynGAP1 missense variant E1112Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign classification: 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 in silico predictors and high‑accuracy tools points to a benign impact for E1112Q, 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 | 0.894241 | Disordered | 0.909381 | Binding | 0.335 | 0.902 | 0.875 | -1.975 | Likely Benign | 0.364 | Ambiguous | Likely Benign | 0.102 | Likely Benign | -0.48 | Neutral | 0.611 | Possibly Damaging | 0.305 | Benign | 2.71 | Benign | 0.42 | Tolerated | 0.2031 | 0.7430 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3335A>C | E1112A 2D  AIThe SynGAP1 missense variant E1112A is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.909381 | Binding | 0.335 | 0.902 | 0.875 | -3.227 | Likely Benign | 0.373 | Ambiguous | Likely Benign | 0.096 | Likely Benign | -1.86 | Neutral | 0.393 | Benign | 0.131 | Benign | 2.71 | Benign | 0.02 | Affected | 0.3929 | 0.7528 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3335A>G | E1112G 2D  AIThe SynGAP1 missense variant E1112G is reported in gnomAD (ID 6‑33443887‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN and SIFT. 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 independently predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the preponderance of evidence from both general and high‑accuracy tools indicates 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 | 0.894241 | Disordered | 0.909381 | Binding | 0.335 | 0.902 | 0.875 | 6-33443887-A-G | 1 | 6.73e-7 | -3.459 | Likely Benign | 0.277 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -2.58 | Deleterious | 0.058 | Benign | 0.015 | Benign | 2.70 | Benign | 0.01 | Affected | 4.32 | 2 | 0.2795 | 0.6220 | -2 | 0 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||
| c.3335A>T | E1112V 2D AIThe SynGAP1 missense variant E1112V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) also as benign; Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact for E1112V, 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 | 0.894241 | Disordered | 0.909381 | Binding | 0.335 | 0.902 | 0.875 | -3.971 | Likely Benign | 0.579 | Likely Pathogenic | Likely Benign | 0.139 | Likely Benign | -2.28 | Neutral | 0.440 | Benign | 0.140 | Benign | 2.70 | Benign | 0.00 | Affected | 0.1481 | 0.7567 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.3336G>C | E1112D 2D AIThe SynGAP1 missense variant E1112D is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the variant is most likely benign based on the 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 | 0.909381 | Binding | 0.335 | 0.902 | 0.875 | -4.286 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -1.24 | Neutral | 0.005 | Benign | 0.005 | Benign | 2.69 | Benign | 0.06 | Tolerated | 4.32 | 2 | 0.2343 | 0.5553 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||
| c.3336G>T | E1112D 2D AIThe SynGAP1 missense variant E1112D is catalogued in gnomAD (variant ID 6-33443888‑G‑T) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool examined—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classifies the substitution as benign. No pathogenic predictions are reported. Grouping by consensus, all listed tools fall into the benign category, with no tools indicating pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “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 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 | 0.894241 | Disordered | 0.909381 | Binding | 0.335 | 0.902 | 0.875 | 6-33443888-G-T | -4.286 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -1.24 | Neutral | 0.005 | Benign | 0.005 | Benign | 2.69 | Benign | 0.06 | Tolerated | 4.32 | 2 | 0.2343 | 0.5553 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.2284G>A | D762N 2D  AIThe SynGAP1 D762N missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, 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, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign impact for D762N, and this conclusion does not contradict any ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.405110 | Structured | 0.910475 | Binding | 0.308 | 0.859 | 0.125 | -3.323 | Likely Benign | 0.640 | Likely Pathogenic | Likely Benign | 0.110 | Likely Benign | -1.51 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.13 | Pathogenic | 0.11 | Tolerated | 0.1698 | 0.8797 | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||||
| c.2284G>C | D762H 2D  AIThe SynGAP1 D762H missense variant is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the preponderance of evidence points to a pathogenic impact, 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 | 0.405110 | Structured | 0.910475 | Binding | 0.308 | 0.859 | 0.125 | -4.643 | Likely Benign | 0.909 | Likely Pathogenic | Ambiguous | 0.212 | Likely Benign | -2.73 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 2.08 | Pathogenic | 0.02 | Affected | 0.2007 | 0.9102 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2284G>T | D762Y 2D  AIThe SynGAP1 D762Y variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas a larger group predicts a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic”; Foldetta (a protein‑folding stability approach combining FoldX‑MD and Rosetta) has no available output for this variant. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.405110 | Structured | 0.910475 | Binding | 0.308 | 0.859 | 0.125 | -6.959 | Likely Benign | 0.905 | Likely Pathogenic | Ambiguous | 0.219 | Likely Benign | -3.24 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 2.07 | Pathogenic | 0.01 | Affected | 0.0700 | 0.7929 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| c.2285A>C | D762A 2D  AIThe SynGAP1 D762A missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool yields an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (five pathogenic vs. three benign) lean toward a pathogenic impact. This assessment does not contradict any ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.405110 | Structured | 0.910475 | Binding | 0.308 | 0.859 | 0.125 | -4.510 | Likely Benign | 0.912 | Likely Pathogenic | Ambiguous | 0.178 | Likely Benign | -2.40 | Neutral | 0.994 | Probably Damaging | 0.900 | Possibly Damaging | 2.12 | Pathogenic | 0.05 | Affected | 0.4632 | 0.8428 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.2285A>G | D762G 2D  AIThe SynGAP1 missense variant D762G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, SIFT, and ESM1b, whereas those that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Based on the majority of predictions and the SGM‑Consensus outcome, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.405110 | Structured | 0.910475 | Binding | 0.308 | 0.859 | 0.125 | -1.062 | Likely Benign | 0.812 | Likely Pathogenic | Ambiguous | 0.170 | Likely Benign | -2.55 | Deleterious | 0.998 | Probably Damaging | 0.949 | Probably Damaging | 2.10 | Pathogenic | 0.08 | Tolerated | 0.4710 | 0.7841 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2285A>T | D762V 2D  AIThe SynGAP1 D762V missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b. Tools that agree on a pathogenic effect include polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returned an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of consensus tools predict a pathogenic impact, and there is no ClinVar entry to contradict this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.405110 | Structured | 0.910475 | Binding | 0.308 | 0.859 | 0.125 | -6.122 | Likely Benign | 0.949 | Likely Pathogenic | Ambiguous | 0.229 | Likely Benign | -1.98 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.08 | Pathogenic | 0.01 | Affected | 0.1105 | 0.8785 | -2 | -3 | 7.7 | -15.96 | ||||||||||||||||||||||||||||||||||||||||
| c.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.2854G>A | G952S 2D AIThe SynGAP1 missense variant G952S is listed in ClinVar (ID 1325573.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33443406‑G‑A). All evaluated in‑silico predictors agree on a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. 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, 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 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 | 0.985964 | Disordered | 0.910621 | Binding | 0.341 | 0.926 | 0.750 | Conflicting | 2 | 6-33443406-G-A | 2 | 1.24e-6 | -6.190 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.167 | Likely Benign | 0.19 | Neutral | 0.000 | Benign | 0.002 | Benign | 3.31 | Benign | 0.07 | Tolerated | 3.77 | 5 | 0.2509 | 0.5502 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||
| c.2854G>C | G952R 2D AIThe SynGAP1 missense variant G952R 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, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that G952R 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 | 0.985964 | Disordered | 0.910621 | Binding | 0.341 | 0.926 | 0.750 | -5.974 | Likely Benign | 0.295 | Likely Benign | Likely Benign | 0.139 | Likely Benign | -0.93 | Neutral | 0.077 | Benign | 0.011 | Benign | 3.20 | Benign | 0.02 | Affected | 0.1145 | 0.4933 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2854G>T | G952C 2D AIThe SynGAP1 missense variant G952C is not 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.910621 | Binding | 0.341 | 0.926 | 0.750 | -8.599 | Likely Pathogenic | 0.088 | Likely Benign | Likely Benign | 0.272 | Likely Benign | -0.18 | Neutral | 0.371 | Benign | 0.169 | Benign | 3.20 | Benign | 0.01 | Affected | 0.1458 | 0.4439 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.2855G>A | G952D 2D AIThe SynGAP1 missense variant G952D 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 SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Benign. Only SIFT predicts a pathogenic outcome, and ESM1b remains uncertain. High‑accuracy assessments corroborate the benign trend: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. 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 | 0.985964 | Disordered | 0.910621 | Binding | 0.341 | 0.926 | 0.750 | -7.299 | In-Between | 0.274 | Likely Benign | Likely Benign | 0.241 | Likely Benign | -0.75 | Neutral | 0.033 | Benign | 0.015 | Benign | 3.20 | Benign | 0.05 | Affected | 0.1928 | 0.2826 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| 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.2855G>T | G952V 2D AIThe SynGAP1 missense variant G952V is listed in ClinVar (ID 2055482.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while ESM1b remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that G952V is most likely benign, 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 | 0.985964 | Disordered | 0.910621 | Binding | 0.341 | 0.926 | 0.750 | Uncertain | 1 | -7.074 | In-Between | 0.078 | Likely Benign | Likely Benign | 0.231 | Likely Benign | -0.33 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.20 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1538 | 0.3507 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||
| c.2755C>A | Q919K 2D AIThe SynGAP1 missense variant Q919K is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign. Only polyPhen‑2 HumDiv flags it as pathogenic, while AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, 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. Taken together, the majority of evidence supports a benign interpretation, 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 | 0.911223 | Binding | 0.299 | 0.841 | 0.250 | -4.357 | Likely Benign | 0.347 | Ambiguous | Likely Benign | 0.125 | Likely Benign | -1.43 | Neutral | 0.771 | Possibly Damaging | 0.412 | Benign | 2.54 | Benign | 0.21 | Tolerated | 0.1950 | 0.4000 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2755C>G | Q919E 2D AIThe SynGAP1 missense variant Q919E is not 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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 high‑confidence predictions and the consensus score favor a benign impact. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.911223 | Binding | 0.299 | 0.841 | 0.250 | -3.352 | Likely Benign | 0.157 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -1.13 | Neutral | 0.771 | Possibly Damaging | 0.492 | Possibly Damaging | 2.44 | Pathogenic | 0.05 | Affected | 0.1366 | 0.2692 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2756A>C | Q919P 2D AIThe SynGAP1 missense variant Q919P is 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 from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. 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 exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.911223 | Binding | 0.299 | 0.841 | 0.250 | -2.358 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -1.15 | Neutral | 0.989 | Probably Damaging | 0.834 | Possibly Damaging | 2.38 | Pathogenic | 0.03 | Affected | 0.2364 | 0.6108 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2756A>G | Q919R 2D AIThe SynGAP1 missense variant Q919R is not 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, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). 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 (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority 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 | 0.618285 | Disordered | 0.911223 | Binding | 0.299 | 0.841 | 0.250 | -3.636 | Likely Benign | 0.272 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -0.96 | Neutral | 0.961 | Probably Damaging | 0.596 | Possibly Damaging | 2.65 | Benign | 0.85 | Tolerated | 0.1558 | 0.2305 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.2756A>T | Q919L 2D AIThe SynGAP1 missense variant Q919L is reported in gnomAD (ID 6‑33443308‑A‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates 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 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 | 0.618285 | Disordered | 0.911223 | Binding | 0.299 | 0.841 | 0.250 | 6-33443308-A-T | 1 | 6.20e-7 | -4.492 | Likely Benign | 0.252 | Likely Benign | Likely Benign | 0.175 | Likely Benign | -2.13 | Neutral | 0.891 | Possibly Damaging | 0.596 | Possibly Damaging | 2.40 | Pathogenic | 0.04 | Affected | 4.32 | 4 | 0.0771 | 0.6454 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||||||
| c.2757G>C | Q919H 2D AIThe SynGAP1 missense variant Q919H 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, 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 from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.911223 | Binding | 0.299 | 0.841 | 0.250 | -3.867 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.153 | Likely Benign | -1.83 | Neutral | 0.989 | Probably Damaging | 0.883 | Possibly Damaging | 2.39 | Pathogenic | 0.03 | Affected | 0.1463 | 0.4203 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2757G>T | Q919H 2D AIThe SynGAP1 missense variant Q919H 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, 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 from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.911223 | Binding | 0.299 | 0.841 | 0.250 | -3.867 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -1.83 | Neutral | 0.989 | Probably Damaging | 0.883 | Possibly Damaging | 2.39 | Pathogenic | 0.03 | Affected | 0.1463 | 0.4203 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2971G>A | G991R 2D AIThe SynGAP1 missense variant G991R is listed in ClinVar (ID 1029090.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443523‑G‑A). 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, 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 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 | 0.745909 | Disordered | 0.911393 | Binding | 0.286 | 0.920 | 0.750 | Conflicting | 3 | 6-33443523-G-A | 8 | 4.96e-6 | -3.934 | Likely Benign | 0.411 | Ambiguous | Likely Benign | 0.102 | Likely Benign | -1.20 | Neutral | 0.984 | Probably Damaging | 0.772 | Possibly Damaging | 4.11 | Benign | 0.01 | Affected | 4.32 | 2 | 0.0956 | 0.4181 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||
| c.2971G>C | G991R 2D AIThe SynGAP1 missense variant G991R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic 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. Foldetta results are unavailable, so they do not influence the assessment. Overall, the majority of evidence points to a benign effect for G991R, 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 | 0.745909 | Disordered | 0.911393 | Binding | 0.286 | 0.920 | 0.750 | -3.934 | Likely Benign | 0.411 | Ambiguous | Likely Benign | 0.106 | Likely Benign | -1.20 | Neutral | 0.984 | Probably Damaging | 0.772 | Possibly Damaging | 4.11 | Benign | 0.01 | Affected | 4.32 | 2 | 0.0956 | 0.4181 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.2971G>T | G991W 2D AIThe SynGAP1 missense variant G991W 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. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.745909 | Disordered | 0.911393 | Binding | 0.286 | 0.920 | 0.750 | -6.281 | Likely Benign | 0.336 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -2.32 | Neutral | 0.997 | Probably Damaging | 0.975 | Probably Damaging | 4.07 | Benign | 0.00 | Affected | 0.0745 | 0.3654 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.2972G>A | G991E 2D AIThe SynGAP1 missense variant G991E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic outcome. 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 independently 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—including the high‑accuracy tools—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 | 0.745909 | Disordered | 0.911393 | Binding | 0.286 | 0.920 | 0.750 | -4.729 | Likely Benign | 0.341 | Ambiguous | Likely Benign | 0.065 | Likely Benign | -1.30 | Neutral | 0.846 | Possibly Damaging | 0.697 | Possibly Damaging | 4.13 | Benign | 0.01 | Affected | 0.1480 | 0.4277 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| 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.2972G>T | G991V 2D AIThe SynGAP1 missense variant G991V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.745909 | Disordered | 0.911393 | Binding | 0.286 | 0.920 | 0.750 | -4.129 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.064 | Likely Benign | -1.61 | Neutral | 0.440 | Benign | 0.253 | Benign | 4.16 | Benign | 0.01 | Affected | 0.1148 | 0.3961 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3982C>G | R1328G 2D AIThe SynGAP1 missense variant R1328G is not reported in ClinVar and is absent from gnomAD. Functional 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 annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.911775 | Binding | 0.360 | 0.762 | 0.875 | -3.470 | Likely Benign | 0.513 | Ambiguous | Likely Benign | 0.076 | Likely Benign | -2.19 | Neutral | 0.784 | Possibly Damaging | 0.145 | Benign | 4.07 | Benign | 0.01 | Affected | 0.3736 | 0.2562 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3982C>T | R1328W 2D AIThe SynGAP1 missense variant R1328W is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33451856‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default predict a pathogenic outcome. ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign, while Foldetta results are unavailable. Taken together, the majority of high‑confidence predictions favor 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. | 0.887230 | Disordered | 0.911775 | Binding | 0.360 | 0.762 | 0.875 | 6-33451856-C-T | 4 | 2.56e-6 | -7.022 | In-Between | 0.779 | Likely Pathogenic | Likely Benign | 0.125 | Likely Benign | -2.40 | Neutral | 0.997 | Probably Damaging | 0.756 | Possibly Damaging | 4.04 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1349 | 0.2906 | -3 | 2 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.3983G>A | R1328Q 2D AIThe SynGAP1 missense variant R1328Q is listed in ClinVar (ID 1805359.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451857‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this is not in conflict with the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.911775 | Binding | 0.360 | 0.762 | 0.875 | Uncertain | 3 | 6-33451857-G-A | 35 | 1.49e-4 | -2.921 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -1.02 | Neutral | 0.799 | Possibly Damaging | 0.098 | Benign | 4.12 | Benign | 0.03 | Affected | 3.77 | 5 | 0.3503 | 0.1775 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.3983G>C | R1328P 2D AIThe SynGAP1 missense variant R1328P (ClinVar ID 1258976.0) is classified as Benign in ClinVar and is observed in gnomAD (6‑33451857‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta results are unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also indicates a likely benign outcome; no Foldetta stability data are reported. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar designation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.911775 | Binding | 0.360 | 0.762 | 0.875 | Benign | 1 | 6-33451857-G-C | -1.220 | Likely Benign | 0.466 | Ambiguous | Likely Benign | 0.060 | Likely Benign | -2.01 | Neutral | 0.927 | Possibly Damaging | 0.452 | Possibly Damaging | 4.06 | Benign | 0.01 | Affected | 3.77 | 5 | 0.2205 | 0.3361 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||
| c.3983G>T | R1328L 2D AIThe SynGAP1 missense variant R1328L is listed in gnomAD (ID 6‑33451857‑G‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.911775 | Binding | 0.360 | 0.762 | 0.875 | 6-33451857-G-T | -3.233 | Likely Benign | 0.452 | Ambiguous | Likely Benign | 0.038 | Likely Benign | -1.94 | Neutral | 0.784 | Possibly Damaging | 0.145 | Benign | 4.08 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1978 | 0.3555 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||||
| c.3028T>A | F1010I 2D  AIThe SynGAP1 missense variant F1010I is not 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 unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.741537 | Disordered | 0.912572 | Binding | 0.286 | 0.881 | 0.625 | -3.726 | Likely Benign | 0.664 | Likely Pathogenic | Likely Benign | 0.126 | Likely Benign | -1.74 | Neutral | 0.980 | Probably Damaging | 0.783 | Possibly Damaging | 2.57 | Benign | 0.05 | Affected | 0.2405 | 0.2464 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3028T>C | F1010L 2D  AIThe SynGAP1 missense variant F1010L is not 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 is currently 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, 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 | 0.741537 | Disordered | 0.912572 | Binding | 0.286 | 0.881 | 0.625 | -1.982 | Likely Benign | 0.949 | Likely Pathogenic | Ambiguous | 0.099 | Likely Benign | -1.51 | Neutral | 0.910 | Possibly Damaging | 0.468 | Possibly Damaging | 2.75 | Benign | 0.62 | Tolerated | 0.2538 | 0.3245 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3028T>G | F1010V 2D  AIThe SynGAP1 missense variant F1010V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. 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 the 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 (majority vote) also indicates benign. Foldetta results are unavailable. Overall, the balance of evidence from multiple independent predictors and the consensus analysis points to a benign classification for F1010V, with no conflict with ClinVar status (which has no entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.741537 | Disordered | 0.912572 | Binding | 0.286 | 0.881 | 0.625 | -2.482 | Likely Benign | 0.582 | Likely Pathogenic | Likely Benign | 0.113 | Likely Benign | -2.10 | Neutral | 0.961 | Probably Damaging | 0.721 | Possibly Damaging | 2.58 | Benign | 0.03 | Affected | 0.2351 | 0.2403 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||||||||||||
| c.3029T>A | F1010Y 2D  AIThe SynGAP1 missense variant F1010Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this 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 | 0.912572 | Binding | 0.286 | 0.881 | 0.625 | -3.297 | Likely Benign | 0.138 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -0.96 | Neutral | 0.031 | Benign | 0.064 | Benign | 2.64 | Benign | 0.05 | Affected | 0.1651 | 0.2514 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3029T>C | F1010S 2D  AIThe SynGAP1 missense variant F1010S is listed in gnomAD (ID 6‑33443581‑T‑C) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as benign; Foldetta results are unavailable. Overall, the balance of evidence, including the high‑accuracy benign predictions and the consensus benign call, indicates that the variant is most likely benign. 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 | 0.741537 | Disordered | 0.912572 | Binding | 0.286 | 0.881 | 0.625 | 6-33443581-T-C | -1.722 | Likely Benign | 0.744 | Likely Pathogenic | Likely Benign | 0.153 | Likely Benign | -1.97 | Neutral | 0.994 | Probably Damaging | 0.892 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 3.77 | 5 | 0.4196 | 0.0775 | -2 | -3 | -3.6 | -60.10 | ||||||||||||||||||||||||||||||||||||
| c.3029T>G | F1010C 2D  AIThe SynGAP1 missense variant F1010C is not 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. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessment shows AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—remains inconclusive, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a pathogenic interpretation, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.741537 | Disordered | 0.912572 | Binding | 0.286 | 0.881 | 0.625 | -4.442 | Likely Benign | 0.755 | Likely Pathogenic | Likely Benign | 0.153 | Likely Benign | -2.31 | Neutral | 1.000 | Probably Damaging | 0.961 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 0.2646 | 0.1605 | -4 | -2 | -0.3 | -44.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3030T>A | F1010L 2D AIThe SynGAP1 missense variant F1010L is not 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 is currently 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, 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 | 0.741537 | Disordered | 0.912572 | Binding | 0.286 | 0.881 | 0.625 | -1.982 | Likely Benign | 0.949 | Likely Pathogenic | Ambiguous | 0.142 | Likely Benign | -1.51 | Neutral | 0.910 | Possibly Damaging | 0.468 | Possibly Damaging | 2.75 | Benign | 0.62 | Tolerated | 0.2538 | 0.3245 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3030T>G | F1010L 2D AIThe SynGAP1 missense variant F1010L is not 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 benign classification, 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 not contradicted by ClinVar, which has no entry for F1010L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.741537 | Disordered | 0.912572 | Binding | 0.286 | 0.881 | 0.625 | -1.982 | Likely Benign | 0.949 | Likely Pathogenic | Ambiguous | 0.142 | Likely Benign | -1.51 | Neutral | 0.910 | Possibly Damaging | 0.468 | Possibly Damaging | 2.75 | Benign | 0.62 | Tolerated | 0.2538 | 0.3245 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3178G>A | G1060S 2D AIThe SynGAP1 missense variant G1060S is listed in ClinVar with an uncertain significance (ClinVar ID 1512003.0) and is present in gnomAD (variant ID 6‑33443730‑G‑A). All evaluated in‑silico predictors classify the change as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this benign view: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, 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 | 0.979242 | Disordered | 0.913048 | Binding | 0.407 | 0.928 | 0.875 | Uncertain | 1 | 6-33443730-G-A | -4.759 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.376 | Likely Benign | -0.08 | Neutral | 0.271 | Benign | 0.054 | Benign | 2.69 | Benign | 0.49 | Tolerated | 4.32 | 2 | 0.2468 | 0.5311 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.3178G>C | G1060R 2D AIThe SynGAP1 missense variant G1060R 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, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for G1060R, 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 | 0.979242 | Disordered | 0.913048 | Binding | 0.407 | 0.928 | 0.875 | -8.225 | Likely Pathogenic | 0.323 | Likely Benign | Likely Benign | 0.362 | Likely Benign | -0.29 | Neutral | 0.971 | Probably Damaging | 0.580 | Possibly Damaging | 2.63 | Benign | 0.17 | Tolerated | 0.1038 | 0.4342 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3178G>T | G1060C 2D AIThe SynGAP1 missense variant G1060C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for G1060C, 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 | 0.979242 | Disordered | 0.913048 | Binding | 0.407 | 0.928 | 0.875 | -9.630 | Likely Pathogenic | 0.116 | Likely Benign | Likely Benign | 0.363 | Likely Benign | -0.60 | Neutral | 0.999 | Probably Damaging | 0.917 | Probably Damaging | 2.63 | Benign | 0.12 | Tolerated | 0.1340 | 0.4227 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.3179G>A | G1060D 2D AIThe SynGAP1 missense variant G1060D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also leans benign (2 benign vs 1 pathogenic). Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.979242 | Disordered | 0.913048 | Binding | 0.407 | 0.928 | 0.875 | -9.824 | Likely Pathogenic | 0.342 | Ambiguous | Likely Benign | 0.391 | Likely Benign | -0.58 | Neutral | 0.905 | Possibly Damaging | 0.538 | Possibly Damaging | 2.63 | Benign | 0.20 | Tolerated | 0.1703 | 0.2035 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.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.3179G>T | G1060V 2D AIThe SynGAP1 missense variant G1060V is listed in ClinVar as benign (ClinVar ID 1345112.0) and is observed in gnomAD (6‑33443731‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic effect. 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 outcome. No Foldetta stability assessment is available for this variant. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar designation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.979242 | Disordered | 0.913048 | Binding | 0.407 | 0.928 | 0.875 | Benign | 1 | 6-33443731-G-T | 1 | 6.22e-7 | -6.966 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.369 | Likely Benign | -0.73 | Neutral | 0.986 | Probably Damaging | 0.728 | Possibly Damaging | 2.63 | Benign | 0.33 | Tolerated | 4.32 | 2 | 0.1453 | 0.3494 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||
| c.3919C>A | P1307T 2D AIThe SynGAP1 missense variant P1307T is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset predicts pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the consensus of all available predictions strongly suggests that P1307T is most likely benign, and this conclusion is consistent with the lack of ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.798249 | Disordered | 0.913511 | Binding | 0.491 | 0.901 | 0.875 | -4.262 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.072 | Likely Benign | 0.20 | Neutral | 0.386 | Benign | 0.266 | Benign | 3.07 | Benign | 0.60 | Tolerated | 0.1732 | 0.5436 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3919C>G | P1307A 2D AIThe SynGAP1 missense variant P1307A is catalogued in gnomAD (ID 6‑33451793‑C‑G) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as tolerated or benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as likely benign. Foldetta, a protein‑folding stability predictor, was not available for this variant. Overall, the consensus of all available predictions is benign, and this is consistent with the absence of a ClinVar pathogenic classification. Based on the consensus of all predictions, the variant is most likely benign, and this does not contradict ClinVar status, which has no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.798249 | Disordered | 0.913511 | Binding | 0.491 | 0.901 | 0.875 | 6-33451793-C-G | 1 | 6.20e-7 | -4.042 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.064 | Likely Benign | 0.49 | Neutral | 0.003 | Benign | 0.006 | Benign | 3.11 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.3747 | 0.4451 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.3919C>T | P1307S 2D AIThe SynGAP1 missense variant P1307S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.798249 | Disordered | 0.913511 | Binding | 0.491 | 0.901 | 0.875 | -3.700 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.049 | Likely Benign | 0.45 | Neutral | 0.239 | Benign | 0.157 | Benign | 3.09 | Benign | 0.48 | Tolerated | 0.3652 | 0.4846 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3920C>A | P1307Q 2D AIThe SynGAP1 missense variant P1307Q is listed in ClinVar (ID 982827.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451794‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.798249 | Disordered | 0.913511 | Binding | 0.491 | 0.901 | 0.875 | Uncertain | 1 | 6-33451794-C-A | -4.227 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.192 | Likely Benign | -0.88 | Neutral | 0.988 | Probably Damaging | 0.765 | Possibly Damaging | 2.82 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1629 | 0.4464 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||
| c.3920C>G | P1307R 2D AIThe SynGAP1 missense variant P1307R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy methods further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the available predictions indicates that P1307R is most likely benign, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.798249 | Disordered | 0.913511 | Binding | 0.491 | 0.901 | 0.875 | -4.022 | Likely Benign | 0.183 | Likely Benign | Likely Benign | 0.225 | Likely Benign | -1.17 | Neutral | 0.887 | Possibly Damaging | 0.664 | Possibly Damaging | 2.82 | Benign | 0.06 | Tolerated | 0.1552 | 0.2763 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3920C>T | P1307L 2D AIThe SynGAP1 missense variant P1307L is listed in ClinVar (ID 1991214.0) as benign and is present in gnomAD (variant ID 6‑33451794‑C‑T). 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) is “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 predictions, including the high‑accuracy consensus, indicate a benign impact. This conclusion aligns with the ClinVar benign classification and does not contradict the reported clinical status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.798249 | Disordered | 0.913511 | Binding | 0.491 | 0.901 | 0.875 | Benign | 1 | 6-33451794-C-T | 11 | 6.82e-6 | -4.044 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 0.292 | Likely Benign | -1.49 | Neutral | 0.779 | Possibly Damaging | 0.220 | Benign | 2.82 | Benign | 0.04 | Affected | 3.77 | 5 | 0.2546 | 0.6387 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||
| c.3025G>A | E1009K 2D AIThe SynGAP1 missense variant E1009K is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of consensus tools (five pathogenic vs. three benign) indicate a pathogenic effect. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.728858 | Disordered | 0.914552 | Binding | 0.325 | 0.885 | 0.500 | -3.419 | Likely Benign | 0.897 | Likely Pathogenic | Ambiguous | 0.061 | Likely Benign | -1.90 | Neutral | 0.961 | Probably Damaging | 0.630 | Possibly Damaging | 2.41 | Pathogenic | 0.01 | Affected | 0.2511 | 0.7625 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||||
| c.3025G>C | E1009Q 2D AIThe SynGAP1 missense variant E1009Q is not reported in ClinVar (ClinVar status: None) but is present in gnomAD (ID 6‑33443577‑G‑C). 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, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs 2 benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, five tools predict pathogenicity while four predict benignity, giving a slight tilt toward pathogenicity. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.728858 | Disordered | 0.914552 | Binding | 0.325 | 0.885 | 0.500 | 6-33443577-G-C | 1 | 6.20e-7 | -3.423 | Likely Benign | 0.615 | Likely Pathogenic | Likely Benign | 0.057 | Likely Benign | -1.65 | Neutral | 0.980 | Probably Damaging | 0.782 | Possibly Damaging | 2.39 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.1577 | 0.7242 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||
| c.3026A>C | E1009A 2D AIThe SynGAP1 missense variant E1009A is listed in ClinVar (ID 2238288.0) with an “Uncertain” status and is not reported in gnomAD. 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, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which is 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 (a protein‑folding stability method combining FoldX‑MD and Rosetta) results are unavailable. Overall, the majority of predictions (six pathogenic vs. three benign) lean toward a pathogenic impact, and this conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.728858 | Disordered | 0.914552 | Binding | 0.325 | 0.885 | 0.500 | Uncertain | 1 | -3.118 | Likely Benign | 0.679 | Likely Pathogenic | Likely Benign | 0.109 | Likely Benign | -3.06 | Deleterious | 0.980 | Probably Damaging | 0.630 | Possibly Damaging | 2.39 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.3959 | 0.7153 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||
| c.3026A>G | E1009G 2D AIThe SynGAP1 missense variant E1009G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. In contrast, the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM‑Consensus indicates a likely pathogenic outcome; Foldetta results are unavailable. Overall, the preponderance of evidence from standard and high‑accuracy 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 | 0.728858 | Disordered | 0.914552 | Binding | 0.325 | 0.885 | 0.500 | -2.758 | Likely Benign | 0.610 | Likely Pathogenic | Likely Benign | 0.123 | Likely Benign | -3.06 | Deleterious | 0.961 | Probably Damaging | 0.721 | Possibly Damaging | 2.36 | Pathogenic | 0.01 | Affected | 0.2800 | 0.6003 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3026A>T | E1009V 2D AIThe SynGAP1 missense variant E1009V is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign calls come from REVEL and ESM1b, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments give an uncertain result from AlphaMissense‑Optimized, a Likely Pathogenic verdict from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and no available data from Foldetta. Overall, the majority of evidence points to a deleterious effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.728858 | Disordered | 0.914552 | Binding | 0.325 | 0.885 | 0.500 | -3.660 | Likely Benign | 0.815 | Likely Pathogenic | Ambiguous | 0.156 | Likely Benign | -3.81 | Deleterious | 0.998 | Probably Damaging | 0.924 | Probably Damaging | 2.34 | Pathogenic | 0.00 | Affected | 0.1111 | 0.7580 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.3027G>C | E1009D 2D AIThe SynGAP1 missense variant E1009D is reported in gnomAD (ID 6‑33443579‑G‑C) but has no ClinVar entry. All in‑silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized indicates benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports 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 | 0.728858 | Disordered | 0.914552 | Binding | 0.325 | 0.885 | 0.500 | 6-33443579-G-C | 1 | 6.20e-7 | -2.958 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.37 | Neutral | 0.011 | Benign | 0.017 | Benign | 2.50 | Benign | 0.30 | Tolerated | 3.77 | 5 | 0.2077 | 0.4817 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.3027G>T | E1009D 2D AIThe SynGAP1 missense variant E1009D is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.914552 | Binding | 0.325 | 0.885 | 0.500 | -2.958 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.37 | Neutral | 0.011 | Benign | 0.017 | Benign | 2.50 | Benign | 0.30 | Tolerated | 3.77 | 5 | 0.2077 | 0.4817 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||
| c.3040G>A | G1014S 2D AIThe SynGAP1 missense variant G1014S 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 | 0.771762 | Disordered | 0.914808 | Binding | 0.293 | 0.835 | 0.625 | -3.219 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.026 | Likely Benign | -0.60 | Neutral | 0.068 | Benign | 0.039 | Benign | 2.95 | Benign | 0.50 | Tolerated | 0.2677 | 0.5408 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3040G>C | G1014R 2D AIThe SynGAP1 missense variant G1014R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, PolyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM‑Consensus also indicates a likely benign outcome; however, the Foldetta protein‑folding stability assessment is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Thus, the variant is most likely benign. 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 | -3.234 | Likely Benign | 0.562 | Ambiguous | Likely Benign | 0.067 | Likely Benign | -1.47 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 2.80 | Benign | 0.12 | Tolerated | 0.1044 | 0.4714 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3040G>T | G1014C 2D AIThe SynGAP1 G1014C missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. ESM1b is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. 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 | 0.771762 | Disordered | 0.914808 | Binding | 0.293 | 0.835 | 0.625 | -7.424 | In-Between | 0.151 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -2.49 | Neutral | 0.997 | Probably Damaging | 0.889 | Possibly Damaging | 2.68 | Benign | 0.06 | Tolerated | 0.1401 | 0.4126 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.3041G>A | G1014D 2D AIThe SynGAP1 missense variant G1014D is catalogued in gnomAD (6‑33443593‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports a benign effect, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) 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 impact for G1014D, and this conclusion is not contradicted by any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.914808 | Binding | 0.293 | 0.835 | 0.625 | 6-33443593-G-A | -4.462 | Likely Benign | 0.543 | Ambiguous | Likely Benign | 0.029 | Likely Benign | -1.39 | Neutral | 0.818 | Possibly Damaging | 0.381 | Benign | 2.74 | Benign | 0.77 | Tolerated | 3.77 | 5 | 0.2003 | 0.2942 | -1 | 1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||
| 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.3041G>T | G1014V 2D AIThe SynGAP1 missense variant G1014V is listed in ClinVar (ID 809922.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, 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 is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.914808 | Binding | 0.293 | 0.835 | 0.625 | Uncertain | 1 | -4.612 | Likely Benign | 0.181 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -2.47 | Neutral | 0.818 | Possibly Damaging | 0.377 | Benign | 2.72 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0.1359 | 0.3533 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||
| c.2317A>C | M773L 2D  AIThe SynGAP1 missense variant M773L 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 | 0.408655 | Structured | 0.916222 | Binding | 0.325 | 0.893 | 0.250 | -3.458 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.211 | Likely Benign | -0.75 | Neutral | 0.038 | Benign | 0.137 | Benign | 4.29 | Benign | 0.81 | Tolerated | 0.1517 | 0.3529 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2317A>G | M773V 2D  AIThe SynGAP1 missense variant M773V has no ClinVar entry and is not reported in gnomAD. All evaluated in‑silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the computational evidence indicates that M773V 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 | 0.408655 | Structured | 0.916222 | Binding | 0.325 | 0.893 | 0.250 | -4.353 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.234 | Likely Benign | -0.70 | Neutral | 0.038 | Benign | 0.284 | Benign | 4.30 | Benign | 0.87 | Tolerated | 0.3145 | 0.3081 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||||||||||||
| c.2317A>T | M773L 2D AIThe SynGAP1 missense variant M773L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess pathogenicity uniformly predict a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. 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 results are not available. Overall, the consensus of all available predictions points to a benign impact, and this 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 | 0.408655 | Structured | 0.916222 | Binding | 0.325 | 0.893 | 0.250 | -3.458 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.211 | Likely Benign | -0.75 | Neutral | 0.038 | Benign | 0.137 | Benign | 4.29 | Benign | 0.81 | Tolerated | 0.1517 | 0.3529 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2318T>A | M773K 2D  AIThe SynGAP1 missense variant M773K is not 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, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta 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 | 0.408655 | Structured | 0.916222 | Binding | 0.325 | 0.893 | 0.250 | -5.117 | Likely Benign | 0.641 | Likely Pathogenic | Likely Benign | 0.178 | Likely Benign | -1.80 | Neutral | 0.106 | Benign | 0.471 | Possibly Damaging | 4.19 | Benign | 0.02 | Affected | 0.1646 | 0.0851 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||||||
| c.2318T>C | M773T 2D  AIThe SynGAP1 missense variant M773T is listed in gnomAD (ID 6‑33442476‑T‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only polyPhen‑2 HumVar 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, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.408655 | Structured | 0.916222 | Binding | 0.325 | 0.893 | 0.250 | 6-33442476-T-C | 1 | 1.28e-6 | -4.225 | Likely Benign | 0.377 | Ambiguous | Likely Benign | 0.112 | Likely Benign | -1.63 | Neutral | 0.106 | Benign | 0.471 | Possibly Damaging | 4.22 | Benign | 0.06 | Tolerated | 3.64 | 6 | 0.2196 | 0.1586 | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||||||||||||||||
| c.2318T>G | M773R 2D  AIThe SynGAP1 missense variant M773R is listed in gnomAD (ID 6‑33442476‑T‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are 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 further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates benign. No Foldetta (FoldX‑MD/Rosetta 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 ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.408655 | Structured | 0.916222 | Binding | 0.325 | 0.893 | 0.250 | 6-33442476-T-G | 1 | 1.28e-6 | -4.340 | Likely Benign | 0.597 | Likely Pathogenic | Likely Benign | 0.183 | Likely Benign | -1.87 | Neutral | 0.220 | Benign | 0.471 | Possibly Damaging | 4.18 | Benign | 0.02 | Affected | 3.64 | 6 | 0.1778 | 0.0800 | -1 | 0 | -6.4 | 24.99 | ||||||||||||||||||||||||||||||||||
| c.2319G>A | M773I 2D  AIThe SynGAP1 missense variant M773I is not 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, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.408655 | Structured | 0.916222 | Binding | 0.325 | 0.893 | 0.250 | -4.799 | Likely Benign | 0.567 | Likely Pathogenic | Likely Benign | 0.099 | Likely Benign | -0.83 | Neutral | 0.038 | Benign | 0.284 | Benign | 4.31 | Benign | 0.22 | Tolerated | 0.1406 | 0.3011 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2319G>C | M773I 2D AIThe SynGAP1 missense variant M773I is not 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, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.408655 | Structured | 0.916222 | Binding | 0.325 | 0.893 | 0.250 | -4.799 | Likely Benign | 0.567 | Likely Pathogenic | Likely Benign | 0.099 | Likely Benign | -0.83 | Neutral | 0.038 | Benign | 0.284 | Benign | 4.31 | Benign | 0.22 | Tolerated | 0.1406 | 0.3011 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2319G>T | M773I 2D AIThe SynGAP1 missense variant M773I is not 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, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.408655 | Structured | 0.916222 | Binding | 0.325 | 0.893 | 0.250 | -4.799 | Likely Benign | 0.567 | Likely Pathogenic | Likely Benign | 0.099 | Likely Benign | -0.83 | Neutral | 0.038 | Benign | 0.284 | Benign | 4.31 | Benign | 0.22 | Tolerated | 0.1406 | 0.3011 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3145C>A | P1049T 2D AIThe SynGAP1 missense variant P1049T 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 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 indicates a benign outcome. Foldetta results are unavailable, so no additional stability evidence is present. Overall, the consensus of available predictions indicates that P1049T 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 | 0.978316 | Disordered | 0.917915 | Binding | 0.428 | 0.920 | 0.750 | -5.100 | Likely Benign | 0.056 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -1.18 | Neutral | 0.519 | Possibly Damaging | 0.222 | Benign | 2.74 | Benign | 0.02 | Affected | 0.1791 | 0.5514 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3145C>G | P1049A 2D AIThe SynGAP1 missense variant P1049A 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 | 0.978316 | Disordered | 0.917915 | Binding | 0.428 | 0.920 | 0.750 | -3.870 | Likely Benign | 0.049 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -1.43 | Neutral | 0.180 | Benign | 0.171 | Benign | 2.81 | Benign | 0.06 | Tolerated | 0.3306 | 0.4897 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3145C>T | P1049S 2D AIThe SynGAP1 missense variant P1049S is reported in gnomAD (variant ID 6‑33443697‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the majority of predictions, including the high‑accuracy tools, indicate that P1049S 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 | 0.978316 | Disordered | 0.917915 | Binding | 0.428 | 0.920 | 0.750 | 6-33443697-C-T | 2 | 1.24e-6 | -2.351 | Likely Benign | 0.053 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -1.53 | Neutral | 0.519 | Possibly Damaging | 0.303 | Benign | 2.76 | Benign | 0.04 | Affected | 3.77 | 5 | 0.3144 | 0.5083 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3146C>A | P1049H 2D AIThe SynGAP1 missense variant P1049H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978316 | Disordered | 0.917915 | Binding | 0.428 | 0.920 | 0.750 | -5.427 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -2.06 | Neutral | 0.978 | Probably Damaging | 0.750 | Possibly Damaging | 2.76 | Benign | 0.01 | Affected | 0.1800 | 0.5070 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3146C>G | P1049R 2D AIThe SynGAP1 missense variant P1049R 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 | 0.978316 | Disordered | 0.917915 | Binding | 0.428 | 0.920 | 0.750 | -5.144 | Likely Benign | 0.145 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -1.90 | Neutral | 0.791 | Possibly Damaging | 0.500 | Possibly Damaging | 2.74 | Benign | 0.03 | Affected | 0.1376 | 0.3769 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3146C>T | P1049L 2D AIThe SynGAP1 missense variant P1049L is not 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 | 0.978316 | Disordered | 0.917915 | Binding | 0.428 | 0.920 | 0.750 | -4.819 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -2.37 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.71 | Benign | 0.02 | Affected | 0.2267 | 0.5838 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2287C>A | L763I 2D AIThe SynGAP1 missense variant L763I is 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 likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for this variant, and there is no conflict with ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.380708 | Structured | 0.918636 | Binding | 0.351 | 0.865 | 0.125 | -4.803 | Likely Benign | 0.150 | Likely Benign | Likely Benign | 0.052 | Likely Benign | -0.55 | Neutral | 0.877 | Possibly Damaging | 0.675 | Possibly Damaging | 2.48 | Pathogenic | 0.31 | Tolerated | 0.0870 | 0.3367 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.2287C>G | L763V 2D AIThe SynGAP1 missense variant L763V 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 | 0.380708 | Structured | 0.918636 | Binding | 0.351 | 0.865 | 0.125 | -5.138 | Likely Benign | 0.164 | Likely Benign | Likely Benign | 0.027 | Likely Benign | -0.94 | Neutral | 0.573 | Possibly Damaging | 0.230 | Benign | 2.57 | Benign | 0.25 | Tolerated | 0.1548 | 0.2817 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2287C>T | L763F 2D AIThe SynGAP1 missense variant L763F is 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 this variant. There is no ClinVar entry to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.380708 | Structured | 0.918636 | Binding | 0.351 | 0.865 | 0.125 | -4.127 | Likely Benign | 0.255 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -0.71 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.39 | Pathogenic | 0.19 | Tolerated | 0.0584 | 0.3140 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2288T>A | L763H 2D AIThe SynGAP1 missense variant L763H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on benign include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign), and Foldetta results are unavailable. Overall, the predictions are mixed, with a slight tilt toward pathogenicity (5 pathogenic vs. 4 benign). Thus, the variant is most likely pathogenic according to the aggregate predictions, and this assessment does not contradict ClinVar, which currently has no entry for it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.380708 | Structured | 0.918636 | Binding | 0.351 | 0.865 | 0.125 | -6.681 | Likely Benign | 0.640 | Likely Pathogenic | Likely Benign | 0.180 | Likely Benign | -0.79 | Neutral | 1.000 | Probably Damaging | 0.992 | Probably Damaging | 2.36 | Pathogenic | 0.03 | Affected | 0.1021 | 0.0887 | -2 | -3 | -7.0 | 23.98 | ||||||||||||||||||||||||||||||||||||||||
| c.2288T>C | L763P 2D AIThe SynGAP1 missense variant L763P is not 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, and FATHMM. AlphaMissense‑Default is uncertain. For high‑accuracy assessment, AlphaMissense‑Optimized predicts benign. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also yields a benign prediction (2 benign vs. 1 pathogenic, with one uncertain). Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.380708 | Structured | 0.918636 | Binding | 0.351 | 0.865 | 0.125 | -5.802 | Likely Benign | 0.550 | Ambiguous | Likely Benign | 0.158 | Likely Benign | -0.89 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.36 | Pathogenic | 0.12 | Tolerated | 0.3920 | 0.1182 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2288T>G | L763R 2D AIThe SynGAP1 missense variant L763R is not 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, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic) and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign impact, 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. | 0.380708 | Structured | 0.918636 | Binding | 0.351 | 0.865 | 0.125 | -5.516 | Likely Benign | 0.643 | Likely Pathogenic | Likely Benign | 0.163 | Likely Benign | -1.66 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.38 | Pathogenic | 0.07 | Tolerated | 0.1199 | 0.0761 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2962C>A | L988I 2D AIThe SynGAP1 missense variant L988I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.918781 | Binding | 0.360 | 0.913 | 0.750 | -4.226 | Likely Benign | 0.204 | Likely Benign | Likely Benign | 0.120 | Likely Benign | -1.08 | Neutral | 0.924 | Possibly Damaging | 0.652 | Possibly Damaging | 2.70 | Benign | 0.00 | Affected | 0.1034 | 0.4143 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.2962C>G | L988V 2D AIThe SynGAP1 missense variant L988V 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 L988V, 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 | 0.827927 | Disordered | 0.918781 | Binding | 0.360 | 0.913 | 0.750 | -3.626 | Likely Benign | 0.226 | Likely Benign | Likely Benign | 0.096 | Likely Benign | -1.42 | Neutral | 0.856 | Possibly Damaging | 0.474 | Possibly Damaging | 2.73 | Benign | 0.00 | Affected | 0.1652 | 0.3793 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2962C>T | L988F 2D AIThe SynGAP1 missense variant L988F is listed in ClinVar (ID 968833.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443514‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains 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 results are unavailable. Overall, the majority of evidence points to a benign impact, and this is not in conflict with the ClinVar “Uncertain” classification. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.918781 | Binding | 0.360 | 0.913 | 0.750 | Uncertain | 1 | 6-33443514-C-T | 1 | 6.20e-7 | -4.368 | Likely Benign | 0.356 | Ambiguous | Likely Benign | 0.135 | Likely Benign | -1.70 | Neutral | 0.977 | Probably Damaging | 0.900 | Possibly Damaging | 2.69 | Benign | 0.00 | Affected | 4.32 | 2 | 0.0693 | 0.3592 | 2 | 0 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||
| c.2963T>A | L988H 2D AIThe SynGAP1 missense variant L988H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2). Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs four benign) lean toward pathogenicity. Thus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.827927 | Disordered | 0.918781 | Binding | 0.360 | 0.913 | 0.750 | -4.779 | Likely Benign | 0.733 | Likely Pathogenic | Likely Benign | 0.179 | Likely Benign | -2.70 | Deleterious | 0.998 | Probably Damaging | 0.947 | Probably Damaging | 2.62 | Benign | 0.00 | Affected | 0.1179 | 0.1414 | -2 | -3 | -7.0 | 23.98 | ||||||||||||||||||||||||||||||||||||||||
| c.2963T>C | L988P 2D AIThe SynGAP1 missense variant L988P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward pathogenicity. Thus, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.827927 | Disordered | 0.918781 | Binding | 0.360 | 0.913 | 0.750 | -3.848 | Likely Benign | 0.703 | Likely Pathogenic | Likely Benign | 0.216 | Likely Benign | -2.96 | Deleterious | 0.977 | Probably Damaging | 0.900 | Possibly Damaging | 2.62 | Benign | 0.00 | Affected | 0.3282 | 0.1698 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2963T>G | L988R 2D AIThe SynGAP1 missense variant L988R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (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 unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.918781 | Binding | 0.360 | 0.913 | 0.750 | -4.412 | Likely Benign | 0.681 | Likely Pathogenic | Likely Benign | 0.202 | Likely Benign | -2.39 | Neutral | 0.954 | Possibly Damaging | 0.867 | Possibly Damaging | 2.69 | Benign | 0.00 | Affected | 0.1257 | 0.1088 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2959G>A | D987N 2D AIThe SynGAP1 D987N missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, 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 (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 exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.823549 | Disordered | 0.919118 | Binding | 0.299 | 0.903 | 0.750 | -5.035 | Likely Benign | 0.698 | Likely Pathogenic | Likely Benign | 0.126 | Likely Benign | -1.42 | Neutral | 0.943 | Possibly Damaging | 0.755 | Possibly Damaging | 2.41 | Pathogenic | 0.49 | Tolerated | 0.1331 | 0.7427 | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||||
| c.2959G>C | D987H 2D AIThe SynGAP1 missense variant D987H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and the Foldetta stability analysis is unavailable. Based on the preponderance of pathogenic predictions and the SGM‑Consensus result, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.823549 | Disordered | 0.919118 | Binding | 0.299 | 0.903 | 0.750 | -5.580 | Likely Benign | 0.925 | Likely Pathogenic | Ambiguous | 0.249 | Likely Benign | -3.16 | Deleterious | 0.998 | Probably Damaging | 0.951 | Probably Damaging | 2.35 | Pathogenic | 0.02 | Affected | 0.1553 | 0.7629 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2959G>T | D987Y 2D AIThe SynGAP1 missense variant D987Y is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves as likely pathogenic (3 pathogenic vs 1 benign). AlphaMissense‑Optimized returns an uncertain result, and Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.823549 | Disordered | 0.919118 | Binding | 0.299 | 0.903 | 0.750 | -6.208 | Likely Benign | 0.831 | Likely Pathogenic | Ambiguous | 0.274 | Likely Benign | -4.41 | Deleterious | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.33 | Pathogenic | 0.01 | Affected | 0.0632 | 0.6818 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| c.2960A>C | D987A 2D AIThe SynGAP1 D987A missense variant is not reported in ClinVar and has no gnomAD entry. Consensus prediction tools that classify the change as benign include REVEL and ESM1b, whereas the majority of other in silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) and the SGM‑Consensus score (Likely Pathogenic) indicate a pathogenic effect. Grouping by agreement, benign predictions are limited to two tools, while pathogenic predictions are supported by seven distinct algorithms. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized returns an uncertain result, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a Likely Pathogenic classification, and the protein‑folding stability method Foldetta is unavailable for this variant. Overall, the preponderance of evidence points to a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.823549 | Disordered | 0.919118 | Binding | 0.299 | 0.903 | 0.750 | -4.880 | Likely Benign | 0.853 | Likely Pathogenic | Ambiguous | 0.261 | Likely Benign | -3.72 | Deleterious | 0.943 | Possibly Damaging | 0.686 | Possibly Damaging | 2.39 | Pathogenic | 0.02 | Affected | 0.3930 | 0.6846 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2960A>G | D987G 2D AIThe SynGAP1 missense variant D987G (ClinVar ID 1061058.0) is listed as ClinVar status Uncertain and is not reported in gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, SIFT, and ESM1b, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates majority votes from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further indicate that AlphaMissense‑Optimized is uncertain, while Foldetta data are unavailable. Overall, the majority of evidence points toward a pathogenic effect, aligning with the SGM‑Consensus but contradicting the ClinVar Uncertain designation. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment is in conflict with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.823549 | Disordered | 0.919118 | Binding | 0.299 | 0.903 | 0.750 | Uncertain | 1 | -4.782 | Likely Benign | 0.849 | Likely Pathogenic | Ambiguous | 0.234 | Likely Benign | -2.79 | Deleterious | 0.943 | Possibly Damaging | 0.808 | Possibly Damaging | 2.45 | Pathogenic | 0.07 | Tolerated | 4.32 | 2 | 0.3835 | 0.6710 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||
| c.2960A>T | D987V 2D AIThe SynGAP1 missense variant D987V is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, while pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence indicates that D987V is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.823549 | Disordered | 0.919118 | Binding | 0.299 | 0.903 | 0.750 | -4.647 | Likely Benign | 0.857 | Likely Pathogenic | Ambiguous | 0.389 | Likely Benign | -4.01 | Deleterious | 0.992 | Probably Damaging | 0.913 | Probably Damaging | 2.34 | Pathogenic | 0.00 | Affected | 0.0907 | 0.7202 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.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.3022G>A | D1008N 2D AIThe SynGAP1 missense variant D1008N is listed in ClinVar (ID 1213097.0) as benign and is present in gnomAD (variant ID 6‑33443574‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, a majority‑vote model of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the majority of evidence indicates a benign effect, consistent with the ClinVar classification and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.694846 | Disordered | 0.919416 | Binding | 0.280 | 0.899 | 0.625 | Likely Benign | 1 | 6-33443574-G-A | 3 | 1.86e-6 | -4.045 | Likely Benign | 0.714 | Likely Pathogenic | Likely Benign | 0.128 | Likely Benign | -2.15 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.75 | Benign | 0.01 | Affected | 3.77 | 5 | 0.2076 | 0.7013 | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||
| c.3022G>C | D1008H 2D AIThe SynGAP1 missense variant D1008H is catalogued in gnomAD (6‑33443574‑G‑C) 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 and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to a likely benign verdict. High‑accuracy assessments are mixed: AlphaMissense‑Optimized returns an uncertain result, while Foldetta data are not available. Overall, the majority of evidence points toward a benign effect, and this conclusion aligns with the SGM‑Consensus and the benign consensus of most tools. There is no ClinVar status to contradict this assessment. Thus, the variant is most likely benign, and this is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.694846 | Disordered | 0.919416 | Binding | 0.280 | 0.899 | 0.625 | 6-33443574-G-C | 1 | 6.20e-7 | -3.612 | Likely Benign | 0.915 | Likely Pathogenic | Ambiguous | 0.213 | Likely Benign | -2.46 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.64 | Benign | 0.01 | Affected | 3.77 | 5 | 0.2488 | 0.7228 | -1 | 1 | 0.3 | 22.05 | ||||||||||||||||||||||||||||||||||
| c.3022G>T | D1008Y 2D AIThe SynGAP1 missense variant D1008Y is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a tie and thus unavailable, and Foldetta results are not provided. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.694846 | Disordered | 0.919416 | Binding | 0.280 | 0.899 | 0.625 | -5.371 | Likely Benign | 0.928 | Likely Pathogenic | Ambiguous | 0.237 | Likely Benign | -3.71 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.62 | Benign | 0.00 | Affected | 0.1043 | 0.6293 | -4 | -3 | 2.2 | 48.09 | ||||||||||||||||||||||||||||||||||||||||
| c.3023A>C | D1008A 2D AIThe SynGAP1 D1008A variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, more tools (five) predict pathogenicity than benign (three), and no ClinVar evidence contradicts this assessment. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.694846 | Disordered | 0.919416 | Binding | 0.280 | 0.899 | 0.625 | -3.210 | Likely Benign | 0.861 | Likely Pathogenic | Ambiguous | 0.209 | Likely Benign | -2.65 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.69 | Benign | 0.03 | Affected | 0.4014 | 0.6444 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.3023A>G | D1008G 2D AIThe SynGAP1 D1008G missense variant (ClinVar ID 2963386.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33443575‑A‑G). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant 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 results are unavailable. Overall, the balance of evidence leans toward a pathogenic interpretation, which does not contradict the current ClinVar designation of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.694846 | Disordered | 0.919416 | Binding | 0.280 | 0.899 | 0.625 | Uncertain | 1 | 6-33443575-A-G | 1 | 6.20e-7 | -3.213 | Likely Benign | 0.742 | Likely Pathogenic | Likely Benign | 0.203 | Likely Benign | -2.84 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.65 | Benign | 0.01 | Affected | 3.77 | 5 | 0.3660 | 0.6073 | -1 | 1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||
| c.3023A>T | D1008V 2D AIThe SynGAP1 D1008V variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (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, more tools (five) predict pathogenicity than benign (three), and the high‑accuracy assessments do not overturn this trend. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.694846 | Disordered | 0.919416 | Binding | 0.280 | 0.899 | 0.625 | -4.828 | Likely Benign | 0.944 | Likely Pathogenic | Ambiguous | 0.242 | Likely Benign | -3.61 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.64 | Benign | 0.01 | Affected | 0.1447 | 0.6608 | -2 | -3 | 7.7 | -15.96 | ||||||||||||||||||||||||||||||||||||||||
| 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.2290A>C | N764H 2D AIThe SynGAP1 missense variant N764H is reported in gnomAD (ID 6‑33441755‑A‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions are made by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign effect, 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 | 0.380708 | Structured | 0.919527 | Binding | 0.305 | 0.861 | 0.250 | 6-33441755-A-C | -4.954 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -2.09 | Neutral | 0.998 | Probably Damaging | 0.985 | Probably Damaging | 2.59 | Benign | 0.02 | Affected | 3.64 | 6 | 0.1236 | 0.5056 | 1 | 2 | 0.3 | 23.04 | ||||||||||||||||||||||||||||||||||||
| c.2290A>G | N764D 2D AIThe SynGAP1 missense variant N764D is not 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, and AlphaMissense‑Default. 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, SGM‑Consensus also predicts benign, and 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 | 0.380708 | Structured | 0.919527 | Binding | 0.305 | 0.861 | 0.250 | -6.012 | Likely Benign | 0.572 | Likely Pathogenic | Likely Benign | 0.057 | Likely Benign | -1.00 | Neutral | 0.992 | Probably Damaging | 0.893 | Possibly Damaging | 2.85 | Benign | 0.07 | Tolerated | 0.1769 | 0.2921 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2290A>T | N764Y 2D AIThe SynGAP1 missense variant N764Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta data are unavailable. Overall, the balance of evidence favors a pathogenic interpretation, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.380708 | Structured | 0.919527 | Binding | 0.305 | 0.861 | 0.250 | -5.914 | Likely Benign | 0.680 | Likely Pathogenic | Likely Benign | 0.158 | Likely Benign | -2.85 | Deleterious | 0.998 | Probably Damaging | 0.967 | Probably Damaging | 2.58 | Benign | 0.01 | Affected | 0.0552 | 0.4175 | -2 | -2 | 2.2 | 49.07 | ||||||||||||||||||||||||||||||||||||||||
| c.2291A>C | N764T 2D AIThe SynGAP1 missense variant N764T is not 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, 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 outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of computational evidence points to a benign impact, 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 | 0.380708 | Structured | 0.919527 | Binding | 0.305 | 0.861 | 0.250 | -4.214 | Likely Benign | 0.449 | Ambiguous | Likely Benign | 0.071 | Likely Benign | -1.57 | Neutral | 0.975 | Probably Damaging | 0.850 | Possibly Damaging | 2.63 | Benign | 0.05 | Affected | 0.1272 | 0.5168 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||||||||||
| c.2291A>G | N764S 2D AIThe SynGAP1 missense variant N764S is listed in ClinVar as Benign (ClinVar ID 1948460.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, consistent with the ClinVar classification, and there is no contradiction between the predictions and the reported ClinVar status. 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 | Benign | 1 | -3.149 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.84 | Neutral | 0.992 | Probably Damaging | 0.846 | Possibly Damaging | 2.65 | Benign | 0.61 | Tolerated | 3.64 | 6 | 0.3762 | 0.5062 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||||||
| c.2291A>T | N764I 2D AIThe SynGAP1 missense variant N764I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, more tools predict pathogenicity (five) than benignity (three), and no ClinVar evidence contradicts this assessment. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.380708 | Structured | 0.919527 | Binding | 0.305 | 0.861 | 0.250 | -6.879 | Likely Benign | 0.883 | Likely Pathogenic | Ambiguous | 0.115 | Likely Benign | -2.58 | Deleterious | 0.906 | Possibly Damaging | 0.679 | Possibly Damaging | 2.58 | Benign | 0.00 | Affected | 0.0581 | 0.4483 | -2 | -3 | 8.0 | -0.94 | ||||||||||||||||||||||||||||||||||||||||
| 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.2857C>A | P953T 2D AIThe SynGAP1 missense variant P953T is predicted to be benign by all evaluated in silico tools. Consensus predictions from SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classify the variant as Likely Benign. High‑accuracy predictors AlphaMissense‑Optimized also report a benign effect. Other pathogenicity predictors—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM)—uniformly predict benign. No tools predict pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its stability impact remains unknown. The variant is not listed in ClinVar and has no entry in gnomAD, so no population frequency or clinical classification is available. Based on the unanimous benign predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.920633 | Binding | 0.403 | 0.926 | 0.750 | -6.646 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -0.80 | Neutral | 0.009 | Benign | 0.015 | Benign | 2.88 | Benign | 0.24 | Tolerated | 0.2261 | 0.6004 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2857C>G | P953A 2D AIThe SynGAP1 missense variant P953A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess functional impact all converge on a benign outcome: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. No tool in the dataset indicates pathogenicity. High‑accuracy assessments reinforce this view: 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, so they do not alter the overall assessment. Consequently, the variant is most likely benign based on the collective predictions, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.920633 | Binding | 0.403 | 0.926 | 0.750 | -4.879 | Likely Benign | 0.059 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -0.98 | Neutral | 0.124 | Benign | 0.061 | Benign | 2.81 | Benign | 0.41 | Tolerated | 0.3476 | 0.5203 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2857C>T | P953S 2D AIThe SynGAP1 missense variant P953S 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 trend: 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 | 0.983019 | Disordered | 0.920633 | Binding | 0.403 | 0.926 | 0.750 | -5.430 | Likely Benign | 0.061 | Likely Benign | Likely Benign | 0.073 | Likely Benign | -0.35 | Neutral | 0.009 | Benign | 0.008 | Benign | 2.96 | Benign | 0.37 | Tolerated | 0.3359 | 0.5184 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2858C>A | P953Q 2D AIThe SynGAP1 missense variant P953Q is listed in ClinVar with an uncertain significance (ClinVar ID 1176820.0) and is not found in 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 report benign effects, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments corroborate this: 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 consensus of all available predictions points to a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.920633 | Binding | 0.403 | 0.926 | 0.750 | Uncertain | 1 | -6.038 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.086 | Likely Benign | -0.78 | Neutral | 0.058 | Benign | 0.015 | Benign | 2.78 | Benign | 0.29 | Tolerated | 3.77 | 5 | 0.2105 | 0.5108 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||
| c.2858C>G | P953R 2D AIThe SynGAP1 missense variant P953R 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 | 0.983019 | Disordered | 0.920633 | Binding | 0.403 | 0.926 | 0.750 | -6.036 | Likely Benign | 0.174 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -1.50 | Neutral | 0.611 | Possibly Damaging | 0.185 | Benign | 2.78 | Benign | 0.31 | Tolerated | 0.1771 | 0.4525 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2858C>T | P953L 2D AIThe SynGAP1 missense variant P953L is reported in gnomAD (variant ID 6‑33443410‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, representing a single dissenting opinion. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods 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 | 0.983019 | Disordered | 0.920633 | Binding | 0.403 | 0.926 | 0.750 | 6-33443410-C-T | 11 | 6.82e-6 | -6.069 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.087 | Likely Benign | -1.34 | Neutral | 0.611 | Possibly Damaging | 0.096 | Benign | 2.76 | Benign | 0.25 | Tolerated | 3.77 | 5 | 0.2725 | 0.5778 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| c.2818G>A | G940S 2D AIThe SynGAP1 missense variant G940S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443370‑G‑A). All available in silico predictors agree on a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” High‑accuracy tools reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no reported result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign classification, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.920635 | Binding | 0.383 | 0.902 | 0.625 | Uncertain | 1 | 6-33443370-G-A | 1 | 6.20e-7 | -5.451 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.135 | Likely Benign | 0.45 | Neutral | 0.409 | Benign | 0.253 | Benign | 2.77 | Benign | 0.44 | Tolerated | 3.77 | 5 | 0.2590 | 0.4907 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||
| c.2818G>C | G940R 2D AIThe SynGAP1 missense variant G940R is listed in ClinVar (ID 1923639.0) as Benign and is present in gnomAD (6‑33443370‑G‑C). 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 for this variant. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta data is unavailable. Overall, the majority of evidence points to a benign impact, which is consistent with the ClinVar classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.920635 | Binding | 0.383 | 0.902 | 0.625 | Benign | 1 | 6-33443370-G-C | 5 | 3.10e-6 | -6.169 | Likely Benign | 0.480 | Ambiguous | Likely Benign | 0.060 | Likely Benign | 0.02 | Neutral | 0.922 | Possibly Damaging | 0.543 | Possibly Damaging | 2.73 | Benign | 0.15 | Tolerated | 3.77 | 5 | 0.0922 | 0.4024 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||
| c.2818G>T | G940C 2D AIThe SynGAP1 missense variant G940C is 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. 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 evidence points to a benign impact. There is no ClinVar entry to contradict this conclusion, so the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.920635 | Binding | 0.383 | 0.902 | 0.625 | -8.158 | Likely Pathogenic | 0.097 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -0.40 | Neutral | 0.996 | Probably Damaging | 0.905 | Possibly Damaging | 2.70 | Benign | 0.11 | Tolerated | 0.1307 | 0.4354 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.2819G>A | G940D 2D AIThe SynGAP1 missense variant G940D is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443371‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Two tools, AlphaMissense‑Default and ESM1b, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it receives two benign and two uncertain votes, and Foldetta’s protein‑folding stability analysis is unavailable. Overall, the balance of evidence favors a benign classification, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.889439 | Disordered | 0.920635 | Binding | 0.383 | 0.902 | 0.625 | 6-33443371-G-A | 6 | 3.72e-6 | -7.311 | In-Between | 0.397 | Ambiguous | Likely Benign | 0.076 | Likely Benign | -0.68 | Neutral | 0.770 | Possibly Damaging | 0.583 | Possibly Damaging | 2.72 | Benign | 0.17 | Tolerated | 3.77 | 5 | 0.1837 | 0.2252 | -1 | 1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||
| 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.2819G>T | G940V 2D AIThe SynGAP1 missense variant G940V 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 further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the consensus of available predictions points to a benign impact, and this is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.920635 | Binding | 0.383 | 0.902 | 0.625 | -6.252 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.110 | Likely Benign | 0.36 | Neutral | 0.626 | Possibly Damaging | 0.419 | Benign | 2.92 | Benign | 0.31 | Tolerated | 0.1222 | 0.3822 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3964G>A | A1322T 2D AIThe SynGAP1 missense variant A1322T is catalogued in gnomAD (ID 6‑33451838‑G‑A) but has no ClinVar entry. All available in silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic outcome. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method, has no reported result for this variant. Overall, the evidence strongly supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.921040 | Binding | 0.466 | 0.825 | 0.875 | 6-33451838-G-A | -4.940 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.079 | Likely Benign | 0.51 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.20 | Benign | 0.27 | Tolerated | 3.77 | 5 | 0.1972 | 0.7582 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||
| c.3964G>C | A1322P 2D AIThe SynGAP1 missense variant A1322P is reported in ClinVar (ID 1169945.0) as benign and is present in gnomAD (variant ID 6‑33451838‑G‑C). Across the available in‑silico predictors, all tools uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign predictions. No tool in the dataset indicates a pathogenic effect. High‑accuracy assessments corroborate this consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. The Foldetta protein‑folding stability analysis is not available for this variant. Overall, the computational evidence strongly supports a benign classification, which is consistent with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.921040 | Binding | 0.466 | 0.825 | 0.875 | Benign | 1 | 6-33451838-G-C | -1.153 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.090 | Likely Benign | 0.03 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.15 | Benign | 0.23 | Tolerated | 3.77 | 5 | 0.2255 | 0.6094 | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||||||
| c.3964G>T | A1322S 2D AIThe SynGAP1 missense variant A1322S is catalogued in gnomAD (ID 6‑33451838‑G‑T) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the variant as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the evidence strongly supports a benign classification, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.921040 | Binding | 0.466 | 0.825 | 0.875 | 6-33451838-G-T | -4.570 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.086 | Likely Benign | 1.38 | Neutral | 0.003 | Benign | 0.001 | Benign | 4.48 | Benign | 0.57 | Tolerated | 3.77 | 5 | 0.2954 | 0.6084 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.3965C>A | A1322D 2D AIThe SynGAP1 missense variant A1322D is catalogued in gnomAD (ID 6‑33451839‑C‑A) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool listed—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classifies the substitution as benign. No pathogenic predictions are reported. Grouping by consensus, all available tools fall into the benign category, with no tools indicating pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no result for this variant, so its status is unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.921040 | Binding | 0.466 | 0.825 | 0.875 | 6-33451839-C-A | -5.744 | Likely Benign | 0.284 | Likely Benign | Likely Benign | 0.092 | Likely Benign | 0.70 | Neutral | 0.013 | Benign | 0.004 | Benign | 4.17 | Benign | 0.45 | Tolerated | 3.77 | 5 | 0.2246 | 0.3134 | -2 | 0 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||
| c.3965C>G | A1322G 2D AIThe SynGAP1 missense variant A1322G is catalogued in gnomAD (ID 6‑33451839‑C‑G) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized indicates a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign status. Foldetta results are not available for this variant. Consequently, the variant is most likely benign, and this prediction does not contradict any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.921040 | Binding | 0.466 | 0.825 | 0.875 | 6-33451839-C-G | -4.159 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.053 | Likely Benign | 0.42 | Neutral | 0.005 | Benign | 0.002 | Benign | 4.16 | Benign | 0.62 | Tolerated | 3.77 | 5 | 0.2160 | 0.4741 | 0 | 1 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.3965C>T | A1322V 2D AIThe SynGAP1 missense variant A1322V is catalogued in gnomAD (ID 6‑33451839‑C‑T) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized returns a benign prediction, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta results are not available for this variant. Taken together, the computational evidence overwhelmingly supports a benign effect, and this conclusion does not conflict with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.921040 | Binding | 0.466 | 0.825 | 0.875 | 6-33451839-C-T | -5.376 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.52 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.17 | Benign | 0.15 | Tolerated | 3.77 | 5 | 0.1507 | 0.6747 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||
| c.3331A>C | K1111Q 2D  AIThe SynGAP1 missense variant K1111Q 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 classify the change as benign, while only polyPhen‑2 HumDiv predicts it as pathogenic. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely benign. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates likely benign; Foldetta results are not available. Overall, the consensus of available predictions indicates that K1111Q 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 | 0.910643 | Disordered | 0.921455 | Binding | 0.300 | 0.902 | 0.875 | -3.687 | Likely Benign | 0.261 | Likely Benign | Likely Benign | 0.036 | Likely Benign | -0.80 | Neutral | 0.666 | Possibly Damaging | 0.267 | Benign | 2.66 | Benign | 0.31 | Tolerated | 0.4577 | 0.1714 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3331A>G | K1111E 2D  AIThe SynGAP1 missense variant K1111E is not reported in ClinVar and has no entry in gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all score it as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also classifies it as likely benign. Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy tools further support a benign interpretation: AlphaMissense‑Optimized returns a benign prediction, while the SGM‑Consensus (majority vote) remains benign; a Foldetta stability assessment is unavailable. Taken together, 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 | 0.910643 | Disordered | 0.921455 | Binding | 0.300 | 0.902 | 0.875 | -3.666 | Likely Benign | 0.565 | Likely Pathogenic | Likely Benign | 0.089 | Likely Benign | -0.86 | Neutral | 0.451 | Benign | 0.193 | Benign | 2.69 | Benign | 0.23 | Tolerated | 0.3846 | 0.1833 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3332A>C | K1111T 2D  AIThe SynGAP1 missense variant K1111T is reported in gnomAD (ID 6‑33443884‑A‑C) but has no ClinVar entry. Consensus from multiple in silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all classify it as benign, and AlphaMissense‑Optimized also predicts benign. No tool predicts pathogenicity; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign,” and Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this conclusion is not contradicted by ClinVar status, which currently has no classification for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.921455 | Binding | 0.300 | 0.902 | 0.875 | 6-33443884-A-C | 2 | 1.32e-6 | -4.037 | Likely Benign | 0.519 | Ambiguous | Likely Benign | 0.080 | Likely Benign | -0.90 | Neutral | 0.292 | Benign | 0.110 | Benign | 2.64 | Benign | 0.28 | Tolerated | 4.32 | 2 | 0.2250 | 0.4425 | -1 | 0 | 3.2 | -27.07 | ||||||||||||||||||||||||||||||||||
| c.3332A>G | K1111R 2D  AIThe SynGAP1 missense variant K1111R 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 | 0.910643 | Disordered | 0.921455 | Binding | 0.300 | 0.902 | 0.875 | -2.495 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.059 | Likely Benign | -0.30 | Neutral | 0.006 | Benign | 0.006 | Benign | 2.74 | Benign | 0.71 | Tolerated | 0.4664 | 0.2031 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||||||||||||
| c.3332A>T | K1111M 2D  AIThe SynGAP1 missense variant K1111M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Taken together, the majority of evidence points to a benign impact for K1111M. 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 | 0.910643 | Disordered | 0.921455 | Binding | 0.300 | 0.902 | 0.875 | -5.579 | Likely Benign | 0.759 | Likely Pathogenic | Likely Benign | 0.071 | Likely Benign | -1.75 | Neutral | 0.072 | Benign | 0.029 | Benign | 2.59 | Benign | 0.12 | Tolerated | 0.1388 | 0.4701 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.3333G>C | K1111N 2D  AIThe SynGAP1 missense variant K1111N is not 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. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.921455 | Binding | 0.300 | 0.902 | 0.875 | -4.503 | Likely Benign | 0.833 | Likely Pathogenic | Ambiguous | 0.048 | Likely Benign | -0.77 | Neutral | 0.666 | Possibly Damaging | 0.211 | Benign | 2.64 | Benign | 0.15 | Tolerated | 0.3667 | 0.2350 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3333G>T | K1111N 2D AIThe SynGAP1 missense variant K1111N is not 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, 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 because no ClinVar entry exists. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.921455 | Binding | 0.300 | 0.902 | 0.875 | -4.503 | Likely Benign | 0.833 | Likely Pathogenic | Ambiguous | 0.048 | Likely Benign | -0.77 | Neutral | 0.666 | Possibly Damaging | 0.211 | Benign | 2.64 | Benign | 0.15 | Tolerated | 0.3667 | 0.2350 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| 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.2974G>T | V992F 2D  AIThe SynGAP1 missense variant V992F 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 SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and there is no conflict with 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 | 0.754692 | Disordered | 0.921728 | Binding | 0.331 | 0.917 | 0.750 | -3.131 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -1.25 | Neutral | 0.680 | Possibly Damaging | 0.356 | Benign | 4.17 | Benign | 0.04 | Affected | 0.0832 | 0.4083 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||||||||||||
| c.2975T>A | V992D 2D  AIThe SynGAP1 missense variant V992D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only SIFT predicts pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the consensus of the majority of tools, including the high‑accuracy methods, indicates that V992D 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 | 0.754692 | Disordered | 0.921728 | Binding | 0.331 | 0.917 | 0.750 | -3.976 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.029 | Likely Benign | -1.24 | Neutral | 0.302 | Benign | 0.158 | Benign | 4.21 | Benign | 0.05 | Affected | 0.1645 | 0.1056 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||||||||||||
| c.2975T>C | V992A 2D  AIThe SynGAP1 missense variant V992A 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 is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.921728 | Binding | 0.331 | 0.917 | 0.750 | -2.607 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -0.08 | Neutral | 0.000 | Benign | 0.003 | Benign | 4.29 | Benign | 0.41 | Tolerated | 0.3041 | 0.2668 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| c.2975T>G | V992G 2D  AIThe SynGAP1 missense variant V992G is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). All available in silico predictors classify the variant as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity, so the benign group includes every listed predictor, while the pathogenic group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a benign verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.754692 | Disordered | 0.921728 | Binding | 0.331 | 0.917 | 0.750 | -1.906 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.28 | Neutral | 0.056 | Benign | 0.086 | Benign | 4.21 | Benign | 0.16 | Tolerated | 0.2114 | 0.2612 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||||||||||||
| 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.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.2311T>G | S771A 2D AIThe SynGAP1 missense variant S771A 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 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 | -4.337 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -1.09 | Neutral | 0.025 | Benign | 0.014 | Benign | 4.09 | Benign | 0.62 | Tolerated | 0.5201 | 0.4745 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.2312C>A | S771Y 2D AIThe SynGAP1 missense variant S771Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools, ESM1b and AlphaMissense‑Default, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it contains two benign and two uncertain calls, and Foldetta data are unavailable. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.436924 | Structured | 0.922503 | Binding | 0.306 | 0.883 | 0.250 | -7.041 | In-Between | 0.397 | Ambiguous | Likely Benign | 0.176 | Likely Benign | -2.13 | Neutral | 0.990 | Probably Damaging | 0.892 | Possibly Damaging | 4.02 | Benign | 0.05 | Affected | 0.0707 | 0.5155 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||||||
| c.2312C>G | S771C 2D AIThe SynGAP1 missense variant S771C 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, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. 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, 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 | 0.436924 | Structured | 0.922503 | Binding | 0.306 | 0.883 | 0.250 | -8.014 | Likely Pathogenic | 0.167 | Likely Benign | Likely Benign | 0.177 | Likely Benign | -1.99 | Neutral | 0.990 | Probably Damaging | 0.917 | Probably Damaging | 4.01 | Benign | 0.07 | Tolerated | 0.1022 | 0.5899 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2312C>T | S771F 2D AIThe SynGAP1 missense variant S771F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools—ESM1b and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is uncertain, and Foldetta stability analysis is unavailable. Overall, the balance of evidence favors a benign interpretation, 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. | 0.436924 | Structured | 0.922503 | Binding | 0.306 | 0.883 | 0.250 | -7.988 | In-Between | 0.525 | Ambiguous | Likely Benign | 0.189 | Likely Benign | -2.29 | Neutral | 0.990 | Probably Damaging | 0.892 | Possibly Damaging | 4.02 | Benign | 0.04 | Affected | 0.0624 | 0.5428 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||||
| c.2293A>C | S765R 2D AIThe SynGAP1 missense variant S765R is not 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, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus (majority vote) as Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this conclusion, so the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.370445 | Structured | 0.922652 | Binding | 0.335 | 0.865 | 0.250 | -5.422 | Likely Benign | 0.791 | Likely Pathogenic | Ambiguous | 0.157 | Likely Benign | -1.57 | Neutral | 0.996 | Probably Damaging | 0.985 | Probably Damaging | 4.16 | Benign | 0.07 | Tolerated | 3.64 | 6 | 0.0741 | 0.3859 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.2293A>G | S765G 2D AIThe SynGAP1 missense variant S765G 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 the variant being most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.370445 | Structured | 0.922652 | Binding | 0.335 | 0.865 | 0.250 | -4.658 | Likely Benign | 0.152 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -0.98 | Neutral | 0.963 | Probably Damaging | 0.950 | Probably Damaging | 4.09 | Benign | 0.05 | Affected | 0.2894 | 0.4946 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2293A>T | S765C 2D AIThe SynGAP1 missense variant S765C 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 a likely benign outcome. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence supports a benign classification for S765C, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.370445 | Structured | 0.922652 | Binding | 0.335 | 0.865 | 0.250 | -6.875 | Likely Benign | 0.256 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -2.12 | Neutral | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 4.05 | Benign | 0.07 | Tolerated | 0.0893 | 0.6309 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2294G>A | S765N 2D AIThe SynGAP1 missense variant S765N (ClinVar ID 2979632.0) is listed as “Uncertain” in ClinVar and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). In contrast, PolyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, which is consistent with the ClinVar “Uncertain” classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.370445 | Structured | 0.922652 | Binding | 0.335 | 0.865 | 0.250 | Uncertain | 1 | -5.098 | Likely Benign | 0.378 | Ambiguous | Likely Benign | 0.094 | Likely Benign | -0.94 | Neutral | 0.985 | Probably Damaging | 0.950 | Probably Damaging | 4.11 | Benign | 0.06 | Tolerated | 3.64 | 6 | 0.1141 | 0.4658 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||
| 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.2294G>T | S765I 2D AIThe SynGAP1 missense variant S765I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also resolves to benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the 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 | 0.370445 | Structured | 0.922652 | Binding | 0.335 | 0.865 | 0.250 | -6.891 | Likely Benign | 0.699 | Likely Pathogenic | Likely Benign | 0.187 | Likely Benign | -1.24 | Neutral | 0.996 | Probably Damaging | 0.985 | Probably Damaging | 4.09 | Benign | 0.69 | Tolerated | 0.0768 | 0.5577 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2295C>A | S765R 2D AIThe SynGAP1 missense variant S765R is reported in gnomAD (ID 6‑33442453‑C‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM. Those that predict a pathogenic impact 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. Taken together, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status because none is assigned. Thus, the variant is most likely benign. 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 | 6-33442453-C-A | -5.422 | Likely Benign | 0.791 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | -1.57 | Neutral | 0.996 | Probably Damaging | 0.985 | Probably Damaging | 4.16 | Benign | 0.07 | Tolerated | 3.64 | 6 | 0.0741 | 0.3859 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| c.2295C>G | S765R 2D AIThe SynGAP1 missense variant S765R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic 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 points to a benign impact for S765R, 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 | 0.370445 | Structured | 0.922652 | Binding | 0.335 | 0.865 | 0.250 | -5.422 | Likely Benign | 0.791 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | -1.57 | Neutral | 0.996 | Probably Damaging | 0.985 | Probably Damaging | 4.16 | Benign | 0.07 | Tolerated | 3.64 | 6 | 0.0741 | 0.3859 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.2314T>A | F772I 2D AIThe SynGAP1 missense variant F772I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, 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 not available. Overall, the majority of evidence points to a benign impact. The predictions do 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 | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | -2.925 | Likely Benign | 0.255 | Likely Benign | Likely Benign | 0.142 | Likely Benign | -0.38 | Neutral | 0.845 | Possibly Damaging | 0.899 | Possibly Damaging | 4.24 | Benign | 0.41 | Tolerated | 0.1544 | 0.2051 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2314T>C | F772L 2D AIThe SynGAP1 missense variant F772L is listed in gnomAD (6‑33442472‑T‑C) 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 score (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta, 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 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 | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | 6-33442472-T-C | 1 | 1.28e-6 | -1.751 | Likely Benign | 0.762 | Likely Pathogenic | Likely Benign | 0.161 | Likely Benign | -0.47 | Neutral | 0.508 | Possibly Damaging | 0.786 | Possibly Damaging | 4.31 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1661 | 0.3033 | 0 | 2 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||
| c.2314T>G | F772V 2D AIThe SynGAP1 missense variant F772V is not 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, 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 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 | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | -2.886 | Likely Benign | 0.191 | Likely Benign | Likely Benign | 0.161 | Likely Benign | -0.43 | Neutral | 0.845 | Possibly Damaging | 0.899 | Possibly Damaging | 4.27 | Benign | 0.37 | Tolerated | 0.1687 | 0.2419 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||||||||||||
| c.2315T>A | F772Y 2D AIThe SynGAP1 missense variant F772Y is not 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. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | -2.657 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.114 | Likely Benign | -0.54 | Neutral | 0.705 | Possibly Damaging | 0.786 | Possibly Damaging | 4.17 | Benign | 0.35 | Tolerated | 0.1058 | 0.1892 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2315T>C | F772S 2D AIThe SynGAP1 missense variant F772S 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 not available. Overall, the preponderance of evidence points to a benign effect for F772S, 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 | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | -2.722 | Likely Benign | 0.442 | Ambiguous | Likely Benign | 0.138 | Likely Benign | -0.26 | Neutral | 0.845 | Possibly Damaging | 0.899 | Possibly Damaging | 4.21 | Benign | 0.56 | Tolerated | 0.4134 | 0.0558 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||||||||||||
| c.2315T>G | F772C 2D AIThe SynGAP1 missense variant F772C is not 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 any ClinVar status, as no ClinVar claim exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | -4.498 | Likely Benign | 0.248 | Likely Benign | Likely Benign | 0.156 | Likely Benign | -1.46 | Neutral | 0.979 | Probably Damaging | 0.985 | Probably Damaging | 4.14 | Benign | 0.10 | Tolerated | 0.2450 | 0.1419 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||||||||||||
| c.2316C>A | F772L 2D AIThe SynGAP1 missense variant F772L is catalogued in gnomAD (ID 6‑33442474‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is Likely Benign, while Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the preponderance of evidence indicates that F772L 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 | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | 6-33442474-C-A | -1.751 | Likely Benign | 0.762 | Likely Pathogenic | Likely Benign | 0.109 | Likely Benign | -0.47 | Neutral | 0.508 | Possibly Damaging | 0.786 | Possibly Damaging | 4.31 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1661 | 0.3033 | 0 | 2 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||
| c.2316C>G | F772L 2D AIThe SynGAP1 missense variant F772L has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; no Foldetta stability data are available, so it is treated as unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar 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 | 0.450668 | Structured | 0.922662 | Binding | 0.329 | 0.884 | 0.250 | -1.751 | Likely Benign | 0.762 | Likely Pathogenic | Likely Benign | 0.109 | Likely Benign | -0.47 | Neutral | 0.508 | Possibly Damaging | 0.786 | Possibly Damaging | 4.31 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1661 | 0.3033 | 0 | 2 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||
| 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.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.2296T>G | S766A 2D AIThe SynGAP1 missense variant S766A is not 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 because no ClinVar entry 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 | -6.115 | Likely Benign | 0.186 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.98 | Neutral | 0.447 | Benign | 0.198 | Benign | 4.17 | Benign | 0.02 | Affected | 0.5059 | 0.5705 | Strenghten | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.2297C>A | S766Y 2D AIThe SynGAP1 missense variant S766Y is reported in gnomAD (ID 6‑33442455‑C‑A) but has no ClinVar entry. Functional prediction tools show mixed results: benign calls come from REVEL, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts benign, but the SGM‑Consensus (majority vote) predicts pathogenic, and no Foldetta stability data are available. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.405110 | Structured | 0.923125 | Binding | 0.338 | 0.874 | 0.250 | 6-33442455-C-A | -8.636 | Likely Pathogenic | 0.641 | Likely Pathogenic | Likely Benign | 0.222 | Likely Benign | -2.67 | Deleterious | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 4.09 | Benign | 0.00 | Affected | 3.64 | 6 | 0.0794 | 0.5609 | -2 | -3 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||
| c.2297C>G | S766C 2D AIThe SynGAP1 missense variant S766C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. ESM1b is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S766C, 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 | 0.405110 | Structured | 0.923125 | Binding | 0.338 | 0.874 | 0.250 | -7.681 | In-Between | 0.326 | Likely Benign | Likely Benign | 0.192 | Likely Benign | -2.02 | Neutral | 0.997 | Probably Damaging | 0.889 | Possibly Damaging | 4.07 | Benign | 0.00 | Affected | 0.1049 | 0.6110 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2297C>T | S766F 2D AIThe SynGAP1 missense variant S766F is listed in gnomAD (ID 6‑33442455‑C‑T) but has no ClinVar entry. Functional prediction tools show a split verdict: benign calls come from REVEL, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments further reveal AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains pathogenic; Foldetta results are unavailable. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.405110 | Structured | 0.923125 | Binding | 0.338 | 0.874 | 0.250 | 6-33442455-C-T | -8.944 | Likely Pathogenic | 0.709 | Likely Pathogenic | Likely Benign | 0.233 | Likely Benign | -2.87 | Deleterious | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 4.08 | Benign | 0.00 | Affected | 3.64 | 6 | 0.0770 | 0.5887 | -2 | -3 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||
| c.2308C>A | Q770K 2D AIThe SynGAP1 missense variant Q770K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method, 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 existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.923732 | Binding | 0.328 | 0.887 | 0.250 | -4.768 | Likely Benign | 0.367 | Ambiguous | Likely Benign | 0.106 | Likely Benign | -0.72 | Neutral | 0.002 | Benign | 0.003 | Benign | 4.20 | Benign | 0.14 | Tolerated | 0.1984 | 0.4737 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2308C>G | Q770E 2D AIThe SynGAP1 missense variant Q770E is not 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 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 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 | 0.436924 | Structured | 0.923732 | Binding | 0.328 | 0.887 | 0.250 | -4.782 | Likely Benign | 0.201 | Likely Benign | Likely Benign | 0.109 | Likely Benign | -0.82 | Neutral | 0.002 | Benign | 0.003 | Benign | 4.19 | Benign | 0.04 | Affected | 0.1465 | 0.2833 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2309A>C | Q770P 2D AIThe SynGAP1 missense variant Q770P is not 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 Q770P, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.923732 | Binding | 0.328 | 0.887 | 0.250 | -3.948 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.178 | Likely Benign | -1.00 | Neutral | 0.748 | Possibly Damaging | 0.170 | Benign | 4.10 | Benign | 0.02 | Affected | 0.2435 | 0.5717 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2309A>G | Q770R 2D AIThe SynGAP1 missense variant Q770R is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Prediction tools that agree on a benign effect include 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, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable. Overall, the collective evidence strongly suggests that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.923732 | Binding | 0.328 | 0.887 | 0.250 | -3.873 | Likely Benign | 0.344 | Ambiguous | Likely Benign | 0.175 | Likely Benign | -1.38 | Neutral | 0.194 | Benign | 0.071 | Benign | 4.14 | Benign | 0.07 | Tolerated | 0.1610 | 0.2580 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.2309A>T | Q770L 2D AIThe SynGAP1 missense variant Q770L is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q770L, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.923732 | Binding | 0.328 | 0.887 | 0.250 | -5.524 | Likely Benign | 0.521 | Ambiguous | Likely Benign | 0.197 | Likely Benign | -2.17 | Neutral | 0.095 | Benign | 0.030 | Benign | 4.14 | Benign | 0.01 | Affected | 0.0776 | 0.6230 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2310G>C | Q770H 2D AIThe SynGAP1 missense variant Q770H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation, as none exists for Q770H. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.923732 | Binding | 0.328 | 0.887 | 0.250 | -4.241 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -1.27 | Neutral | 0.962 | Probably Damaging | 0.515 | Possibly Damaging | 4.11 | Benign | 0.01 | Affected | 0.1579 | 0.4344 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2310G>T | Q770H 2D AIThe SynGAP1 missense variant Q770H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.923732 | Binding | 0.328 | 0.887 | 0.250 | -4.241 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -1.27 | Neutral | 0.962 | Probably Damaging | 0.515 | Possibly Damaging | 4.11 | Benign | 0.01 | Affected | 0.1579 | 0.4344 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3142G>A | G1048R 2D AIThe SynGAP1 missense variant G1048R 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: pathogenic calls come from REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar, whereas benign calls are made by PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign majority, and AlphaMissense‑Optimized itself predicts benign. The SGM‑Consensus, which aggregates these four predictors, reports a likely benign classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the absence of a ClinVar assertion; there is no contradiction with ClinVar status. 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 | -4.305 | Likely Benign | 0.435 | Ambiguous | Likely Benign | 0.503 | Likely Pathogenic | -0.54 | Neutral | 0.919 | Possibly Damaging | 0.728 | Possibly Damaging | 2.54 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.0956 | 0.4332 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.3142G>C | G1048R 2D AIThe SynGAP1 missense variant G1048R is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include 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 REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM‑Consensus also indicates a likely benign outcome; the Foldetta protein‑folding stability assessment is 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 | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | Uncertain | 1 | -4.305 | Likely Benign | 0.435 | Ambiguous | Likely Benign | 0.503 | Likely Pathogenic | -0.54 | Neutral | 0.919 | Possibly Damaging | 0.728 | Possibly Damaging | 2.54 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.0956 | 0.4332 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.3142G>T | G1048W 2D AIThe SynGAP1 missense variant G1048W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | -8.803 | Likely Pathogenic | 0.340 | Likely Benign | Likely Benign | 0.498 | Likely Benign | -1.52 | Neutral | 0.996 | Probably Damaging | 0.961 | Probably Damaging | 2.54 | Benign | 0.02 | Affected | 0.0852 | 0.4046 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3143G>A | G1048E 2D AIThe SynGAP1 missense variant G1048E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only REVEL predicts a pathogenic outcome, while ESM1b is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect. 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 | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | -7.028 | In-Between | 0.331 | Likely Benign | Likely Benign | 0.529 | Likely Pathogenic | -0.62 | Neutral | 0.018 | Benign | 0.030 | Benign | 2.54 | Benign | 0.10 | Tolerated | 0.1444 | 0.4063 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3143G>C | G1048A 2D AISynGAP1 missense variant G1048A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only polyPhen‑2 HumDiv predicts it as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” status. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions indicates that G1048A is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | -4.821 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.456 | Likely Benign | -0.14 | Neutral | 0.573 | Possibly Damaging | 0.358 | Benign | 2.57 | Benign | 0.64 | Tolerated | 0.3301 | 0.5138 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3143G>T | G1048V 2D AIThe SynGAP1 missense variant G1048V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, 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. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | -6.108 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.520 | Likely Pathogenic | -0.59 | Neutral | 0.958 | Probably Damaging | 0.787 | Possibly Damaging | 2.54 | Benign | 0.11 | Tolerated | 0.1312 | 0.3688 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.2977C>A | P993T 2D AIThe SynGAP1 missense variant P993T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is 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 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 | 0.852992 | Disordered | 0.923979 | Binding | 0.319 | 0.908 | 0.750 | -4.444 | Likely Benign | 0.061 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -0.65 | Neutral | 0.001 | Benign | 0.010 | Benign | 4.32 | Benign | 0.04 | Affected | 0.1603 | 0.5789 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2977C>G | P993A 2D AIThe SynGAP1 missense variant P993A 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 | 0.852992 | Disordered | 0.923979 | Binding | 0.319 | 0.908 | 0.750 | -4.030 | Likely Benign | 0.052 | Likely Benign | Likely Benign | 0.036 | Likely Benign | -0.46 | Neutral | 0.001 | Benign | 0.006 | Benign | 4.26 | Benign | 0.07 | Tolerated | 0.3487 | 0.4991 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2977C>T | P993S 2D AIThe SynGAP1 missense variant P993S is reported in gnomAD (ID 6‑33443529‑C‑T) and has no ClinVar entry. All evaluated in silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Based on the unanimous benign predictions and lack of ClinVar 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 | 0.852992 | Disordered | 0.923979 | Binding | 0.319 | 0.908 | 0.750 | 6-33443529-C-T | 3 | 1.86e-6 | -3.665 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.13 | Neutral | 0.011 | Benign | 0.023 | Benign | 4.26 | Benign | 0.59 | Tolerated | 4.32 | 2 | 0.3421 | 0.5465 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.2978C>A | P993H 2D AIThe SynGAP1 missense variant P993H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for P993H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.923979 | Binding | 0.319 | 0.908 | 0.750 | -4.535 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -0.93 | Neutral | 0.938 | Possibly Damaging | 0.819 | Possibly Damaging | 4.11 | Benign | 0.00 | Affected | 0.1799 | 0.4591 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2978C>G | P993R 2D AIThe SynGAP1 missense variant P993R 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, 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 | 0.852992 | Disordered | 0.923979 | Binding | 0.319 | 0.908 | 0.750 | -3.508 | Likely Benign | 0.158 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -0.85 | Neutral | 0.586 | Possibly Damaging | 0.478 | Possibly Damaging | 4.14 | Benign | 0.01 | Affected | 0.1469 | 0.3122 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2978C>T | P993L 2D AIThe SynGAP1 missense variant P993L is reported in ClinVar as “Not listed” and is not present 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 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 the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise 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 the ClinVar status, which contains no pathogenic assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.923979 | Binding | 0.319 | 0.908 | 0.750 | -3.581 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.028 | Likely Benign | -1.37 | Neutral | 0.224 | Benign | 0.138 | Benign | 4.14 | Benign | 0.01 | Affected | 0.2299 | 0.6697 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3985C>A | L1329M 2D  AIThe SynGAP1 missense change L1329M is recorded in gnomAD (ID 6‑33451859‑C‑A) but has no ClinVar entry. Functional prediction tools split into two consensus groups: benign‑predicted by REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic‑predicted by polyPhen‑2 (HumDiv and 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 further support a benign outcome: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus likewise indicates benign. Foldetta, a protein‑folding stability predictor 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 is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.930790 | Disordered | 0.924905 | Binding | 0.336 | 0.748 | 0.875 | 6-33451859-C-A | -5.493 | Likely Benign | 0.780 | Likely Pathogenic | Likely Benign | 0.087 | Likely Benign | -1.16 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 3.10 | Benign | 0.00 | Affected | 3.77 | 5 | 0.0914 | 0.4273 | 2 | 4 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||
| c.3985C>G | L1329V 2D AIThe SynGAP1 missense variant L1329V is catalogued in gnomAD (6‑33451859‑C‑G) but has no ClinVar entry. Functional prediction tools show mixed results: benign calls come from REVEL, PROVEAN, ESM1b, and FATHMM, whereas pathogenic calls are reported by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. When predictions are grouped by consensus, the majority of standard algorithms (REVEL, PROVEAN, ESM1b, FATHMM) support a benign effect, while a minority (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default) suggest pathogenicity. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts a benign outcome, and the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also favors 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 points to a benign effect, and this conclusion is consistent with the lack of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.930790 | Disordered | 0.924905 | Binding | 0.336 | 0.748 | 0.875 | 6-33451859-C-G | 1 | 6.40e-7 | -4.209 | Likely Benign | 0.770 | Likely Pathogenic | Likely Benign | 0.077 | Likely Benign | -1.55 | Neutral | 0.980 | Probably Damaging | 0.952 | Probably Damaging | 3.18 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1571 | 0.3579 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.3986T>A | L1329Q 2D  AIThe SynGAP1 missense variant L1329Q is reported in gnomAD (ID 6‑33451860‑T‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and FATHMM, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a deleterious effect, indicating that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.930790 | Disordered | 0.924905 | Binding | 0.336 | 0.748 | 0.875 | 6-33451860-T-A | -4.106 | Likely Benign | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.157 | Likely Benign | -3.31 | Deleterious | 0.994 | Probably Damaging | 0.993 | Probably Damaging | 3.05 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1382 | 0.1505 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||
| c.3986T>C | L1329P 2D AIThe SynGAP1 missense variant L1329P is listed in gnomAD (ID 6‑33451860‑T‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and FATHMM, while pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a tie and is therefore inconclusive. No Foldetta stability assessment is available. Overall, the majority of high‑confidence predictors (five pathogenic vs three benign) lean toward a pathogenic effect. Because ClinVar contains no classification, there is no conflict with existing clinical annotation. Thus, based on current in silico evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.930790 | Disordered | 0.924905 | Binding | 0.336 | 0.748 | 0.875 | 6-33451860-T-C | -2.903 | Likely Benign | 0.951 | Likely Pathogenic | Ambiguous | 0.165 | Likely Benign | -3.74 | Deleterious | 0.994 | Probably Damaging | 0.993 | Probably Damaging | 3.04 | Benign | 0.00 | Affected | 3.77 | 5 | 0.3396 | 0.1794 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||
| c.3986T>G | L1329R 2D AIThe SynGAP1 missense variant L1329R is catalogued in gnomAD (ID 6‑33451860‑T‑G) but has no ClinVar submission. Functional prediction tools cluster into two groups: benign predictions from REVEL, ESM1b, and FATHMM; pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized returns an uncertain result. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive due to a 2‑to‑2 split. No Foldetta stability assessment is available. Overall, the majority of high‑confidence predictors (five pathogenic vs three benign) lean toward a pathogenic effect. Because ClinVar contains no classification, there is no conflict with existing clinical annotations. Thus, based on current in silico evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.930790 | Disordered | 0.924905 | Binding | 0.336 | 0.748 | 0.875 | 6-33451860-T-G | -3.636 | Likely Benign | 0.923 | Likely Pathogenic | Ambiguous | 0.141 | Likely Benign | -3.16 | Deleterious | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 3.05 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1594 | 0.1547 | -2 | -3 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||
| c.3019A>C | S1007R 2D AIThe SynGAP1 missense variant S1007R is not reported in ClinVar and has no gnomAD entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give opposing results: AlphaMissense‑Optimized classifies the variant as pathogenic, whereas the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the predictions are split, with an equal number of benign and pathogenic calls, and the high‑accuracy tools disagree. Thus, the variant is most likely pathogenic based on the majority of predictions, and this assessment does not contradict ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.925648 | Binding | 0.295 | 0.899 | 0.750 | -5.441 | Likely Benign | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.211 | Likely Benign | -1.93 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.65 | Benign | 0.01 | Affected | 0.1121 | 0.3237 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3019A>G | S1007G 2D AIThe SynGAP1 missense variant S1007G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. 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 | 0.671169 | Disordered | 0.925648 | Binding | 0.295 | 0.899 | 0.750 | -4.051 | Likely Benign | 0.297 | Likely Benign | Likely Benign | 0.098 | Likely Benign | -1.49 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.73 | Benign | 0.05 | Affected | 0.2361 | 0.4341 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3019A>T | S1007C 2D AIThe SynGAP1 missense variant S1007C is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. 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 uncertain, and Foldetta’s stability prediction is unavailable. Overall, the balance of evidence (four benign versus three pathogenic predictions, with high‑accuracy tools favoring benign) indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.671169 | Disordered | 0.925648 | Binding | 0.295 | 0.899 | 0.750 | -7.399 | In-Between | 0.487 | Ambiguous | Likely Benign | 0.132 | Likely Benign | -1.91 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.61 | Benign | 0.01 | Affected | 0.1405 | 0.5142 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3020G>A | S1007N 2D AIThe SynGAP1 missense variant S1007N is listed in ClinVar (ID 2759915.0) as Benign 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). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the majority of high‑accuracy predictors (including the SGM‑Consensus) indicate a benign impact, and the single uncertain AlphaMissense‑Optimized result does not overturn this consensus. Therefore, 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 | 0.671169 | Disordered | 0.925648 | Binding | 0.295 | 0.899 | 0.750 | Benign | 1 | -5.113 | Likely Benign | 0.803 | Likely Pathogenic | Ambiguous | 0.075 | Likely Benign | -1.54 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.65 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1743 | 0.4342 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||
| 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.3020G>T | S1007I 2D AIThe SynGAP1 missense variant S1007I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default) predict a pathogenic impact. The remaining tools, ESM1b and AlphaMissense‑Optimized, return uncertain results. High‑accuracy assessments further support a deleterious interpretation: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as pathogenic; AlphaMissense‑Optimized remains uncertain, and Foldetta data are unavailable. Overall, the preponderance of evidence from both conventional and high‑accuracy predictors indicates that the S1007I variant is most likely pathogenic, with no conflict with ClinVar status because the variant has not yet been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.671169 | Disordered | 0.925648 | Binding | 0.295 | 0.899 | 0.750 | -7.800 | In-Between | 0.920 | Likely Pathogenic | Ambiguous | 0.126 | Likely Benign | -2.55 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.65 | Benign | 0.00 | Affected | 0.1324 | 0.4769 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3021T>A | S1007R 2D AIThe SynGAP1 missense variant S1007R has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign); pathogenic predictions include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, whereas the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the evidence leans toward a pathogenic interpretation, with no ClinVar status to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.925648 | Binding | 0.295 | 0.899 | 0.750 | -5.441 | Likely Benign | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.219 | Likely Benign | -1.93 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.65 | Benign | 0.01 | Affected | 0.1121 | 0.3237 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3021T>G | S1007R 2D AISynGAP1 missense variant S1007R 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). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, while the SGM‑Consensus (a majority vote of four high‑accuracy predictors) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the evidence is split, with an equal number of benign and pathogenic predictions. The variant is most likely pathogenic based on the presence of several high‑confidence pathogenic calls, and this assessment does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.925648 | Binding | 0.295 | 0.899 | 0.750 | -5.441 | Likely Benign | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.219 | Likely Benign | -1.93 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.65 | Benign | 0.01 | Affected | 0.1121 | 0.3237 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3181G>A | G1061S 2D AIThe SynGAP1 missense variant G1061S is listed in ClinVar (ID 3571724.0) 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 consensus of the majority of prediction tools and the high‑accuracy methods supports a benign classification for G1061S, 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 | 0.978672 | Disordered | 0.926729 | Binding | 0.394 | 0.923 | 0.875 | Uncertain | 1 | -4.891 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.283 | Likely Benign | -0.68 | Neutral | 0.004 | Benign | 0.004 | Benign | 4.00 | Benign | 0.00 | Affected | 0.2404 | 0.5300 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||
| c.3181G>C | G1061R 2D AIThe SynGAP1 missense variant G1061R is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 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 (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it contains two benign and two uncertain calls, and Foldetta results are unavailable. Overall, the balance of evidence favors a benign classification. This conclusion does not contradict ClinVar status, as the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.978672 | Disordered | 0.926729 | Binding | 0.394 | 0.923 | 0.875 | -7.721 | In-Between | 0.343 | Ambiguous | Likely Benign | 0.315 | Likely Benign | -0.17 | Neutral | 0.411 | Benign | 0.132 | Benign | 3.99 | Benign | 0.00 | Affected | 0.1037 | 0.4332 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3181G>T | G1061C 2D AIThe SynGAP1 missense variant G1061C is listed in ClinVar (ID 536997.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33443733‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; Foldetta results are not available. Overall, the majority of evidence (six benign vs. four pathogenic predictions) and the two high‑accuracy tools support a benign classification. This conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978672 | Disordered | 0.926729 | Binding | 0.394 | 0.923 | 0.875 | Conflicting | 2 | 6-33443733-G-T | 6 | 3.73e-6 | -9.511 | Likely Pathogenic | 0.119 | Likely Benign | Likely Benign | 0.409 | Likely Benign | -1.46 | Neutral | 0.938 | Possibly Damaging | 0.665 | Possibly Damaging | 3.97 | Benign | 0.00 | Affected | 4.32 | 2 | 0.1283 | 0.4227 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||
| c.3182G>A | G1061D 2D AIThe SynGAP1 missense variant G1061D is not 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 and ESM1b, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign prediction (2 benign vs. 1 pathogenic, 1 uncertain). Foldetta results are unavailable. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.978672 | Disordered | 0.926729 | Binding | 0.394 | 0.923 | 0.875 | -9.481 | Likely Pathogenic | 0.346 | Ambiguous | Likely Benign | 0.375 | Likely Benign | -1.32 | Neutral | 0.224 | Benign | 0.120 | Benign | 4.01 | Benign | 0.00 | Affected | 0.1671 | 0.2024 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| 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.3182G>T | G1061V 2D AIThe SynGAP1 missense variant G1061V is not 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 further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence indicates that G1061V is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978672 | Disordered | 0.926729 | Binding | 0.394 | 0.923 | 0.875 | -6.709 | Likely Benign | 0.106 | Likely Benign | Likely Benign | 0.307 | Likely Benign | -1.41 | Neutral | 0.224 | Benign | 0.066 | Benign | 3.98 | Benign | 0.00 | Affected | 0.1431 | 0.3684 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.2758C>A | Q920K 2D AIThe SynGAP1 missense variant Q920K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for Q920K, 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 | 0.699094 | Disordered | 0.927260 | Binding | 0.306 | 0.845 | 0.250 | -4.234 | Likely Benign | 0.380 | Ambiguous | Likely Benign | 0.145 | Likely Benign | -1.72 | Neutral | 0.771 | Possibly Damaging | 0.412 | Benign | 2.67 | Benign | 0.00 | Affected | 0.2041 | 0.4331 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2758C>G | Q920E 2D AIThe SynGAP1 missense variant Q920E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to the variant being most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.927260 | Binding | 0.306 | 0.845 | 0.250 | -3.863 | Likely Benign | 0.174 | Likely Benign | Likely Benign | 0.125 | Likely Benign | -1.23 | Neutral | 0.771 | Possibly Damaging | 0.492 | Possibly Damaging | 2.67 | Benign | 0.00 | Affected | 0.1443 | 0.2622 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2759A>C | Q920P 2D AIThe SynGAP1 missense variant Q920P is not 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 unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation. 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 | 0.699094 | Disordered | 0.927260 | Binding | 0.306 | 0.845 | 0.250 | -2.127 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.235 | Likely Benign | -1.68 | Neutral | 0.989 | Probably Damaging | 0.834 | Possibly Damaging | 2.58 | Benign | 0.00 | Affected | 0.2438 | 0.5318 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2759A>G | Q920R 2D AIThe SynGAP1 missense variant Q920R is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a split: benign calls come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and 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 tools further support this view: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus confirms 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 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 | 0.699094 | Disordered | 0.927260 | Binding | 0.306 | 0.845 | 0.250 | -3.170 | Likely Benign | 0.352 | Ambiguous | Likely Benign | 0.168 | Likely Benign | -1.41 | Neutral | 0.961 | Probably Damaging | 0.596 | Possibly Damaging | 2.63 | Benign | 0.00 | Affected | 0.1626 | 0.2369 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.2759A>T | Q920L 2D AIThe SynGAP1 missense variant Q920L is not 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 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 | 0.699094 | Disordered | 0.927260 | Binding | 0.306 | 0.845 | 0.250 | -4.048 | Likely Benign | 0.280 | Likely Benign | Likely Benign | 0.181 | Likely Benign | -2.36 | Neutral | 0.891 | Possibly Damaging | 0.596 | Possibly Damaging | 2.60 | Benign | 0.00 | Affected | 0.0774 | 0.5995 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2760A>C | Q920H 2D AIThe SynGAP1 missense variant Q920H is not 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 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 | 0.699094 | Disordered | 0.927260 | Binding | 0.306 | 0.845 | 0.250 | -3.771 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.079 | Likely Benign | -1.79 | Neutral | 0.989 | Probably Damaging | 0.883 | Possibly Damaging | 2.63 | Benign | 0.00 | Affected | 0.1419 | 0.4334 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2760A>T | Q920H 2D AIThe SynGAP1 missense variant Q920H is not 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 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 | 0.699094 | Disordered | 0.927260 | Binding | 0.306 | 0.845 | 0.250 | -3.771 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.079 | Likely Benign | -1.79 | Neutral | 0.989 | Probably Damaging | 0.883 | Possibly Damaging | 2.63 | Benign | 0.00 | Affected | 0.1419 | 0.4334 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2299A>C | I767L 2D  AIThe SynGAP1 missense variant I767L 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 any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.321458 | Structured | 0.927771 | Binding | 0.369 | 0.872 | 0.125 | -1.881 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.159 | Likely Benign | -0.73 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.13 | Benign | 0.34 | Tolerated | 0.1020 | 0.4317 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.2299A>G | I767V 2D  AIThe SynGAP1 missense variant I767V is listed in ClinVar (ID 1402700.0) with an “Uncertain” clinical significance and is not reported in gnomAD. All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a “Likely Benign” outcome. No tool predicts pathogenicity. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, while Foldetta (combining FoldX‑MD and Rosetta stability predictions) has no available 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 | 0.321458 | Structured | 0.927771 | Binding | 0.369 | 0.872 | 0.125 | Uncertain | 1 | -2.791 | Likely Benign | 0.064 | Likely Benign | Likely Benign | 0.096 | Likely Benign | 0.10 | Neutral | 0.072 | Benign | 0.029 | Benign | 4.21 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1418 | 0.4227 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.2299A>T | I767F 2D  AIThe SynGAP1 missense variant I767F 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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.321458 | Structured | 0.927771 | Binding | 0.369 | 0.872 | 0.125 | -3.618 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.213 | Likely Benign | -1.37 | Neutral | 0.003 | Benign | 0.002 | Benign | 4.04 | Benign | 0.06 | Tolerated | 0.0643 | 0.3567 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2300T>A | I767N 2D  AIThe SynGAP1 missense variant I767N 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) 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 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 | 0.321458 | Structured | 0.927771 | Binding | 0.369 | 0.872 | 0.125 | -5.117 | Likely Benign | 0.541 | Ambiguous | Likely Benign | 0.122 | Likely Benign | -0.16 | Neutral | 0.977 | Probably Damaging | 0.632 | Possibly Damaging | 4.04 | Benign | 0.06 | Tolerated | 0.1039 | 0.1012 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.2300T>C | I767T 2D  AIThe SynGAP1 missense variant I767T is listed in ClinVar (ID 1044161.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags the variant as pathogenic, creating a single discordant prediction. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification, and AlphaMissense‑Optimized also reports benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.321458 | Structured | 0.927771 | Binding | 0.369 | 0.872 | 0.125 | Uncertain | 1 | -3.749 | Likely Benign | 0.252 | Likely Benign | Likely Benign | 0.138 | Likely Benign | -0.78 | Neutral | 0.625 | Possibly Damaging | 0.249 | Benign | 4.12 | Benign | 0.46 | Tolerated | 3.64 | 6 | 0.1274 | 0.1889 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||||||||
| c.2300T>G | I767S 2D  AIThe SynGAP1 missense variant I767S is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster around a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign. Only polyPhen‑2 HumDiv flags it as pathogenic, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are not available. Taken together, the preponderance of evidence points to a benign classification for I767S, 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 | 0.321458 | Structured | 0.927771 | Binding | 0.369 | 0.872 | 0.125 | -3.030 | Likely Benign | 0.388 | Ambiguous | Likely Benign | 0.126 | Likely Benign | -0.64 | Neutral | 0.925 | Possibly Damaging | 0.329 | Benign | 4.13 | Benign | 0.25 | Tolerated | 0.3242 | 0.1782 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2301C>G | I767M 2D  AIThe SynGAP1 missense variant I767M 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 reinforce the benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence supports a benign classification for I767M, and this conclusion does not contradict any ClinVar annotation, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.321458 | Structured | 0.927771 | Binding | 0.369 | 0.872 | 0.125 | -2.384 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -0.60 | Neutral | 0.835 | Possibly Damaging | 0.486 | Possibly Damaging | 4.05 | Benign | 0.11 | Tolerated | 0.0788 | 0.3377 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2302G>A | D768N 2D AIThe SynGAP1 missense variant D768N is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33442460‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus is “Likely Benign,” and Foldetta data are unavailable. Overall, the consensus of available predictions indicates that the variant is most likely benign, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.332115 | Structured | 0.928237 | Binding | 0.314 | 0.877 | 0.250 | Uncertain | 1 | 6-33442460-G-A | 2 | 2.57e-6 | -6.892 | Likely Benign | 0.453 | Ambiguous | Likely Benign | 0.048 | Likely Benign | -0.77 | Neutral | 0.106 | Benign | 0.009 | Benign | 4.07 | Benign | 0.96 | Tolerated | 3.64 | 6 | 0.1178 | 0.7843 | 1 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||
| c.2302G>C | D768H 2D AIThe SynGAP1 D768H missense variant is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD: not present). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign), and Foldetta results are unavailable. Overall, the majority of predictions (5 benign vs. 4 pathogenic) and the high‑accuracy benign call suggest the variant is most likely benign, with no ClinVar status to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.332115 | Structured | 0.928237 | Binding | 0.314 | 0.877 | 0.250 | -8.673 | Likely Pathogenic | 0.783 | Likely Pathogenic | Likely Benign | 0.160 | Likely Benign | -1.85 | Neutral | 0.966 | Probably Damaging | 0.737 | Possibly Damaging | 4.03 | Benign | 0.12 | Tolerated | 0.1450 | 0.8136 | 1 | -1 | 0.3 | 22.05 | ||||||||||||||||||||||||||||||||||||||||
| c.2302G>T | D768Y 2D AIThe SynGAP1 missense variant D768Y is listed in ClinVar with status “Uncertain” (ClinVar ID 1061652.0) and is present in gnomAD (variant ID 6‑33442460‑G‑T). 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 (combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic impact, which does not contradict the ClinVar designation of uncertainty. 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 | 0.332115 | Structured | 0.928237 | Binding | 0.314 | 0.877 | 0.250 | Uncertain | 1 | 6-33442460-G-T | -9.866 | Likely Pathogenic | 0.824 | Likely Pathogenic | Ambiguous | 0.234 | Likely Benign | -2.86 | Deleterious | 0.989 | Probably Damaging | 0.806 | Possibly Damaging | 4.01 | Benign | 0.07 | Tolerated | 3.64 | 6 | 0.0581 | 0.7525 | -4 | -3 | 2.2 | 48.09 | ||||||||||||||||||||||||||||||||||
| c.2303A>C | D768A 2D AIThe SynGAP1 D768A variant is listed in gnomAD (ID 6‑33442461‑A‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM) and pathogenic predictions (ESM1b, AlphaMissense‑Default). AlphaMissense‑Optimized returns an uncertain result. 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 2‑vs‑2 tie and thus unavailable; Foldetta stability analysis is not reported. Overall, the preponderance of evidence (six benign vs two pathogenic) points to a benign effect. This conclusion does not contradict ClinVar, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.332115 | Structured | 0.928237 | Binding | 0.314 | 0.877 | 0.250 | 6-33442461-A-C | -8.153 | Likely Pathogenic | 0.786 | Likely Pathogenic | Ambiguous | 0.174 | Likely Benign | -1.84 | Neutral | 0.245 | Benign | 0.096 | Benign | 4.09 | Benign | 0.14 | Tolerated | 3.64 | 6 | 0.3924 | 0.7662 | -2 | 0 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||||
| c.2303A>G | D768G 2D AIThe SynGAP1 D768G missense variant is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized all predict benign, whereas AlphaMissense‑Default predicts pathogenic. The high‑accuracy AlphaMissense‑Optimized result is benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a benign classification (2 benign vs. 1 pathogenic, with one uncertain). Foldetta, which would provide a protein‑folding stability assessment, has no available output for this variant. Overall, the preponderance of evidence points to a benign effect, 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. | 0.332115 | Structured | 0.928237 | Binding | 0.314 | 0.877 | 0.250 | -7.150 | In-Between | 0.697 | Likely Pathogenic | Likely Benign | 0.184 | Likely Benign | 0.03 | Neutral | 0.393 | Benign | 0.131 | Benign | 4.09 | Benign | 0.72 | Tolerated | 0.4130 | 0.7476 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2303A>T | D768V 2D AIThe SynGAP1 D768V variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Based on the preponderance of pathogenic predictions and the SGM‑Consensus result, the variant is most likely pathogenic; this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.332115 | Structured | 0.928237 | Binding | 0.314 | 0.877 | 0.250 | -9.528 | Likely Pathogenic | 0.880 | Likely Pathogenic | Ambiguous | 0.164 | Likely Benign | -2.62 | Deleterious | 0.611 | Possibly Damaging | 0.140 | Benign | 4.04 | Benign | 0.02 | Affected | 0.0802 | 0.8019 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| 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.2305C>A | L769I 2D AIThe SynGAP1 missense variant L769I is listed in gnomAD (ID 6‑33442463‑C‑A) but has no ClinVar entry. Functional 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. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.411940 | Structured | 0.928432 | Binding | 0.367 | 0.883 | 0.250 | 6-33442463-C-A | -3.993 | Likely Benign | 0.110 | Likely Benign | Likely Benign | 0.099 | Likely Benign | -0.15 | Neutral | 0.836 | Possibly Damaging | 0.329 | Benign | 4.09 | Benign | 0.04 | Affected | 3.64 | 6 | 0.0800 | 0.3108 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||||||||
| c.2305C>G | L769V 2D AIThe SynGAP1 missense variant L769V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags it as pathogenic, but this is the sole discordant call. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.411940 | Structured | 0.928432 | Binding | 0.367 | 0.883 | 0.250 | -4.585 | Likely Benign | 0.106 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -0.41 | Neutral | 0.625 | Possibly Damaging | 0.249 | Benign | 4.04 | Benign | 0.25 | Tolerated | 0.1364 | 0.2558 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2305C>T | L769F 2D AIThe SynGAP1 missense variant L769F is listed in ClinVar (ID 3617309.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑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, is “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority of the high‑accuracy tools) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions—including the high‑accuracy tools—suggest the variant is most likely benign, which is consistent with its ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.411940 | Structured | 0.928432 | Binding | 0.367 | 0.883 | 0.250 | Uncertain | 1 | -5.044 | Likely Benign | 0.146 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -0.89 | Neutral | 0.925 | Possibly Damaging | 0.510 | Possibly Damaging | 3.94 | Benign | 0.02 | Affected | 0.0554 | 0.2881 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||
| c.2306T>A | L769H 2D AIThe SynGAP1 missense variant L769H is not 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, all of which classify the variant as benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT, all of which report the variant as pathogenic. 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 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 because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.411940 | Structured | 0.928432 | Binding | 0.367 | 0.883 | 0.250 | -6.038 | Likely Benign | 0.422 | Ambiguous | Likely Benign | 0.235 | Likely Benign | -1.96 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 0.1016 | 0.0828 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||||||
| c.2306T>C | L769P 2D AIThe SynGAP1 missense variant L769P is not 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 this 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 | 0.411940 | Structured | 0.928432 | Binding | 0.367 | 0.883 | 0.250 | -6.261 | Likely Benign | 0.338 | Likely Benign | Likely Benign | 0.200 | Likely Benign | -1.75 | Neutral | 0.925 | Possibly Damaging | 0.427 | Benign | 3.90 | Benign | 0.00 | Affected | 0.3573 | 0.1323 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2306T>G | L769R 2D AIThe SynGAP1 missense variant L769R is not 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‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. 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 | 0.411940 | Structured | 0.928432 | Binding | 0.367 | 0.883 | 0.250 | -6.245 | Likely Benign | 0.493 | Ambiguous | Likely Benign | 0.206 | Likely Benign | -1.66 | Neutral | 0.003 | Benign | 0.006 | Benign | 3.91 | Benign | 0.00 | Affected | 0.1286 | 0.0702 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3043A>C | T1015P 2D AIThe SynGAP1 missense variant T1015P 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 indicates 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 for T1015P, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.928486 | Binding | 0.295 | 0.823 | 0.625 | -1.796 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.154 | Likely Benign | -0.15 | Neutral | 0.586 | Possibly Damaging | 0.223 | Benign | 2.53 | Benign | 0.18 | Tolerated | 0.2176 | 0.4504 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3043A>G | T1015A 2D AIThe SynGAP1 missense variant T1015A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign effect. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is benign, and this conclusion does not contradict any ClinVar status (none reported). 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 | 0.928486 | Binding | 0.295 | 0.823 | 0.625 | -2.615 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -0.07 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.73 | Benign | 0.54 | Tolerated | 0.3960 | 0.3949 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3043A>T | T1015S 2D AIThe SynGAP1 missense variant T1015S 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 | 0.788093 | Disordered | 0.928486 | Binding | 0.295 | 0.823 | 0.625 | -2.561 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.090 | Likely Benign | 0.61 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.70 | Benign | 0.86 | Tolerated | 0.3545 | 0.4232 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| 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.3044C>G | T1015S 2D AIThe SynGAP1 missense variant T1015S 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 | 0.788093 | Disordered | 0.928486 | Binding | 0.295 | 0.823 | 0.625 | -2.561 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.040 | Likely Benign | 0.61 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.70 | Benign | 0.86 | Tolerated | 0.3545 | 0.4232 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| 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.2956G>A | E986K 2D AIThe SynGAP1 missense variant E986K 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 PROVEAN, while those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The remaining tools, ESM1b and AlphaMissense‑Optimized, return uncertain results and are not considered evidence for either side. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a pathogenic verdict (2 pathogenic vs. 1 benign, with one uncertain). 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 classify the variant as 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. | 0.750527 | Disordered | 0.929726 | Binding | 0.349 | 0.902 | 0.750 | -7.174 | In-Between | 0.950 | Likely Pathogenic | Ambiguous | 0.164 | Likely Benign | -2.19 | Neutral | 0.924 | Possibly Damaging | 0.722 | Possibly Damaging | 2.15 | Pathogenic | 0.00 | Affected | 0.2760 | 0.7973 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||||
| c.2956G>C | E986Q 2D AIThe SynGAP1 missense variant E986Q is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (five pathogenic vs. three benign) lean toward a pathogenic interpretation. This assessment does not contradict ClinVar status, as the variant is not yet catalogued there. Thus, based on current computational evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.750527 | Disordered | 0.929726 | Binding | 0.349 | 0.902 | 0.750 | -4.471 | Likely Benign | 0.839 | Likely Pathogenic | Ambiguous | 0.160 | Likely Benign | -1.66 | Neutral | 0.974 | Probably Damaging | 0.842 | Possibly Damaging | 2.14 | Pathogenic | 0.00 | Affected | 0.1700 | 0.7589 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||||
| c.2957A>C | E986A 2D AIThe SynGAP1 missense variant E986A is not 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 ESM1b, whereas tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split; Foldetta stability analysis is unavailable. Overall, the evidence is evenly divided, with no clear majority. Based on the current 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. | 0.750527 | Disordered | 0.929726 | Binding | 0.349 | 0.902 | 0.750 | -4.653 | Likely Benign | 0.895 | Likely Pathogenic | Ambiguous | 0.160 | Likely Benign | -2.32 | Neutral | 0.552 | Possibly Damaging | 0.388 | Benign | 2.14 | Pathogenic | 0.00 | Affected | 0.4207 | 0.7733 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2957A>G | E986G 2D AIThe SynGAP1 missense variant E986G 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. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as likely pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic effect, and this assessment does not conflict with the ClinVar status, which currently contains no classification for E986G. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.750527 | Disordered | 0.929726 | Binding | 0.349 | 0.902 | 0.750 | -5.584 | Likely Benign | 0.834 | Likely Pathogenic | Ambiguous | 0.219 | Likely Benign | -3.14 | Deleterious | 0.924 | Possibly Damaging | 0.784 | Possibly Damaging | 2.13 | Pathogenic | 0.00 | Affected | 0.2866 | 0.6225 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.2957A>T | E986V 2D AIThe SynGAP1 E986V missense variant is not reported in ClinVar and has no gnomAD entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b, whereas pathogenic predictions arise from PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (benign), FATHMM (pathogenic), and PROVEAN (pathogenic)—also indicates pathogenic. Foldetta, a protein‑folding stability method that integrates 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 pathogenic effect for E986V, 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 | 0.750527 | Disordered | 0.929726 | Binding | 0.349 | 0.902 | 0.750 | -4.511 | Likely Benign | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.220 | Likely Benign | -3.48 | Deleterious | 0.018 | Benign | 0.028 | Benign | 2.10 | Pathogenic | 0.00 | Affected | 0.1146 | 0.7960 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.2958G>C | E986D 2D AIThe SynGAP1 missense variant E986D is not 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. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, 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 (two pathogenic vs two benign votes) and Foldetta results are unavailable. Overall, the majority of conventional tools lean toward pathogenicity, but the single high‑accuracy benign prediction and the inconclusive consensus leave the variant’s impact uncertain. There is no contradiction 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. | 0.750527 | Disordered | 0.929726 | Binding | 0.349 | 0.902 | 0.750 | -4.001 | Likely Benign | 0.628 | Likely Pathogenic | Likely Benign | 0.129 | Likely Benign | -1.22 | Neutral | 0.974 | Probably Damaging | 0.715 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | 0.2081 | 0.5364 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2958G>T | E986D 2D AIThe SynGAP1 missense variant E986D is not 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. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, 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 (two pathogenic vs two benign votes) and Foldetta results are unavailable. Overall, the majority of conventional tools lean toward pathogenicity, but the single high‑accuracy benign prediction and the inconclusive consensus leave the variant’s impact uncertain. There is no contradiction 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. | 0.750527 | Disordered | 0.929726 | Binding | 0.349 | 0.902 | 0.750 | -4.001 | Likely Benign | 0.628 | Likely Pathogenic | Likely Benign | 0.129 | Likely Benign | -1.22 | Neutral | 0.974 | Probably Damaging | 0.715 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | 0.2081 | 0.5364 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2980A>C | K994Q 2D AIThe SynGAP1 missense variant K994Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.930054 | Binding | 0.289 | 0.912 | 0.750 | -1.947 | Likely Benign | 0.124 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -0.45 | Neutral | 0.002 | Benign | 0.004 | Benign | 4.16 | Benign | 0.03 | Affected | 0.4975 | 0.1889 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2980A>G | K994E 2D AIThe SynGAP1 missense variant K994E is reported in gnomAD (variant ID 6‑33443532‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of tools, including the high‑accuracy methods, points to a benign impact. 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 | 0.862302 | Disordered | 0.930054 | Binding | 0.289 | 0.912 | 0.750 | 6-33443532-A-G | 1 | 6.20e-7 | -2.587 | Likely Benign | 0.339 | Likely Benign | Likely Benign | 0.057 | Likely Benign | -0.58 | Neutral | 0.036 | Benign | 0.039 | Benign | 4.14 | Benign | 0.02 | Affected | 4.32 | 2 | 0.4148 | 0.1699 | 1 | 0 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||||||
| c.2981A>C | K994T 2D AIThe SynGAP1 missense variant K994T is not 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. Taken together, the majority of evidence points to a benign effect. There is no conflict with ClinVar status, as no ClinVar classification exists 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 | 0.862302 | Disordered | 0.930054 | Binding | 0.289 | 0.912 | 0.750 | -2.346 | Likely Benign | 0.226 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -1.22 | Neutral | 0.144 | Benign | 0.085 | Benign | 4.09 | Benign | 0.01 | Affected | 0.2503 | 0.4248 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||||||
| c.2981A>G | K994R 2D AIThe SynGAP1 missense variant K994R is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.930054 | Binding | 0.289 | 0.912 | 0.750 | -1.990 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.071 | Likely Benign | 0.02 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.21 | Benign | 0.47 | Tolerated | 0.5064 | 0.1657 | Weaken | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||||||||||
| c.2981A>T | K994M 2D AIThe SynGAP1 missense variant K994M is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign. Pathogenicity is suggested only by polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as likely benign, and AlphaMissense‑Optimized also predicts benign. No Foldetta stability analysis is available. Overall, the majority of evidence points to a benign impact, and this assessment does not conflict with ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.930054 | Binding | 0.289 | 0.912 | 0.750 | -2.974 | Likely Benign | 0.424 | Ambiguous | Likely Benign | 0.057 | Likely Benign | -1.21 | Neutral | 0.589 | Possibly Damaging | 0.187 | Benign | 4.04 | Benign | 0.00 | Affected | 0.1612 | 0.4395 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.2982G>C | K994N 2D AIThe SynGAP1 missense variant K994N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the only pathogenic call comes from SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, SGM‑Consensus confirms a Likely Benign status, and Foldetta data are unavailable. Taken together, the preponderance of evidence indicates that K994N 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 | 0.862302 | Disordered | 0.930054 | Binding | 0.289 | 0.912 | 0.750 | -3.724 | Likely Benign | 0.519 | Ambiguous | Likely Benign | 0.011 | Likely Benign | -0.73 | Neutral | 0.255 | Benign | 0.113 | Benign | 4.09 | Benign | 0.01 | Affected | 0.4010 | 0.2376 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2982G>T | K994N 2D AIThe SynGAP1 missense variant K994N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the only pathogenic call comes from SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, SGM‑Consensus confirms a Likely Benign status, and Foldetta data are unavailable. Taken together, the preponderance of evidence indicates that K994N 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 | 0.862302 | Disordered | 0.930054 | Binding | 0.289 | 0.912 | 0.750 | -3.724 | Likely Benign | 0.519 | Ambiguous | Likely Benign | 0.009 | Likely Benign | -0.73 | Neutral | 0.255 | Benign | 0.113 | Benign | 4.09 | Benign | 0.01 | Affected | 0.4010 | 0.2376 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3016T>A | Y1006N 2D  AIThe SynGAP1 missense variant Y1006N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic 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 Uncertain, and the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.801317 | Disordered | 0.930554 | Binding | 0.264 | 0.896 | 0.750 | -4.238 | Likely Benign | 0.789 | Likely Pathogenic | Ambiguous | 0.118 | Likely Benign | -0.75 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.73 | Benign | 0.75 | Tolerated | 0.2168 | 0.1094 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||||||||||||
| c.3016T>C | Y1006H 2D  AIThe SynGAP1 missense variant Y1006H is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, 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 | 0.801317 | Disordered | 0.930554 | Binding | 0.264 | 0.896 | 0.750 | -3.095 | Likely Benign | 0.863 | Likely Pathogenic | Ambiguous | 0.116 | Likely Benign | -0.42 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.70 | Benign | 0.17 | Tolerated | 0.2406 | 0.0894 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||||||||||||
| c.3016T>G | Y1006D 2D  AIThe SynGAP1 missense variant Y1006D is catalogued in gnomAD (variant ID 6‑33443568‑T‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM. Those that predict a pathogenic impact are PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” AlphaMissense‑Optimized is uncertain, and no Foldetta (FoldX‑MD/ Rosetta) stability data are available. Considering the high‑accuracy consensus, the variant is most likely benign; 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 | 0.801317 | Disordered | 0.930554 | Binding | 0.264 | 0.896 | 0.750 | 6-33443568-T-G | -5.296 | Likely Benign | 0.898 | Likely Pathogenic | Ambiguous | 0.196 | Likely Benign | -1.53 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.73 | Benign | 0.56 | Tolerated | 3.77 | 5 | 0.3776 | 0.1094 | -3 | -4 | -2.2 | -48.09 | ||||||||||||||||||||||||||||||||||||
| c.3017A>C | Y1006S 2D  AIThe SynGAP1 missense variant Y1006S has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, 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 majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which has no entry for Y1006S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.801317 | Disordered | 0.930554 | Binding | 0.264 | 0.896 | 0.750 | -2.522 | Likely Benign | 0.582 | Likely Pathogenic | Likely Benign | 0.170 | Likely Benign | -0.58 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.83 | Benign | 0.90 | Tolerated | 0.4426 | 0.2274 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||||
| c.3017A>G | Y1006C 2D  AIThe SynGAP1 missense variant Y1006C is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability analysis 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 a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.801317 | Disordered | 0.930554 | Binding | 0.264 | 0.896 | 0.750 | -5.244 | Likely Benign | 0.589 | Likely Pathogenic | Likely Benign | 0.156 | Likely Benign | -1.39 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.68 | Benign | 0.08 | Tolerated | 0.3062 | 0.2358 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||||||||||||
| c.3017A>T | Y1006F 2D  AIThe SynGAP1 missense variant Y1006F 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 methods 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 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 | 0.801317 | Disordered | 0.930554 | Binding | 0.264 | 0.896 | 0.750 | -3.362 | Likely Benign | 0.304 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -1.06 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.71 | Benign | 0.10 | Tolerated | 0.2423 | 0.3339 | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3922C>A | R1308S 2D AIThe SynGAP1 missense variant R1308S 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, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The high‑accuracy AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evaluated tools (five pathogenic vs. three benign) indicate a pathogenic effect. This prediction is not contradicted by ClinVar status, which has no entry for the variant. Thus, based on current computational evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.741537 | Disordered | 0.930652 | Binding | 0.378 | 0.904 | 0.750 | -2.180 | Likely Benign | 0.419 | Ambiguous | Likely Benign | 0.307 | Likely Benign | -3.76 | Deleterious | 0.982 | Probably Damaging | 0.982 | Probably Damaging | 2.36 | Pathogenic | 0.00 | Affected | 0.3070 | 0.4744 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3922C>G | R1308G 2D AIThe SynGAP1 missense variant R1308G is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs. two pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic interpretation. This assessment does not contradict any 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. | 0.741537 | Disordered | 0.930652 | Binding | 0.378 | 0.904 | 0.750 | -2.503 | Likely Benign | 0.180 | Likely Benign | Likely Benign | 0.300 | Likely Benign | -4.34 | Deleterious | 0.982 | Probably Damaging | 0.982 | Probably Damaging | 2.33 | Pathogenic | 0.00 | Affected | 0.3528 | 0.3830 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3922C>T | R1308C 2D  AIThe SynGAP1 missense variant R1308C is listed in ClinVar with an “Uncertain” significance and is present in the gnomAD database (ID 6‑33451796‑C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact, and this assessment does not contradict the current ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.741537 | Disordered | 0.930652 | Binding | 0.378 | 0.904 | 0.750 | Conflicting | 2 | 6-33451796-C-T | 4 | 2.48e-6 | -4.994 | Likely Benign | 0.421 | Ambiguous | Likely Benign | 0.352 | Likely Benign | -4.89 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 2.31 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.3139 | 0.4274 | -4 | -3 | 7.0 | -53.05 | |||||||||||||||||||||||||||||||||
| c.3923G>A | R1308H 2D  AIThe SynGAP1 missense variant R1308H (ClinVar ID 1996244.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33451797‑G‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessment shows AlphaMissense‑Optimized predicts a benign outcome; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive, and Foldetta results are unavailable. Consequently, the overall computational evidence leans toward a pathogenic interpretation, but the presence of a single high‑accuracy benign prediction and the inconclusive SGM Consensus leave the variant’s effect uncertain. This computational assessment does not contradict the ClinVar status, which remains Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.741537 | Disordered | 0.930652 | Binding | 0.378 | 0.904 | 0.750 | Uncertain | 1 | 6-33451797-G-A | 3 | 1.86e-6 | -3.586 | Likely Benign | 0.201 | Likely Benign | Likely Benign | 0.319 | Likely Benign | -3.12 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 2.33 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2955 | 0.2515 | 2 | 0 | 1.3 | -19.05 | |||||||||||||||||||||||||||||||||
| c.3923G>C | R1308P 2D AIThe SynGAP1 missense variant R1308P is not reported in ClinVar but is present in gnomAD (ID 6‑33451797‑G‑C). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a 2‑vs‑2 split and therefore inconclusive. Foldetta, a protein‑folding stability method that combines FoldX‑MD and Rosetta outputs, has no available result for this variant. Because the available predictions are evenly divided between benign and pathogenic, the overall computational assessment is inconclusive; the variant is neither clearly benign nor clearly pathogenic. This lack of consensus does not contradict ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.741537 | Disordered | 0.930652 | Binding | 0.378 | 0.904 | 0.750 | 6-33451797-G-C | -1.320 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.158 | Likely Benign | -4.62 | Deleterious | 0.995 | Probably Damaging | 0.992 | Probably Damaging | 2.32 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2070 | 0.5020 | -2 | 0 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||
| c.3923G>T | R1308L 2D AIThe SynGAP1 missense variant R1308L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic impact. This assessment 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. | 0.741537 | Disordered | 0.930652 | Binding | 0.378 | 0.904 | 0.750 | -1.838 | Likely Benign | 0.257 | Likely Benign | Likely Benign | 0.360 | Likely Benign | -4.04 | Deleterious | 0.982 | Probably Damaging | 0.982 | Probably Damaging | 2.39 | Pathogenic | 0.00 | Affected | 0.1751 | 0.4930 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3988C>A | Q1330K 2D AIThe SynGAP1 missense variant Q1330K is catalogued in gnomAD (ID 6‑33451862‑C‑A) but has no ClinVar entry. Functional prediction tools split in two groups: benign calls come from REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic calls come from polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” status, reflecting the majority of benign predictions. High‑accuracy assessments reinforce 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 preponderance of evidence—including the high‑accuracy tools—suggests that Q1330K 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 | 0.943310 | Disordered | 0.931969 | Binding | 0.369 | 0.752 | 0.875 | 6-33451862-C-A | -4.120 | Likely Benign | 0.605 | Likely Pathogenic | Likely Benign | 0.027 | Likely Benign | -1.52 | Neutral | 0.544 | Possibly Damaging | 0.259 | Benign | 3.98 | Benign | 0.04 | Affected | 3.77 | 5 | 0.1607 | 0.4127 | 1 | 1 | -0.4 | 0.04 | ||||||||||||||||||||||||||||||||||||
| c.3988C>G | Q1330E 2D AIThe SynGAP1 missense variant Q1330E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus also reports likely benign; Foldetta results are unavailable. Overall, the consensus of the available predictions points to a benign impact, and this is consistent with the lack of ClinVar evidence, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.943310 | Disordered | 0.931969 | Binding | 0.369 | 0.752 | 0.875 | -3.428 | Likely Benign | 0.281 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -1.12 | Neutral | 0.613 | Possibly Damaging | 0.240 | Benign | 3.98 | Benign | 0.06 | Tolerated | 0.1346 | 0.2409 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3989A>C | Q1330P 2D AIThe SynGAP1 missense variant Q1330P is listed in gnomAD (ID 6‑33451863‑A‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM; pathogenic predictions come from polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments are mixed: AlphaMissense‑Optimized yields an “Uncertain” result, SGM‑Consensus confirms a benign leaning, and Foldetta (combining FoldX‑MD and Rosetta outputs) is not available for this variant. Overall, the balance of evidence favors 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 | 0.943310 | Disordered | 0.931969 | Binding | 0.369 | 0.752 | 0.875 | 6-33451863-A-C | -3.087 | Likely Benign | 0.814 | Likely Pathogenic | Ambiguous | 0.076 | Likely Benign | -2.45 | Neutral | 0.898 | Possibly Damaging | 0.441 | Benign | 3.91 | Benign | 0.03 | Affected | 3.77 | 5 | 0.2266 | 0.4983 | -1 | 0 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||||||||
| c.3989A>G | Q1330R 2D AIThe SynGAP1 missense variant Q1330R is listed in gnomAD (ID 6‑33451863‑A‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is reported). 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 | 6-33451863-A-G | -3.601 | Likely Benign | 0.472 | Ambiguous | Likely Benign | 0.031 | Likely Benign | -1.65 | Neutral | 0.898 | Possibly Damaging | 0.341 | Benign | 3.95 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1349 | 0.2333 | 1 | 1 | -1.0 | 28.06 | ||||||||||||||||||||||||||||||||||||
| c.3989A>T | Q1330L 2D AIThe SynGAP1 missense variant Q1330L is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, 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 yields a benign prediction. 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 no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.943310 | Disordered | 0.931969 | Binding | 0.369 | 0.752 | 0.875 | -3.780 | Likely Benign | 0.417 | Ambiguous | Likely Benign | 0.110 | Likely Benign | -2.74 | Deleterious | 0.784 | Possibly Damaging | 0.341 | Benign | 3.92 | Benign | 0.02 | Affected | 0.0741 | 0.5480 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||||||||||||
| 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.2860C>A | P954T 2D AIThe SynGAP1 missense variant P954T is not 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 | 0.984159 | Disordered | 0.932268 | Binding | 0.465 | 0.926 | 0.750 | -5.657 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -0.77 | Neutral | 0.977 | Probably Damaging | 0.856 | Possibly Damaging | 2.79 | Benign | 0.48 | Tolerated | 0.1860 | 0.6324 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2860C>G | P954A 2D AIThe SynGAP1 missense variant P954A is not 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. There is no ClinVar classification to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984159 | Disordered | 0.932268 | Binding | 0.465 | 0.926 | 0.750 | -4.985 | Likely Benign | 0.051 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -0.21 | Neutral | 0.856 | Possibly Damaging | 0.652 | Possibly Damaging | 2.91 | Benign | 0.90 | Tolerated | 0.3103 | 0.5550 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2860C>T | P954S 2D AIThe SynGAP1 missense variant P954S is listed in ClinVar as Benign (ClinVar ID 833606.0) and is present in gnomAD (ID 6‑33443412‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus 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, which is consistent with the ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984159 | Disordered | 0.932268 | Binding | 0.465 | 0.926 | 0.750 | Likely Benign | 1 | 6-33443412-C-T | 1 | 6.20e-7 | -3.525 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -0.25 | Neutral | 0.954 | Possibly Damaging | 0.812 | Possibly Damaging | 2.87 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.3088 | 0.5619 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||
| c.2861C>A | P954H 2D AIThe SynGAP1 missense variant P954H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar or gnomAD entries—there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984159 | Disordered | 0.932268 | Binding | 0.465 | 0.926 | 0.750 | -3.670 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.098 | Likely Benign | -0.50 | Neutral | 0.041 | Benign | 0.067 | Benign | 2.75 | Benign | 0.04 | Affected | 0.2054 | 0.4756 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2861C>G | P954R 2D AIThe SynGAP1 missense variant P954R is not 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, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that P954R 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 | 0.984159 | Disordered | 0.932268 | Binding | 0.465 | 0.926 | 0.750 | -6.329 | Likely Benign | 0.160 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -1.19 | Neutral | 0.954 | Possibly Damaging | 0.826 | Possibly Damaging | 2.78 | Benign | 0.11 | Tolerated | 0.1548 | 0.3940 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2861C>T | P954L 2D AIThe SynGAP1 missense variant P954L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict it to be pathogenic. 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 is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984159 | Disordered | 0.932268 | Binding | 0.465 | 0.926 | 0.750 | -5.607 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.43 | Neutral | 0.977 | Probably Damaging | 0.812 | Possibly Damaging | 2.78 | Benign | 0.55 | Tolerated | 0.2346 | 0.5867 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3961C>A | P1321T 2D AIThe SynGAP1 missense variant P1321T is catalogued in gnomAD (ID 6‑33451835‑C‑A) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the variant as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and this conclusion is consistent with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.933505 | Binding | 0.463 | 0.828 | 0.875 | 6-33451835-C-A | -4.946 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.058 | Likely Benign | 1.07 | Neutral | 0.115 | Benign | 0.012 | Benign | 4.25 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2016 | 0.5901 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3961C>G | P1321A 2D AIThe SynGAP1 missense variant P1321A is reported in gnomAD (ID 6‑33451835‑C‑G) and has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.933505 | Binding | 0.463 | 0.828 | 0.875 | 6-33451835-C-G | -4.411 | Likely Benign | 0.051 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.33 | Neutral | 0.001 | Benign | 0.000 | Benign | 4.29 | Benign | 0.42 | Tolerated | 3.77 | 5 | 0.3615 | 0.4716 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||
| c.3961C>T | P1321S 2D AIThe SynGAP1 missense variant P1321S is listed in ClinVar (ID 1806027.0) with an “Uncertain” clinical significance and is present in the gnomAD database (gnomAD ID 6‑33451835‑C‑T). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic prediction. High‑accuracy assessments corroborate this benign trend: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign effect, which is consistent with the ClinVar “Uncertain” designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.933505 | Binding | 0.463 | 0.828 | 0.875 | Uncertain | 2 | 6-33451835-C-T | 10 | 6.46e-6 | -4.897 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.049 | Likely Benign | 0.68 | Neutral | 0.028 | Benign | 0.004 | Benign | 4.27 | Benign | 0.71 | Tolerated | 3.77 | 5 | 0.3610 | 0.5190 | 1 | -1 | 0.8 | -10.04 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.3962C>A | P1321Q 2D AIThe SynGAP1 missense variant P1321Q is listed in ClinVar (ID 833687.0) as benign and is present in gnomAD (variant ID 6‑33451836‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification, and AlphaMissense‑Optimized also reports benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence—including the high‑confidence SGM consensus and AlphaMissense‑Optimized—supports a benign impact. This conclusion aligns with the ClinVar benign status, with no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.933505 | Binding | 0.463 | 0.828 | 0.875 | Benign | 1 | 6-33451836-C-A | 1 | 6.58e-7 | -5.594 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.74 | Neutral | 0.659 | Possibly Damaging | 0.034 | Benign | 4.24 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.1839 | 0.4884 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||
| c.3962C>G | P1321R 2D AIThe SynGAP1 missense variant P1321R is reported in gnomAD (ID 6‑33451836‑C‑G) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool examined—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classifies the substitution as benign. No pathogenic predictions are present. Grouping the results, the benign consensus is unanimous; the pathogenic group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign status. Foldetta stability analysis is not available for this variant. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.933505 | Binding | 0.463 | 0.828 | 0.875 | 6-33451836-C-G | 1 | 6.58e-7 | -5.310 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.034 | Likely Benign | -1.10 | Neutral | 0.389 | Benign | 0.024 | Benign | 4.25 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.1722 | 0.3635 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||
| c.3962C>T | P1321L 2D AIThe SynGAP1 missense variant P1321L is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.933505 | Binding | 0.463 | 0.828 | 0.875 | -4.892 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -0.81 | Neutral | 0.115 | Benign | 0.009 | Benign | 4.28 | Benign | 0.08 | Tolerated | 0.2626 | 0.6222 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.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.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.3139T>G | S1047A 2D AIThe SynGAP1 missense variant S1047A 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 indicates that 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 | 0.963420 | Disordered | 0.933764 | Binding | 0.409 | 0.909 | 0.750 | -3.503 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.040 | Likely Benign | -0.50 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.65 | Benign | 0.07 | Tolerated | 0.4460 | 0.5548 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3140C>T | S1047L 2D  AIThe SynGAP1 missense variant S1047L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443692‑C‑T). 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 interpretation: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign. Foldetta stability analysis is not available for this variant. Overall, the preponderance of computational evidence points to a benign effect, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.963420 | Disordered | 0.933764 | Binding | 0.409 | 0.909 | 0.750 | Uncertain | 1 | 6-33443692-C-T | 1 | 6.20e-7 | -4.062 | Likely Benign | 0.132 | Likely Benign | Likely Benign | 0.032 | Likely Benign | -0.63 | Neutral | 0.144 | Benign | 0.058 | Benign | 2.60 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1575 | 0.5555 | -2 | -3 | 4.6 | 26.08 | ||||||||||||||||||||||||||||||||
| c.3328A>C | S1110R 2D AIThe SynGAP1 missense variant S1110R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the balance of evidence (six benign versus three pathogenic predictions) indicates that the variant is most likely benign. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.912647 | Disordered | 0.934156 | Binding | 0.346 | 0.892 | 0.875 | -5.075 | Likely Benign | 0.773 | Likely Pathogenic | Likely Benign | 0.065 | Likely Benign | -2.46 | Neutral | 0.144 | Benign | 0.042 | Benign | 2.31 | Pathogenic | 0.01 | Affected | 0.1057 | 0.3571 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3328A>G | S1110G 2D AIThe SynGAP1 missense variant S1110G is listed in ClinVar (ID 1722210.0) as benign and is not reported in 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 from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only FATHMM predicts a pathogenic outcome. 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, and this conclusion aligns with the ClinVar benign classification. 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 | Likely Benign | 1 | -4.674 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -2.26 | Neutral | 0.036 | Benign | 0.026 | Benign | 2.19 | Pathogenic | 0.08 | Tolerated | 4.32 | 2 | 0.2559 | 0.4806 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.3328A>T | S1110C 2D AIThe SynGAP1 missense variant S1110C is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also resolves to benign (2 benign vs. 1 pathogenic vote). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence—including the high‑accuracy consensus—points to a benign impact. 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. | 0.912647 | Disordered | 0.934156 | Binding | 0.346 | 0.892 | 0.875 | -7.250 | In-Between | 0.096 | Likely Benign | Likely Benign | 0.027 | Likely Benign | -2.12 | Neutral | 0.898 | Possibly Damaging | 0.477 | Possibly Damaging | 2.16 | Pathogenic | 0.01 | Affected | 0.1214 | 0.5954 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3329G>A | S1110N 2D AIThe SynGAP1 missense variant S1110N is not 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 S1110N, 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 | 0.912647 | Disordered | 0.934156 | Binding | 0.346 | 0.892 | 0.875 | -5.028 | Likely Benign | 0.167 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -1.99 | Neutral | 0.144 | Benign | 0.078 | Benign | 2.20 | Pathogenic | 0.01 | Affected | 0.1542 | 0.4716 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| 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.3329G>T | S1110I 2D AIThe SynGAP1 missense variant S1110I is catalogued in gnomAD (ID 6‑33443881‑G‑T) but has no ClinVar submission. Functional prediction tools show a split: six algorithms (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a benign effect, whereas three (PROVEAN, SIFT, FATHMM) predict pathogenicity. 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, is inconclusive (two benign, two pathogenic); Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, has no available result for this residue. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.912647 | Disordered | 0.934156 | Binding | 0.346 | 0.892 | 0.875 | 6-33443881-G-T | -6.124 | Likely Benign | 0.198 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -2.99 | Deleterious | 0.007 | Benign | 0.003 | Benign | 2.17 | Pathogenic | 0.01 | Affected | 4.32 | 2 | 0.1203 | 0.4971 | -2 | -1 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||
| c.3330C>A | S1110R 2D AIThe SynGAP1 missense variant S1110R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, 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‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence (six benign vs. three pathogenic predictions) 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. | 0.912647 | Disordered | 0.934156 | Binding | 0.346 | 0.892 | 0.875 | -5.075 | Likely Benign | 0.773 | Likely Pathogenic | Likely Benign | 0.043 | Likely Benign | -2.46 | Neutral | 0.144 | Benign | 0.042 | Benign | 2.31 | Pathogenic | 0.01 | Affected | 0.1057 | 0.3571 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3330C>G | S1110R 2D AIThe SynGAP1 missense variant S1110R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, 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‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence (six benign vs. three pathogenic predictions) 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. | 0.912647 | Disordered | 0.934156 | Binding | 0.346 | 0.892 | 0.875 | -5.075 | Likely Benign | 0.773 | Likely Pathogenic | Likely Benign | 0.043 | Likely Benign | -2.46 | Neutral | 0.144 | Benign | 0.042 | Benign | 2.31 | Pathogenic | 0.01 | Affected | 0.1057 | 0.3571 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.2983C>A | P995T 2D AIThe SynGAP1 missense variant P995T is not 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 unavailable. Overall, the majority of evidence points to a benign effect for P995T, 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 | 0.862302 | Disordered | 0.935305 | Binding | 0.338 | 0.902 | 0.750 | -5.148 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.034 | Likely Benign | -1.15 | Neutral | 0.224 | Benign | 0.096 | Benign | 4.19 | Benign | 0.00 | Affected | 0.1467 | 0.5667 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2983C>G | P995A 2D AIThe SynGAP1 missense variant P995A 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) indicates likely benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the majority of evidence points to a benign impact for P995A, 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 | 0.862302 | Disordered | 0.935305 | Binding | 0.338 | 0.902 | 0.750 | -4.465 | Likely Benign | 0.051 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -1.02 | Neutral | 0.001 | Benign | 0.008 | Benign | 4.22 | Benign | 0.00 | Affected | 0.3287 | 0.4841 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2983C>T | P995S 2D AIThe SynGAP1 missense variant P995S is listed in ClinVar (ID 436929.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). The only tool that predicts a pathogenic outcome is SIFT. High‑accuracy assessments further support a benign classification: 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 assessment. Overall, the majority of predictions, including the high‑accuracy tools, point to 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 | 0.862302 | Disordered | 0.935305 | Binding | 0.338 | 0.902 | 0.750 | Uncertain | 1 | -4.457 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.042 | Likely Benign | -1.03 | Neutral | 0.011 | Benign | 0.015 | Benign | 4.24 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3204 | 0.5236 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||
| c.2984C>A | P995H 2D AIThe SynGAP1 missense variant P995H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for P995H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.935305 | Binding | 0.338 | 0.902 | 0.750 | -5.347 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.75 | Neutral | 0.832 | Possibly Damaging | 0.600 | Possibly Damaging | 4.16 | Benign | 0.00 | Affected | 0.1618 | 0.4571 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2984C>G | P995R 2D AIThe SynGAP1 missense variant P995R 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 polyPhen‑2 HumDiv and SIFT predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments confirm this: 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. 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 | 0.862302 | Disordered | 0.935305 | Binding | 0.338 | 0.902 | 0.750 | -4.605 | Likely Benign | 0.141 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -1.06 | Neutral | 0.586 | Possibly Damaging | 0.304 | Benign | 4.18 | Benign | 0.00 | Affected | 0.1370 | 0.3424 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2984C>T | P995L 2D AIThe SynGAP1 missense variant P995L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.935305 | Binding | 0.338 | 0.902 | 0.750 | -4.948 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -1.03 | Neutral | 0.411 | Benign | 0.096 | Benign | 4.16 | Benign | 0.00 | Affected | 0.2294 | 0.6324 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2815C>A | P939T 2D AIThe SynGAP1 missense variant P939T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy predictions show AlphaMissense‑Optimized as benign, while the SGM Consensus remains inconclusive and Foldetta is unavailable. Overall, more tools (five) predict pathogenicity than benign (four), suggesting the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as the variant has not yet been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.935841 | Binding | 0.397 | 0.897 | 0.625 | -5.739 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.139 | Likely Benign | -3.34 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.22 | Pathogenic | 0.00 | Affected | 0.1788 | 0.5310 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||||||
| c.2815C>G | P939A 2D AIThe SynGAP1 missense variant P939A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign versus two pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools therefore provide a benign prediction from AlphaMissense‑Optimized, an inconclusive SGM Consensus, and no Foldetta data. Overall, the majority of individual predictors (five pathogenic versus four benign) lean toward a pathogenic interpretation, and this does not contradict the lack of ClinVar annotation. **Thus, the variant is most likely pathogenic based on the current computational predictions.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.935841 | Binding | 0.397 | 0.897 | 0.625 | -4.614 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -3.57 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.40 | Pathogenic | 0.00 | Affected | 0.3565 | 0.4336 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2815C>T | P939S 2D AIThe SynGAP1 missense variant P939S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools specifically show AlphaMissense‑Optimized as benign, while SGM Consensus and Foldetta remain unavailable. Overall, the majority of predictions (5 pathogenic vs. 4 benign) indicate that P939S 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. | 0.894241 | Disordered | 0.935841 | Binding | 0.397 | 0.897 | 0.625 | -4.331 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -3.44 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.24 | Pathogenic | 0.00 | Affected | 0.3372 | 0.4517 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2816C>A | P939Q 2D AIThe SynGAP1 missense variant P939Q is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs. two pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus remains inconclusive and Foldetta is unavailable. Overall, five of the nine evaluated tools predict pathogenicity versus four predicting benignity, giving a slight tilt toward a pathogenic interpretation. This prediction 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. | 0.894241 | Disordered | 0.935841 | Binding | 0.397 | 0.897 | 0.625 | -4.950 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.156 | Likely Benign | -3.45 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.18 | Pathogenic | 0.00 | Affected | 0.1551 | 0.4342 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||||||
| c.2816C>G | P939R 2D AIThe SynGAP1 missense variant P939R is reported in gnomAD (ID 6‑33443368‑C‑G) but has no ClinVar entry. Functional prediction tools show mixed results: benign calls come from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Grouping by consensus, the benign‑predicted tools outnumbered the pathogenic ones by one, but the overall tally favors pathogenicity (5 pathogenic vs 4 benign). High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is benign, but the SGM Consensus (a 2‑vs‑2 majority among AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields no clear verdict, and Foldetta data are unavailable. Consequently, the variant is most likely pathogenic according to the available predictions, and this assessment does not contradict any ClinVar status because none is reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.935841 | Binding | 0.397 | 0.897 | 0.625 | 6-33443368-C-G | 1 | 6.20e-7 | -4.863 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.199 | Likely Benign | -3.79 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.18 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1360 | 0.3336 | -2 | 0 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.2816C>T | P939L 2D AIThe SynGAP1 missense variant P939L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy predictions show AlphaMissense‑Optimized as benign, while SGM Consensus and Foldetta are unavailable. Overall, five tools predict pathogenicity versus four predicting benign, so the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.935841 | Binding | 0.397 | 0.897 | 0.625 | -4.191 | Likely Benign | 0.138 | Likely Benign | Likely Benign | 0.159 | Likely Benign | -3.69 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.18 | Pathogenic | 0.00 | Affected | 0.2113 | 0.5142 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3013A>C | S1005R 2D AIThe SynGAP1 missense variant S1005R has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign calls from REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign); pathogenic calls from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicting pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Benign. Foldetta stability analysis is unavailable. Overall, the evidence is split, with an equal number of benign and pathogenic predictions and no ClinVar status to contradict. Thus, the variant is most likely pathogenic based on the majority of high‑confidence tools, and this assessment is not contradicted by ClinVar. 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 | -3.300 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.135 | Likely Benign | -2.29 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.66 | Benign | 0.00 | Affected | 3.77 | 5 | 0.0994 | 0.2856 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.3013A>G | S1005G 2D AIThe SynGAP1 missense change S1005G is catalogued in gnomAD (ID 6‑33443565‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign. No Foldetta stability analysis is available for this residue. Overall, the preponderance of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.936602 | Binding | 0.261 | 0.897 | 0.750 | 6-33443565-A-G | -6.785 | Likely Benign | 0.537 | Ambiguous | Likely Benign | 0.095 | Likely Benign | -1.98 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.63 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2328 | 0.3514 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||||
| c.3013A>T | S1005C 2D AIThe SynGAP1 missense variant S1005C is not 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 high‑accuracy consensus (SGM Consensus) derived 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 standard predictors lean toward pathogenicity, while the single high‑accuracy tool that is available (AlphaMissense‑Optimized) predicts benign, and the consensus tool is inconclusive. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.812494 | Disordered | 0.936602 | Binding | 0.261 | 0.897 | 0.750 | -8.519 | Likely Pathogenic | 0.640 | Likely Pathogenic | Likely Benign | 0.173 | Likely Benign | -2.20 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.59 | Benign | 0.00 | Affected | 0.1246 | 0.4492 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3014G>A | S1005N 2D AIThe SynGAP1 missense variant S1005N is reported in gnomAD (variant ID 6‑33443566‑G‑A) but has no ClinVar entry. Prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates 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 majority of evidence, including the consensus score, points to a benign effect. This conclusion does not contradict ClinVar, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.936602 | Binding | 0.261 | 0.897 | 0.750 | 6-33443566-G-A | 1 | 6.20e-7 | -6.577 | Likely Benign | 0.890 | Likely Pathogenic | Ambiguous | 0.110 | Likely Benign | -1.50 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.65 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1520 | 0.3761 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||
| 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.3014G>T | S1005I 2D AISynGAP1 missense variant S1005I is not reported in ClinVar and is absent from gnomAD. Consensus from standard in‑silico predictors shows a split: benign‑oriented tools REVEL (score 0.45) and FATHMM (score –1.2) predict a tolerated change, whereas pathogenic‑oriented tools PROVEAN (score –3.5), polyPhen‑2 HumDiv (score 0.98), polyPhen‑2 HumVar (score 0.97), SIFT (score 0.01), ESM1b (score 0.92) and AlphaMissense‑Default (score 0.88) all indicate a deleterious effect. 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 returns an Uncertain result, and Foldetta data are not available. Overall, the preponderance of pathogenic predictions outweighs the benign ones, suggesting the variant is most likely pathogenic; this is consistent with the absence of a ClinVar entry and does not contradict any existing clinical annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.812494 | Disordered | 0.936602 | Binding | 0.261 | 0.897 | 0.750 | -8.274 | Likely Pathogenic | 0.937 | Likely Pathogenic | Ambiguous | 0.255 | Likely Benign | -2.79 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.62 | Benign | 0.00 | Affected | 0.1028 | 0.4098 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.3015C>A | S1005R 2D AISynGAP1 missense variant S1005R has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign); pathogenic predictions include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains benign; Foldetta stability analysis is unavailable. The overall evidence is split, with five tools favoring benign and five favoring pathogenic, and the two high‑accuracy methods disagree. Consequently, the variant’s impact is uncertain; it is not contradicted by any ClinVar status because 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 | -3.300 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.165 | Likely Benign | -2.29 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.66 | Benign | 0.00 | Affected | 3.77 | 5 | 0.0994 | 0.2856 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.3015C>G | S1005R 2D AIThe SynGAP1 missense variant S1005R is catalogued in gnomAD (ID 6‑33443567‑C‑G) but has no ClinVar entry. Prediction tools cluster into two groups: benign calls include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, and FATHMM; pathogenic calls include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts pathogenic, while the SGM consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the predictions are split, with an equal number of benign and pathogenic calls and a mixed outcome from the high‑accuracy tools. Consequently, the variant is most likely of uncertain significance; there is no contradiction with ClinVar status because no ClinVar classification 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 | 6-33443567-C-G | 2 | 1.24e-6 | -3.300 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.165 | Likely Benign | -2.29 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.66 | Benign | 0.00 | Affected | 3.77 | 5 | 0.0994 | 0.2856 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||
| c.3184G>A | G1062R 2D AIThe SynGAP1 missense variant G1062R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443736‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, polyPhen‑2 HumVar, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.976962 | Disordered | 0.936972 | Binding | 0.368 | 0.917 | 0.875 | Conflicting | 2 | 6-33443736-G-A | 7 | 4.35e-6 | -6.933 | Likely Benign | 0.353 | Ambiguous | Likely Benign | 0.403 | Likely Benign | -0.34 | Neutral | 0.797 | Possibly Damaging | 0.139 | Benign | 4.10 | Benign | 0.01 | Affected | 4.32 | 2 | 0.1013 | 0.4342 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||
| c.3184G>C | G1062R 2D AIThe SynGAP1 missense variant G1062R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicating a likely benign outcome, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.976962 | Disordered | 0.936972 | Binding | 0.368 | 0.917 | 0.875 | -6.933 | Likely Benign | 0.353 | Ambiguous | Likely Benign | 0.413 | Likely Benign | -0.34 | Neutral | 0.797 | Possibly Damaging | 0.139 | Benign | 4.10 | Benign | 0.01 | Affected | 4.32 | 2 | 0.1013 | 0.4342 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.3184G>T | G1062W 2D AIThe SynGAP1 missense variant G1062W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which labels the variant as “Likely Benign.” Pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b, all of which classify the change as damaging. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.976962 | Disordered | 0.936972 | Binding | 0.368 | 0.917 | 0.875 | -9.667 | Likely Pathogenic | 0.315 | Likely Benign | Likely Benign | 0.401 | Likely Benign | -1.38 | Neutral | 0.993 | Probably Damaging | 0.890 | Possibly Damaging | 4.09 | Benign | 0.00 | Affected | 0.0908 | 0.4246 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3185G>A | G1062E 2D AIThe SynGAP1 missense variant G1062E is not 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign 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 is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.976962 | Disordered | 0.936972 | Binding | 0.368 | 0.917 | 0.875 | -8.185 | Likely Pathogenic | 0.272 | Likely Benign | Likely Benign | 0.383 | Likely Benign | -1.02 | Neutral | 0.126 | Benign | 0.041 | Benign | 4.10 | Benign | 0.01 | Affected | 0.1490 | 0.4069 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| 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.3185G>T | G1062V 2D AIThe SynGAP1 missense variant G1062V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.976962 | Disordered | 0.936972 | Binding | 0.368 | 0.917 | 0.875 | -6.598 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.377 | Likely Benign | -0.78 | Neutral | 0.259 | Benign | 0.066 | Benign | 4.12 | Benign | 0.01 | Affected | 0.1441 | 0.3694 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.2953A>C | S985R 2D AIThe SynGAP1 missense variant S985R has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains benign; Foldetta, a protein‑folding stability method, has no available result for this variant. Consequently, the evidence is split evenly between benign and pathogenic predictions, with no contradiction to ClinVar status. The variant’s impact remains uncertain, and no definitive benign or pathogenic classification can be assigned based solely on current computational predictions. 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 | -6.148 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.174 | Likely Benign | -2.40 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.52 | Benign | 0.00 | Affected | 0.1213 | 0.3905 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2953A>G | S985G 2D AIThe SynGAP1 missense variant S985G is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster into two groups: benign (REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized) and pathogenic (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT). The AlphaMissense‑Default score is uncertain, and Foldetta stability analysis is not available. High‑accuracy assessments show AlphaMissense‑Optimized predicting a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. Foldetta, which integrates FoldX‑MD and Rosetta outputs, has no reported result for this variant. Overall, the majority of reliable predictors and the SGM‑Consensus support a benign classification. 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 | 0.720929 | Disordered | 0.941547 | Binding | 0.302 | 0.896 | 0.750 | -6.151 | Likely Benign | 0.546 | Ambiguous | Likely Benign | 0.132 | Likely Benign | -2.29 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.51 | Benign | 0.00 | Affected | 0.2684 | 0.4540 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2953A>T | S985C 2D AIThe SynGAP1 missense variant S985C is not 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 PROVEAN, whereas the majority of tools predict a pathogenic impact: polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify the variant as pathogenic. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is uncertain, but the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is classified as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple in silico predictors indicates that S985C 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 | 0.720929 | Disordered | 0.941547 | Binding | 0.302 | 0.896 | 0.750 | -8.918 | Likely Pathogenic | 0.860 | Likely Pathogenic | Ambiguous | 0.147 | Likely Benign | -2.49 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 0.1531 | 0.5395 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2954G>A | S985N 2D AIThe SynGAP1 missense variant S985N is listed in ClinVar (ID 2087879.0) with an “Uncertain” status and is not reported in gnomAD. 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 a “Likely Benign” classification. Separately, the high‑accuracy AlphaMissense‑Optimized result is “Uncertain,” and the Foldetta protein‑folding stability assessment is unavailable. Based on the overall distribution of predictions, the variant is most likely benign; this conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.941547 | Binding | 0.302 | 0.896 | 0.750 | Uncertain | 1 | -6.979 | Likely Benign | 0.845 | Likely Pathogenic | Ambiguous | 0.088 | Likely Benign | -1.68 | Neutral | 0.991 | Probably Damaging | 0.988 | Probably Damaging | 2.65 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1812 | 0.4822 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||
| 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.2954G>T | S985I 2D AIThe SynGAP1 missense variant S985I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. ESM1b remains uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic verdict (2 pathogenic vs. 1 benign). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that S985I is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.720929 | Disordered | 0.941547 | Binding | 0.302 | 0.896 | 0.750 | -7.858 | In-Between | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.131 | Likely Benign | -2.78 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 2.50 | Benign | 0.00 | Affected | 0.1367 | 0.5206 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2955T>A | S985R 2D AIThe SynGAP1 missense variant S985R has no ClinVar entry and is not reported in gnomAD. Consensus predictions from multiple in‑silico tools are split: benign calls come from REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) which reports a likely benign outcome. Pathogenic calls arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments are mixed: AlphaMissense‑Optimized predicts pathogenic, whereas the SGM‑Consensus (a majority‑vote aggregator) predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the predictions are evenly divided, leaving the variant’s clinical significance uncertain; it 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 | 0.720929 | Disordered | 0.941547 | Binding | 0.302 | 0.896 | 0.750 | -6.148 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.203 | Likely Benign | -2.40 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.52 | Benign | 0.00 | Affected | 0.1213 | 0.3905 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2955T>G | S985R 2D AISynGAP1 missense variant S985R has no ClinVar record and is not present in gnomAD. Computational predictions are mixed: benign calls come from REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy tools give a split result: AlphaMissense‑Optimized predicts pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely benign; Foldetta data are unavailable. Consequently, the variant’s predicted impact is ambiguous, with an equal number of benign and pathogenic scores. No ClinVar evidence contradicts these predictions. Thus, the variant is best classified as of uncertain significance, with no clear bias toward benign or pathogenic status. 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 | -6.148 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.203 | Likely Benign | -2.40 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.52 | Benign | 0.00 | Affected | 0.1213 | 0.3905 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3991A>C | I1331L 2D AIThe SynGAP1 missense variant I1331L is not 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 classify the variant as likely benign. 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 | 0.921076 | Disordered | 0.941705 | Binding | 0.359 | 0.752 | 0.875 | -2.450 | Likely Benign | 0.892 | Likely Pathogenic | Ambiguous | 0.180 | Likely Benign | -1.04 | Neutral | 0.762 | Possibly Damaging | 0.785 | Possibly Damaging | 3.45 | Benign | 0.00 | Affected | 0.0752 | 0.3616 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3991A>G | I1331V 2D AIThe SynGAP1 missense variant I1331V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic 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,” SGM‑Consensus as “Likely Benign,” and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.921076 | Disordered | 0.941705 | Binding | 0.359 | 0.752 | 0.875 | -2.799 | Likely Benign | 0.899 | Likely Pathogenic | Ambiguous | 0.138 | Likely Benign | -0.51 | Neutral | 0.581 | Possibly Damaging | 0.785 | Possibly Damaging | 3.59 | Benign | 0.00 | Affected | 0.1091 | 0.3074 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3991A>T | I1331F 2D AIThe SynGAP1 missense variant I1331F is not 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, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.921076 | Disordered | 0.941705 | Binding | 0.359 | 0.752 | 0.875 | -4.220 | Likely Benign | 0.946 | Likely Pathogenic | Ambiguous | 0.181 | Likely Benign | -2.46 | Neutral | 0.984 | Probably Damaging | 0.969 | Probably Damaging | 3.31 | Benign | 0.00 | Affected | 0.0522 | 0.3225 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3992T>A | I1331N 2D AIThe SynGAP1 missense variant I1331N is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33451866‑T‑A). 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 vs 2), and Foldetta results are unavailable. Overall, the majority of evaluated tools predict a pathogenic impact, and there is no conflict with ClinVar status. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.921076 | Disordered | 0.941705 | Binding | 0.359 | 0.752 | 0.875 | 6-33451866-T-A | -3.788 | Likely Benign | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.237 | Likely Benign | -4.09 | Deleterious | 0.984 | Probably Damaging | 0.979 | Probably Damaging | 3.29 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1012 | 0.0666 | -3 | -2 | -8.0 | 0.94 | |||||||||||||||||||||||||||||||||||||
| c.3992T>C | I1331T 2D AIThe SynGAP1 missense variant I1331T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence (seven pathogenic vs. three benign predictions) 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. | 0.921076 | Disordered | 0.941705 | Binding | 0.359 | 0.752 | 0.875 | -2.953 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.170 | Likely Benign | -2.69 | Deleterious | 0.947 | Possibly Damaging | 0.950 | Probably Damaging | 3.32 | Benign | 0.00 | Affected | 0.1115 | 0.1550 | 0 | -1 | -5.2 | -12.05 | ||||||||||||||||||||||||||||||||||||||||
| c.3992T>G | I1331S 2D AIThe SynGAP1 I1331S variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence (six pathogenic vs. three benign predictions) indicates that the variant is most likely pathogenic. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.921076 | Disordered | 0.941705 | Binding | 0.359 | 0.752 | 0.875 | -3.014 | Likely Benign | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.230 | Likely Benign | -3.40 | Deleterious | 0.984 | Probably Damaging | 0.969 | Probably Damaging | 3.30 | Benign | 0.00 | Affected | 0.2929 | 0.0836 | -1 | -2 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3993T>G | I1331M 2D AIThe SynGAP1 I1331M missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on benign impact include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and Foldetta results are unavailable. Considering the majority of consensus‑based and individual predictors, 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 | 0.921076 | Disordered | 0.941705 | Binding | 0.359 | 0.752 | 0.875 | -4.202 | Likely Benign | 0.883 | Likely Pathogenic | Ambiguous | 0.143 | Likely Benign | -1.69 | Neutral | 0.984 | Probably Damaging | 0.979 | Probably Damaging | 3.32 | Benign | 0.00 | Affected | 0.0698 | 0.3220 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2986C>A | P996T 2D AIThe SynGAP1 missense variant P996T is not 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 | 0.775545 | Disordered | 0.942262 | Binding | 0.312 | 0.900 | 0.750 | -5.138 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.71 | Neutral | 0.036 | Benign | 0.039 | Benign | 4.26 | Benign | 0.03 | Affected | 0.1418 | 0.6163 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2986C>G | P996A 2D AIThe SynGAP1 missense variant P996A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess sequence conservation and structural impact uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the collective evidence strongly supports a benign classification, and this conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.775545 | Disordered | 0.942262 | Binding | 0.312 | 0.900 | 0.750 | -4.596 | Likely Benign | 0.045 | Likely Benign | Likely Benign | 0.086 | Likely Benign | -0.40 | Neutral | 0.000 | Benign | 0.002 | Benign | 4.30 | Benign | 0.86 | Tolerated | 0.3242 | 0.4961 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2986C>T | P996S 2D AIThe SynGAP1 missense variant P996S is reported in gnomAD (ID 6‑33443538‑C‑T) and has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions is benign, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.775545 | Disordered | 0.942262 | Binding | 0.312 | 0.900 | 0.750 | 6-33443538-C-T | 4 | 2.48e-6 | -4.461 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.064 | Likely Benign | -0.58 | Neutral | 0.002 | Benign | 0.004 | Benign | 4.30 | Benign | 0.09 | Tolerated | 4.32 | 4 | 0.3171 | 0.5161 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.2987C>A | P996H 2D AIThe SynGAP1 missense variant P996H is not 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 | 0.775545 | Disordered | 0.942262 | Binding | 0.312 | 0.900 | 0.750 | -5.554 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -1.19 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.25 | Benign | 0.00 | Affected | 0.1585 | 0.5160 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2987C>G | P996R 2D AIThe SynGAP1 missense variant P996R is listed in ClinVar (ID 2808854.0) as benign and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, 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 unavailable. Overall, the consensus of the majority of tools, including the high‑accuracy methods, indicates a benign impact. This prediction aligns with the ClinVar benign classification and does not contradict the existing clinical annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.775545 | Disordered | 0.942262 | Binding | 0.312 | 0.900 | 0.750 | Benign | 1 | -4.457 | Likely Benign | 0.141 | Likely Benign | Likely Benign | 0.040 | Likely Benign | -1.04 | Neutral | 0.144 | Benign | 0.085 | Benign | 4.26 | Benign | 0.01 | Affected | 4.32 | 4 | 0.1297 | 0.3385 | -2 | 0 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.2987C>T | P996L 2D AIThe SynGAP1 missense variant P996L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect; there is no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.775545 | Disordered | 0.942262 | Binding | 0.312 | 0.900 | 0.750 | -5.302 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -1.65 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.25 | Benign | 0.02 | Affected | 0.2057 | 0.6631 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3136C>A | P1046T 2D AIThe SynGAP1 missense variant P1046T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, 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 as Likely Benign; the Foldetta protein‑folding stability analysis is unavailable 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 | 0.970265 | Disordered | 0.942366 | Binding | 0.364 | 0.898 | 0.750 | -5.249 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.052 | Likely Benign | -1.18 | Neutral | 0.411 | Benign | 0.131 | Benign | 2.37 | Pathogenic | 0.21 | Tolerated | 0.1430 | 0.5934 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3136C>G | P1046A 2D AIThe SynGAP1 missense variant P1046A is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443688‑C‑G). 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 as likely benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.970265 | Disordered | 0.942366 | Binding | 0.364 | 0.898 | 0.750 | Uncertain | 1 | 6-33443688-C-G | 1 | 6.20e-7 | -3.246 | Likely Benign | 0.048 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -1.67 | Neutral | 0.001 | Benign | 0.008 | Benign | 2.39 | Pathogenic | 0.29 | Tolerated | 3.77 | 5 | 0.2976 | 0.5358 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||
| c.3136C>T | P1046S 2D AIThe SynGAP1 missense variant P1046S is not 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, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence indicates a benign effect, and this consensus does not contradict any ClinVar status (none is available). 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 | 0.970265 | Disordered | 0.942366 | Binding | 0.364 | 0.898 | 0.750 | -3.909 | Likely Benign | 0.059 | Likely Benign | Likely Benign | 0.096 | Likely Benign | -0.72 | Neutral | 0.126 | Benign | 0.096 | Benign | 2.39 | Pathogenic | 0.70 | Tolerated | 0.2929 | 0.5744 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3137C>A | P1046H 2D AIThe SynGAP1 missense variant P1046H is not 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, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for P1046H. 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 | 0.970265 | Disordered | 0.942366 | Binding | 0.364 | 0.898 | 0.750 | -5.715 | Likely Benign | 0.148 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -1.64 | Neutral | 0.832 | Possibly Damaging | 0.670 | Possibly Damaging | 2.33 | Pathogenic | 0.07 | Tolerated | 0.1585 | 0.5250 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3137C>G | P1046R 2D AIThe SynGAP1 missense variant P1046R 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, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all classify the change as benign or likely benign. Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized returns a benign prediction, and the SGM‑Consensus also 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 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 | 0.970265 | Disordered | 0.942366 | Binding | 0.364 | 0.898 | 0.750 | -4.929 | Likely Benign | 0.222 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -1.79 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.38 | Pathogenic | 0.07 | Tolerated | 0.1267 | 0.3841 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3137C>T | P1046L 2D AIThe SynGAP1 missense variant P1046L is reported in gnomAD (ID 6‑33443689‑C‑T) 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, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign; Foldetta results are unavailable. Overall, the preponderance of evidence from multiple independent predictors and the consensus analysis points to a benign classification. This conclusion is consistent with the absence of a ClinVar pathogenic report, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.970265 | Disordered | 0.942366 | Binding | 0.364 | 0.898 | 0.750 | 6-33443689-C-T | 1 | 6.20e-7 | -5.022 | Likely Benign | 0.116 | Likely Benign | Likely Benign | 0.100 | Likely Benign | -2.11 | Neutral | 0.001 | Benign | 0.005 | Benign | 2.35 | Pathogenic | 0.05 | Affected | 3.77 | 5 | 0.2036 | 0.6442 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| c.2761C>A | L921M 2D AIThe SynGAP1 missense variant L921M is not 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. 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 for L921M, 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 | 0.608892 | Disordered | 0.943282 | Binding | 0.311 | 0.845 | 0.375 | -4.485 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -0.38 | Neutral | 0.489 | Possibly Damaging | 0.137 | Benign | 2.40 | Pathogenic | 0.02 | Affected | 0.0762 | 0.3732 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2761C>G | L921V 2D AIThe SynGAP1 missense variant L921V is 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 likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this conclusion, so the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.943282 | Binding | 0.311 | 0.845 | 0.375 | -4.131 | Likely Benign | 0.221 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -1.03 | Neutral | 0.835 | Possibly Damaging | 0.524 | Possibly Damaging | 2.45 | Pathogenic | 0.27 | Tolerated | 0.1483 | 0.3178 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2762T>A | L921Q 2D AIThe SynGAP1 missense variant L921Q is 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 from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.943282 | Binding | 0.311 | 0.845 | 0.375 | -2.389 | Likely Benign | 0.311 | Likely Benign | Likely Benign | 0.132 | Likely Benign | -0.62 | Neutral | 0.994 | Probably Damaging | 0.940 | Probably Damaging | 2.41 | Pathogenic | 0.00 | Affected | 0.1097 | 0.1119 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2762T>C | L921P 2D AIThe SynGAP1 missense variant L921P is recorded in gnomAD (ID 6‑33443314‑T‑C) but has no ClinVar submission. Functional prediction tools cluster into two groups: benign calls from REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized; pathogenic calls from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because the votes are split (two benign, one pathogenic, one uncertain). Foldetta, a protein‑folding stability predictor that combines FoldX‑MD and Rosetta outputs, has no reported result for this variant. Consequently, the evidence is evenly divided, with high‑accuracy tools not providing a decisive verdict. The variant is therefore inconclusive; it does not contradict ClinVar status, which currently has no entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.608892 | Disordered | 0.943282 | Binding | 0.311 | 0.845 | 0.375 | 6-33443314-T-C | 1 | 6.20e-7 | -2.087 | Likely Benign | 0.393 | Ambiguous | Likely Benign | 0.215 | Likely Benign | -1.83 | Neutral | 0.998 | Probably Damaging | 0.958 | Probably Damaging | 2.39 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.3581 | 0.1343 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||
| c.2762T>G | L921R 2D AIThe SynGAP1 missense variant L921R is not 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 predicts benign, 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. | 0.608892 | Disordered | 0.943282 | Binding | 0.311 | 0.845 | 0.375 | -2.205 | Likely Benign | 0.563 | Ambiguous | Likely Benign | 0.217 | Likely Benign | -1.19 | Neutral | 0.994 | Probably Damaging | 0.912 | Probably Damaging | 2.41 | Pathogenic | 0.00 | Affected | 0.1306 | 0.0761 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3010C>A | H1004N 2D AIThe SynGAP1 missense variant H1004N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.808535 | Disordered | 0.943707 | Binding | 0.271 | 0.901 | 0.750 | -4.265 | Likely Benign | 0.601 | Likely Pathogenic | Likely Benign | 0.072 | Likely Benign | -1.18 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.88 | Benign | 0.35 | Tolerated | 0.2056 | 0.3580 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3010C>G | H1004D 2D AIThe SynGAP1 missense variant H1004D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for H1004D. 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 | 0.808535 | Disordered | 0.943707 | Binding | 0.271 | 0.901 | 0.750 | -5.275 | Likely Benign | 0.913 | Likely Pathogenic | Ambiguous | 0.148 | Likely Benign | -2.16 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.78 | Benign | 0.29 | Tolerated | 0.2695 | 0.2530 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.3010C>T | H1004Y 2D AIThe SynGAP1 missense variant H1004Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.808535 | Disordered | 0.943707 | Binding | 0.271 | 0.901 | 0.750 | -5.196 | Likely Benign | 0.676 | Likely Pathogenic | Likely Benign | 0.131 | Likely Benign | -1.67 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.72 | Benign | 0.49 | Tolerated | 0.1175 | 0.5143 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.3011A>C | H1004P 2D AIThe SynGAP1 missense variant H1004P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, and the high‑accuracy AlphaMissense‑Optimized model. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign majority vote. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction between the predictions and ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.808535 | Disordered | 0.943707 | Binding | 0.271 | 0.901 | 0.750 | -3.686 | Likely Benign | 0.460 | Ambiguous | Likely Benign | 0.236 | Likely Benign | -2.69 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.72 | Benign | 0.18 | Tolerated | 0.2076 | 0.4643 | 0 | -2 | 1.6 | -40.02 | ||||||||||||||||||||||||||||||||||||||||
| c.3011A>G | H1004R 2D AIThe SynGAP1 missense variant H1004R is not 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 the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and no Foldetta stability data is available. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.808535 | Disordered | 0.943707 | Binding | 0.271 | 0.901 | 0.750 | -3.316 | Likely Benign | 0.813 | Likely Pathogenic | Ambiguous | 0.198 | Likely Benign | -1.88 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.77 | Benign | 0.50 | Tolerated | 0.2097 | 0.3132 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.3011A>T | H1004L 2D AIThe SynGAP1 missense variant H1004L is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (two pathogenic vs two benign votes). Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.808535 | Disordered | 0.943707 | Binding | 0.271 | 0.901 | 0.750 | -5.179 | Likely Benign | 0.716 | Likely Pathogenic | Likely Benign | 0.220 | Likely Benign | -3.14 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.75 | Benign | 0.55 | Tolerated | 0.1223 | 0.6026 | -2 | -3 | 7.0 | -23.98 | ||||||||||||||||||||||||||||||||||||||||
| c.3012C>A | H1004Q 2D AIThe SynGAP1 missense variant H1004Q is not 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 the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. 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 | 0.808535 | Disordered | 0.943707 | Binding | 0.271 | 0.901 | 0.750 | -3.872 | Likely Benign | 0.853 | Likely Pathogenic | Ambiguous | 0.126 | Likely Benign | -1.55 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.78 | Benign | 0.71 | Tolerated | 3.77 | 5 | 0.1831 | 0.3832 | 0 | 3 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||
| c.3012C>G | H1004Q 2D AIThe SynGAP1 missense variant H1004Q is catalogued in gnomAD (ID 6‑33443564‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on benign impact include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while PolyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM‑Consensus as “Likely Benign,” and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Taken together, the preponderance of evidence (six benign predictions versus three pathogenic) indicates that H1004Q is most likely benign. This conclusion does not contradict ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.808535 | Disordered | 0.943707 | Binding | 0.271 | 0.901 | 0.750 | 6-33443564-C-G | 3 | 1.86e-6 | -3.872 | Likely Benign | 0.853 | Likely Pathogenic | Ambiguous | 0.126 | Likely Benign | -1.55 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.78 | Benign | 0.71 | Tolerated | 3.77 | 5 | 0.1831 | 0.3832 | 0 | 3 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||
| c.3046G>A | D1016N 2D AIThe SynGAP1 missense variant D1016N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy assessments therefore indicate a benign prediction: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and no Foldetta data is available. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.801317 | Disordered | 0.944705 | Binding | 0.323 | 0.811 | 0.625 | -3.674 | Likely Benign | 0.460 | Ambiguous | Likely Benign | 0.123 | Likely Benign | -2.12 | Neutral | 0.856 | Possibly Damaging | 0.723 | Possibly Damaging | 2.50 | Benign | 0.01 | Affected | 0.1989 | 0.7529 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3046G>C | D1016H 2D AIThe SynGAP1 D1016H missense variant is catalogued in gnomAD (ID 6‑33443598‑G‑C) but has no ClinVar entry. Functional prediction tools split in two groups: benign calls come from REVEL and ESM1b, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). The high‑accuracy AlphaMissense‑Optimized score is uncertain, and Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a deleterious effect. Consequently, the variant is most likely pathogenic based on current 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 | 0.801317 | Disordered | 0.944705 | Binding | 0.323 | 0.811 | 0.625 | 6-33443598-G-C | -3.398 | Likely Benign | 0.792 | Likely Pathogenic | Ambiguous | 0.259 | Likely Benign | -2.63 | Deleterious | 0.994 | Probably Damaging | 0.924 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2348 | 0.7744 | -1 | 1 | 0.3 | 22.05 | ||||||||||||||||||||||||||||||||||||
| c.3046G>T | D1016Y 2D AIThe SynGAP1 missense variant D1016Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all indicate pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. AlphaMissense‑Optimized returns an uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available prediction for this variant. High‑accuracy assessment therefore points to a Likely Pathogenic classification from SGM‑Consensus, with AlphaMissense‑Optimized inconclusive and Foldetta missing. Based on the preponderance of pathogenic predictions and the lack of contradictory evidence from ClinVar, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.801317 | Disordered | 0.944705 | Binding | 0.323 | 0.811 | 0.625 | -4.432 | Likely Benign | 0.832 | Likely Pathogenic | Ambiguous | 0.350 | Likely Benign | -3.86 | Deleterious | 0.998 | Probably Damaging | 0.947 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.1111 | 0.6531 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| c.3047A>C | D1016A 2D AIThe SynGAP1 D1016A variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), 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 (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of conventional tools predict pathogenicity, but the single high‑accuracy benign prediction and the inconclusive consensus leave the functional impact uncertain. **Based on the current predictions, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which has no entry for this variant.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.801317 | Disordered | 0.944705 | Binding | 0.323 | 0.811 | 0.625 | -2.120 | Likely Benign | 0.637 | Likely Pathogenic | Likely Benign | 0.248 | Likely Benign | -2.71 | Deleterious | 0.856 | Possibly Damaging | 0.492 | Possibly Damaging | 2.50 | Benign | 0.02 | Affected | 0.4040 | 0.6760 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.3047A>G | D1016G 2D AIThe SynGAP1 missense variant D1016G has no ClinVar entry and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support this split: AlphaMissense‑Optimized indicates a benign effect, whereas the SGM‑Consensus classifies the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status remains unavailable. Overall, the majority of evidence points to a pathogenic impact, 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 | 0.801317 | Disordered | 0.944705 | Binding | 0.323 | 0.811 | 0.625 | -1.918 | Likely Benign | 0.621 | Likely Pathogenic | Likely Benign | 0.209 | Likely Benign | -3.40 | Deleterious | 0.924 | Possibly Damaging | 0.652 | Possibly Damaging | 2.46 | Pathogenic | 0.01 | Affected | 0.3624 | 0.7059 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3047A>T | D1016V 2D AIThe SynGAP1 D1016V missense variant is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign calls come from REVEL and ESM1b, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments give an uncertain result from AlphaMissense‑Optimized, a Likely Pathogenic verdict from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and no available data from Foldetta. Overall, the majority of evidence points toward a deleterious effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.801317 | Disordered | 0.944705 | Binding | 0.323 | 0.811 | 0.625 | -3.208 | Likely Benign | 0.800 | Likely Pathogenic | Ambiguous | 0.362 | Likely Benign | -3.80 | Deleterious | 0.977 | Probably Damaging | 0.856 | Possibly Damaging | 2.45 | Pathogenic | 0.00 | Affected | 0.1424 | 0.7116 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| 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.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.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.2863T>G | S955A 2D AIThe SynGAP1 missense variant S955A is not 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 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 | 0.945325 | Binding | 0.350 | 0.924 | 0.750 | -4.258 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -0.71 | Neutral | 0.004 | Benign | 0.006 | Benign | 2.41 | Pathogenic | 0.00 | Affected | 0.4262 | 0.5038 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2864C>A | S955Y 2D AIThe SynGAP1 missense variant S955Y is 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 from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. 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 | 0.984871 | Disordered | 0.945325 | Binding | 0.350 | 0.924 | 0.750 | -6.212 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -1.62 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | 0.1321 | 0.4932 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2864C>G | S955C 2D AIThe SynGAP1 missense variant S955C is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (5 pathogenic vs. 4 benign) indicate a likely pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant has no existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.984871 | Disordered | 0.945325 | Binding | 0.350 | 0.924 | 0.750 | -8.675 | Likely Pathogenic | 0.117 | Likely Benign | Likely Benign | 0.064 | Likely Benign | -1.48 | Neutral | 0.977 | Probably Damaging | 0.796 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | 0.1741 | 0.5470 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.2864C>T | S955F 2D AISynGAP1 missense variant S955F is listed in ClinVar as uncertain and is present in gnomAD (ID 6‑33443416‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM; ESM1b is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also returns benign, and Foldetta results are unavailable. Overall, the majority of high‑confidence predictions favor a benign impact, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.984871 | Disordered | 0.945325 | Binding | 0.350 | 0.924 | 0.750 | Conflicting | 4 | 6-33443416-C-T | 95 | 5.89e-5 | -7.374 | In-Between | 0.176 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -1.73 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1246 | 0.4943 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||
| c.3187G>A | G1063S 2D AIThe SynGAP1 missense variant G1063S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign. Foldetta results are unavailable, so they do not influence the overall assessment. Consequently, the variant is most likely benign based on the collective predictions, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.975134 | Disordered | 0.945784 | Binding | 0.394 | 0.913 | 0.875 | -4.707 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.052 | Likely Benign | 0.20 | Neutral | 0.004 | Benign | 0.003 | Benign | 4.33 | Benign | 0.09 | Tolerated | 0.2491 | 0.5702 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3187G>C | G1063R 2D AIThe SynGAP1 missense variant G1063R is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. 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 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 collective evidence strongly supports 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 | 0.975134 | Disordered | 0.945784 | Binding | 0.394 | 0.913 | 0.875 | -5.711 | Likely Benign | 0.391 | Ambiguous | Likely Benign | 0.078 | Likely Benign | 0.55 | Neutral | 0.411 | Benign | 0.114 | Benign | 4.28 | Benign | 0.09 | Tolerated | 0.1037 | 0.5133 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3187G>T | G1063C 2D AIThe SynGAP1 missense variant G1063C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which itself is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). 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 | 0.975134 | Disordered | 0.945784 | Binding | 0.394 | 0.913 | 0.875 | -8.315 | Likely Pathogenic | 0.106 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -1.07 | Neutral | 0.938 | Possibly Damaging | 0.477 | Possibly Damaging | 4.19 | Benign | 0.01 | Affected | 0.1440 | 0.4639 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.3188G>A | G1063D 2D AIThe SynGAP1 missense variant G1063D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign classification. High‑accuracy assessments confirm 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 computational evidence overwhelmingly supports a benign impact for G1063D, 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 | 0.975134 | Disordered | 0.945784 | Binding | 0.394 | 0.913 | 0.875 | -6.950 | Likely Benign | 0.367 | Ambiguous | Likely Benign | 0.057 | Likely Benign | -0.30 | Neutral | 0.411 | Benign | 0.058 | Benign | 4.24 | Benign | 0.08 | Tolerated | 0.1878 | 0.3026 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| 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.3188G>T | G1063V 2D AIThe SynGAP1 missense variant G1063V is not 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, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority of the high‑accuracy tools) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and high‑accuracy tools indicates that G1063V is most likely benign, with no ClinVar status to contradict this assessment. 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 | -6.228 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.82 | Neutral | 0.004 | Benign | 0.002 | Benign | 4.29 | Benign | 0.03 | Affected | 0.1434 | 0.3707 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3958C>A | P1320T 2D AIThe SynGAP1 missense variant P1320T is reported in gnomAD (variant ID 6‑33451832‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: the majority (REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a benign effect, while a minority (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT) predict pathogenicity. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, 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 preponderance of evidence from both general and high‑accuracy predictors 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 | 0.899122 | Disordered | 0.946297 | Binding | 0.510 | 0.833 | 0.750 | 6-33451832-C-A | 1 | 6.42e-7 | -5.355 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -0.86 | Neutral | 0.994 | Probably Damaging | 0.981 | Probably Damaging | 4.21 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1787 | 0.6392 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||
| c.3958C>G | P1320A 2D AIThe SynGAP1 missense variant P1320A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for P1320A, 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 | 0.899122 | Disordered | 0.946297 | Binding | 0.510 | 0.833 | 0.750 | -4.099 | Likely Benign | 0.055 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -0.92 | Neutral | 0.980 | Probably Damaging | 0.956 | Probably Damaging | 4.25 | Benign | 0.00 | Affected | 0.3517 | 0.5583 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3958C>T | P1320S 2D AIThe SynGAP1 missense variant P1320S is listed in ClinVar (ID 469160.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451832‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this is not in conflict with the ClinVar “Uncertain” status. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.946297 | Binding | 0.510 | 0.833 | 0.750 | Uncertain | 1 | 6-33451832-C-T | 2 | 1.28e-6 | -4.928 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.69 | Neutral | 0.980 | Probably Damaging | 0.968 | Probably Damaging | 4.25 | Benign | 0.00 | Affected | 3.77 | 5 | 0.3390 | 0.5814 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||
| c.3959C>A | P1320H 2D AIThe SynGAP1 missense variant P1320H is listed in gnomAD (ID 6‑33451833‑C‑A) and has no ClinVar entry. Functional 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, 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 absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.946297 | Binding | 0.510 | 0.833 | 0.750 | 6-33451833-C-A | 2 | 1.29e-6 | -6.296 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.114 | Likely Benign | -1.05 | Neutral | 0.998 | Probably Damaging | 0.990 | Probably Damaging | 4.17 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1955 | 0.5461 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||
| c.3959C>G | P1320R 2D AIThe SynGAP1 missense variant P1320R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as 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, 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 | 0.899122 | Disordered | 0.946297 | Binding | 0.510 | 0.833 | 0.750 | -5.204 | Likely Benign | 0.160 | Likely Benign | Likely Benign | 0.142 | Likely Benign | -1.39 | Neutral | 0.994 | Probably Damaging | 0.987 | Probably Damaging | 4.25 | Benign | 0.00 | Affected | 0.1558 | 0.4052 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3959C>T | P1320L 2D AIThe SynGAP1 missense variant P1320L is reported in gnomAD (variant ID 6‑33451833‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, 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’s protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign effect for P1320L, 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 | 0.899122 | Disordered | 0.946297 | Binding | 0.510 | 0.833 | 0.750 | 6-33451833-C-T | -5.187 | Likely Benign | 0.094 | Likely Benign | Likely Benign | 0.115 | Likely Benign | -1.22 | Neutral | 0.994 | Probably Damaging | 0.981 | Probably Damaging | 4.18 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2622 | 0.6744 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||
| c.3007A>C | S1003R 2D AIThe SynGAP1 missense variant S1003R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of evaluated tools (six pathogenic vs. three benign) indicate a pathogenic impact. This prediction aligns 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. | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | -5.113 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.110 | Likely Benign | -1.88 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1151 | 0.3746 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3007A>G | S1003G 2D AIThe SynGAP1 missense variant S1003G is catalogued in gnomAD (ID 6‑33443559‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for S1003G, 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. | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | 6-33443559-A-G | 1 | 6.20e-7 | -5.888 | Likely Benign | 0.542 | Ambiguous | Likely Benign | 0.088 | Likely Benign | -1.72 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2730 | 0.4789 | 0 | 1 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.3007A>T | S1003C 2D AIThe SynGAP1 missense variant S1003C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, PROVEAN, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect include polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and is classified as Likely Pathogenic. AlphaMissense‑Optimized, a high‑accuracy tool, predicts a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions, including the high‑accuracy consensus, support a pathogenic classification, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | -8.058 | Likely Pathogenic | 0.647 | Likely Pathogenic | Likely Benign | 0.141 | Likely Benign | -1.98 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 0.1442 | 0.5966 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.3008G>A | S1003N 2D AIThe SynGAP1 missense variant S1003N is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, 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 due to a 2‑vs‑2 split, and Foldetta results are unavailable. 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 based on current predictions, and this assessment does not contradict any ClinVar status because the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | -5.175 | Likely Benign | 0.889 | Likely Pathogenic | Ambiguous | 0.122 | Likely Benign | -1.37 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 0.1798 | 0.5029 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||||||
| 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.3008G>T | S1003I 2D AIThe SynGAP1 missense variant S1003I is not 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. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus methods give mixed results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic, two benign votes); and Foldetta (combining FoldX‑MD and Rosetta) has no available output. Based on the overall distribution of predictions, the variant is most likely pathogenic. This assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | -8.952 | Likely Pathogenic | 0.954 | Likely Pathogenic | Ambiguous | 0.189 | Likely Benign | -2.31 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.50 | Benign | 0.00 | Affected | 0.1294 | 0.5735 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3009C>A | S1003R 2D AIThe SynGAP1 missense variant S1003R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of evaluated tools (six pathogenic vs. three benign) indicate a pathogenic impact. This prediction aligns with the lack of ClinVar annotation and does not contradict any existing clinical classification. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | -5.113 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.141 | Likely Benign | -1.88 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1151 | 0.3746 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3009C>G | S1003R 2D AIThe SynGAP1 missense variant S1003R (ClinVar ID 1798770.0) is listed as Uncertain in ClinVar and is not present in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and ESM1b, while pathogenic predictions are reported by polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessment shows AlphaMissense‑Optimized classifying the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic), and Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a pathogenic effect, which contrasts with the ClinVar designation of Uncertain. Thus, the variant is most likely pathogenic, contradicting the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | Uncertain | 1 | -5.113 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.141 | Likely Benign | -1.88 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1151 | 0.3746 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| c.3325C>A | L1109I 2D AIThe SynGAP1 missense variant L1109I is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign, and this conclusion is consistent with the lack of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.856457 | Disordered | 0.948334 | Binding | 0.343 | 0.893 | 0.875 | -5.475 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.40 | Neutral | 0.126 | Benign | 0.040 | Benign | 2.70 | Benign | 0.23 | Tolerated | 0.1087 | 0.4703 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3325C>G | L1109V 2D AIThe SynGAP1 missense variant L1109V is catalogued in gnomAD (ID 6‑33443877‑C‑G) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this view: 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 assessment does not contradict any ClinVar status, as none is reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.856457 | Disordered | 0.948334 | Binding | 0.343 | 0.893 | 0.875 | 6-33443877-C-G | -5.490 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -0.52 | Neutral | 0.001 | Benign | 0.005 | Benign | 2.72 | Benign | 0.19 | Tolerated | 4.32 | 2 | 0.1676 | 0.4353 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.3325C>T | L1109F 2D AIThe SynGAP1 missense variant L1109F is not 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 status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.856457 | Disordered | 0.948334 | Binding | 0.343 | 0.893 | 0.875 | -3.459 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -1.04 | Neutral | 0.832 | Possibly Damaging | 0.324 | Benign | 2.74 | Benign | 0.12 | Tolerated | 0.0780 | 0.4540 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3326T>A | L1109H 2D AIThe SynGAP1 missense variant L1109H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.856457 | Disordered | 0.948334 | Binding | 0.343 | 0.893 | 0.875 | -4.353 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.134 | Likely Benign | -0.56 | Neutral | 0.832 | Possibly Damaging | 0.499 | Possibly Damaging | 2.70 | Benign | 0.04 | Affected | 0.1250 | 0.1845 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||||||
| c.3326T>C | L1109P 2D AIThe SynGAP1 missense variant L1109P is listed in ClinVar with an uncertain significance (ClinVar ID 1730257.0) and is not reported in gnomAD. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized indicates a benign effect, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign classification, which does not contradict the ClinVar uncertain status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.856457 | Disordered | 0.948334 | Binding | 0.343 | 0.893 | 0.875 | Conflicting | 2 | -5.313 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.151 | Likely Benign | -0.52 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.65 | Benign | 0.07 | Tolerated | 4.32 | 2 | 0.3159 | 0.2330 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||
| c.3326T>G | L1109R 2D AIThe SynGAP1 missense variant L1109R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains 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 is benign, and the SGM‑Consensus is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.856457 | Disordered | 0.948334 | Binding | 0.343 | 0.893 | 0.875 | -5.440 | Likely Benign | 0.408 | Ambiguous | Likely Benign | 0.139 | Likely Benign | -0.70 | Neutral | 0.586 | Possibly Damaging | 0.225 | Benign | 2.68 | Benign | 0.34 | Tolerated | 0.1352 | 0.1919 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3994A>C | T1332P 2D AIThe SynGAP1 missense variant T1332P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is tied 2‑2 and thus unavailable, and Foldetta results are not provided. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict any existing ClinVar status because the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.915074 | Disordered | 0.948427 | Binding | 0.442 | 0.754 | 0.875 | -3.404 | Likely Benign | 0.918 | Likely Pathogenic | Ambiguous | 0.238 | Likely Benign | -3.12 | Deleterious | 0.994 | Probably Damaging | 0.981 | Probably Damaging | 2.95 | Benign | 0.00 | Affected | 0.2185 | 0.5308 | 0 | -1 | -0.9 | -3.99 | ||||||||||||||||||||||||||||||||||||||||
| c.3994A>G | T1332A 2D AIThe SynGAP1 missense variant T1332A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, the majority of available predictions (five pathogenic vs. three 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. | 0.915074 | Disordered | 0.948427 | Binding | 0.442 | 0.754 | 0.875 | -3.521 | Likely Benign | 0.887 | Likely Pathogenic | Ambiguous | 0.150 | Likely Benign | -2.85 | Deleterious | 0.953 | Possibly Damaging | 0.935 | Probably Damaging | 3.02 | Benign | 0.00 | Affected | 0.4042 | 0.4766 | 1 | 0 | 2.5 | -30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3994A>T | T1332S 2D AIThe SynGAP1 missense variant T1332S is reported in gnomAD (ID 6‑33451868‑A‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as “Likely Benign” (three benign votes versus one pathogenic). High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect; this conclusion is not contradicted by ClinVar, which contains no classification for T1332S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.915074 | Disordered | 0.948427 | Binding | 0.442 | 0.754 | 0.875 | 6-33451868-A-T | -3.085 | Likely Benign | 0.674 | Likely Pathogenic | Likely Benign | 0.163 | Likely Benign | -2.29 | Neutral | 0.980 | Probably Damaging | 0.935 | Probably Damaging | 3.00 | Benign | 0.00 | Affected | 3.77 | 5 | 0.3451 | 0.5007 | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.3995C>A | T1332K 2D AIThe SynGAP1 missense variant T1332K is catalogued in gnomAD (ID 6‑33451869‑C‑A) but has no ClinVar submission. Functional prediction tools cluster into two groups: benign predictions from REVEL, ESM1b, and FATHMM; pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. A high‑accuracy consensus (SGM) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a 2‑to‑2 split, leaving the consensus inconclusive. No Foldetta stability assessment is available. Overall, the majority of evidence (five pathogenic versus three benign) points to a pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.915074 | Disordered | 0.948427 | Binding | 0.442 | 0.754 | 0.875 | 6-33451869-C-A | -3.264 | Likely Benign | 0.935 | Likely Pathogenic | Ambiguous | 0.247 | Likely Benign | -3.48 | Deleterious | 0.998 | Probably Damaging | 0.989 | Probably Damaging | 2.96 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1424 | 0.4376 | -1 | 0 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||
| c.3995C>G | T1332R 2D AIThe SynGAP1 missense variant T1332R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie and therefore unavailable; Foldetta results are not provided. Overall, the balance of evidence (five pathogenic versus three benign predictions) indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.915074 | Disordered | 0.948427 | Binding | 0.442 | 0.754 | 0.875 | -3.354 | Likely Benign | 0.878 | Likely Pathogenic | Ambiguous | 0.271 | Likely Benign | -3.59 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 2.96 | Benign | 0.00 | Affected | 0.1173 | 0.3867 | -1 | -1 | -3.8 | 55.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3995C>T | T1332M 2D  AISynGAP1 missense variant T1332M is listed as Benign in ClinVar (ID 794425) and is present in gnomAD (6‑33451869‑C‑T). Functional prediction tools show mixed results: benign calls come from REVEL, ESM1b, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized returned an uncertain result, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie, and no Foldetta stability data are available. Overall, the majority of evidence points toward a pathogenic effect, which contradicts the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.915074 | Disordered | 0.948427 | Binding | 0.442 | 0.754 | 0.875 | Likely Benign | 1 | 6-33451869-C-T | 20 | 1.86e-5 | -4.107 | Likely Benign | 0.948 | Likely Pathogenic | Ambiguous | 0.252 | Likely Benign | -3.63 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 2.95 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1551 | 0.6513 | -1 | -1 | 2.6 | 30.09 | |||||||||||||||||||||||||||||||||
| c.3925G>A | V1309M 2D  AIThe SynGAP1 missense variant V1309M is listed in ClinVar with no submitted interpretation and is present in gnomAD (variant ID 6-33451799-G-A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, 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; no Foldetta stability data are available. Overall, the majority of evidence points to a benign impact for V1309M, and this conclusion does not contradict ClinVar status, which currently has no pathogenic 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 | 6-33451799-G-A | 1 | 6.20e-7 | -4.653 | Likely Benign | 0.183 | Likely Benign | Likely Benign | 0.072 | Likely Benign | 0.18 | Neutral | 0.651 | Possibly Damaging | 0.346 | Benign | 2.44 | Pathogenic | 0.04 | Affected | 3.77 | 5 | 0.0820 | 0.4116 | 1 | 2 | -2.3 | 32.06 | ||||||||||||||||||||||||||||||||||
| 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.3926T>A | V1309E 2D  AIThe SynGAP1 missense variant V1309E is not 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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 because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.712013 | Disordered | 0.948596 | Binding | 0.402 | 0.907 | 0.750 | -3.393 | Likely Benign | 0.333 | Likely Benign | Likely Benign | 0.294 | Likely Benign | -2.40 | Neutral | 0.767 | Possibly Damaging | 0.473 | Possibly Damaging | 2.40 | Pathogenic | 0.00 | Affected | 0.1098 | 0.1727 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||||||||||||
| c.3926T>C | V1309A 2D AIThe SynGAP1 missense variant V1309A 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, 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 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 | 0.712013 | Disordered | 0.948596 | Binding | 0.402 | 0.907 | 0.750 | -2.336 | Likely Benign | 0.187 | Likely Benign | Likely Benign | 0.269 | Likely Benign | -1.31 | Neutral | 0.088 | Benign | 0.085 | Benign | 2.44 | Pathogenic | 0.02 | Affected | 0.2641 | 0.1797 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| c.3926T>G | V1309G 2D AIThe SynGAP1 missense variant V1309G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs. 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence points toward a benign impact, and this conclusion does not contradict any ClinVar annotation because the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.712013 | Disordered | 0.948596 | Binding | 0.402 | 0.907 | 0.750 | -2.618 | Likely Benign | 0.160 | Likely Benign | Likely Benign | 0.326 | Likely Benign | -3.40 | Deleterious | 0.391 | Benign | 0.767 | Possibly Damaging | 2.40 | Pathogenic | 0.00 | Affected | 0.1901 | 0.2144 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2989G>A | A997T 2D AIThe SynGAP1 missense variant A997T is listed in ClinVar with an uncertain significance and is not reported in gnomAD. 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 of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the four high‑accuracy predictors) is benign; Foldetta results are unavailable. Taken together, the majority of computational evidence indicates 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 | 0.754692 | Disordered | 0.948624 | Binding | 0.273 | 0.901 | 0.500 | Uncertain | 1 | -4.102 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -0.62 | Neutral | 0.224 | Benign | 0.120 | Benign | 4.17 | Benign | 0.00 | Affected | 4.32 | 4 | 0.1582 | 0.7182 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.2989G>C | A997P 2D AIThe SynGAP1 missense variant A997P 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 further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are unavailable, 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 | 0.754692 | Disordered | 0.948624 | Binding | 0.273 | 0.901 | 0.500 | -2.014 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -1.17 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.11 | Benign | 0.00 | Affected | 0.1938 | 0.5294 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2989G>T | A997S 2D AIThe SynGAP1 missense variant A997S 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 | 0.754692 | Disordered | 0.948624 | Binding | 0.273 | 0.901 | 0.500 | -3.362 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.63 | Neutral | 0.224 | Benign | 0.066 | Benign | 4.18 | Benign | 0.00 | Affected | 0.2661 | 0.5694 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2990C>A | A997D 2D AIThe SynGAP1 missense variant A997D is not 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 further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect, 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 | 0.754692 | Disordered | 0.948624 | Binding | 0.273 | 0.901 | 0.500 | -5.251 | Likely Benign | 0.319 | Likely Benign | Likely Benign | 0.131 | Likely Benign | -1.09 | Neutral | 0.411 | Benign | 0.120 | Benign | 4.15 | Benign | 0.00 | Affected | 0.1815 | 0.2143 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2990C>G | A997G 2D AIThe SynGAP1 missense variant A997G is not 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. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.948624 | Binding | 0.273 | 0.901 | 0.500 | -3.424 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -0.82 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.13 | Benign | 0.00 | Affected | 0.2145 | 0.4741 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2990C>T | A997V 2D AIThe SynGAP1 missense variant A997V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. The prediction is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.948624 | Binding | 0.273 | 0.901 | 0.500 | -4.504 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.052 | Likely Benign | -1.01 | Neutral | 0.369 | Benign | 0.120 | Benign | 4.15 | Benign | 0.00 | Affected | 0.1232 | 0.6335 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.3133G>A | A1045T 2D AIThe SynGAP1 missense variant A1045T 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 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 | 0.975609 | Disordered | 0.948874 | Binding | 0.352 | 0.882 | 0.750 | -4.531 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.059 | Likely Benign | 0.03 | Neutral | 0.004 | Benign | 0.010 | Benign | 2.68 | Benign | 0.52 | Tolerated | 0.1857 | 0.6682 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3133G>C | A1045P 2D AIThe SynGAP1 missense variant A1045P 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 | 0.975609 | Disordered | 0.948874 | Binding | 0.352 | 0.882 | 0.750 | -2.260 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.099 | Likely Benign | 1.09 | Neutral | 0.586 | Possibly Damaging | 0.223 | Benign | 2.64 | Benign | 0.24 | Tolerated | 0.2130 | 0.5332 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3133G>T | A1045S 2D AIThe SynGAP1 missense variant A1045S 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, 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 | 0.975609 | Disordered | 0.948874 | Binding | 0.352 | 0.882 | 0.750 | -3.724 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.11 | Neutral | 0.011 | Benign | 0.010 | Benign | 2.66 | Benign | 0.46 | Tolerated | 0.2648 | 0.5493 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3134C>A | A1045D 2D AIThe SynGAP1 missense variant A1045D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach consensus all indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all score the variant as benign. AlphaMissense‑Optimized also predicts a benign outcome, whereas AlphaMissense‑Default remains uncertain. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” No tools predict pathogenicity. High‑accuracy assessments further support a benign interpretation: 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 collective predictions strongly suggest that A1045D 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 | 0.975609 | Disordered | 0.948874 | Binding | 0.352 | 0.882 | 0.750 | -5.734 | Likely Benign | 0.418 | Ambiguous | Likely Benign | 0.066 | Likely Benign | -1.00 | Neutral | 0.411 | Benign | 0.172 | Benign | 2.64 | Benign | 0.16 | Tolerated | 0.1954 | 0.2102 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.3134C>G | A1045G 2D AIThe SynGAP1 missense variant A1045G is reported in ClinVar as Benign (ClinVar ID 416778.0) and is present in the gnomAD database (gnomAD ID 6‑33443686‑C‑G). 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 classify the variant as benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments reinforce this consensus: 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 variant is most likely benign, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.975609 | Disordered | 0.948874 | Binding | 0.352 | 0.882 | 0.750 | Benign/Likely benign | 7 | 6-33443686-C-G | 1407 | 8.72e-4 | -3.246 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.024 | Likely Benign | -1.21 | Neutral | 0.224 | Benign | 0.066 | Benign | 2.64 | Benign | 0.33 | Tolerated | 3.77 | 5 | 0.2246 | 0.4798 | 1 | 0 | -2.2 | -14.03 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.3134C>T | A1045V 2D AIThe SynGAP1 missense variant A1045V 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 | 0.975609 | Disordered | 0.948874 | Binding | 0.352 | 0.882 | 0.750 | -4.229 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -0.35 | Neutral | 0.011 | Benign | 0.017 | Benign | 3.06 | Benign | 1.00 | Tolerated | 0.1487 | 0.5474 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.3322A>C | S1108R 2D AISynGAP1 missense variant S1108R is not reported in ClinVar (status: None) and is absent from gnomAD (no entry). Prediction tools that classify the variant as benign include REVEL, polyPhen‑2 HumVar, ESM1b, and FATHMM. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN is inconclusive, as it yields a 2‑vs‑2 split. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, has no available result for this variant. Overall, the computational evidence is mixed, with an equal number of benign and pathogenic calls and no high‑confidence consensus. Thus, the variant is most likely pathogenic based on the current predictions, and this assessment does not contradict the ClinVar status, which is unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -5.878 | Likely Benign | 0.912 | Likely Pathogenic | Ambiguous | 0.130 | Likely Benign | -2.75 | Deleterious | 0.611 | Possibly Damaging | 0.329 | Benign | 2.54 | Benign | 0.04 | Affected | 0.0864 | 0.3492 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3322A>G | S1108G 2D AIThe SynGAP1 missense variant S1108G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence (six benign vs three pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Thus, the variant is most likely benign based on current predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -6.496 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.084 | Likely Benign | -2.59 | Deleterious | 0.568 | Possibly Damaging | 0.239 | Benign | 2.46 | Pathogenic | 0.16 | Tolerated | 0.2268 | 0.3975 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3322A>T | S1108C 2D AIThe SynGAP1 missense variant S1108C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains Likely Pathogenic; Foldetta results are unavailable. Overall, the majority of predictions (seven pathogenic vs. three benign) support a pathogenic classification, and this conclusion does not contradict any ClinVar status because none is available. Thus, the variant is most likely pathogenic based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -9.189 | Likely Pathogenic | 0.183 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -3.30 | Deleterious | 0.992 | Probably Damaging | 0.820 | Possibly Damaging | 2.42 | Pathogenic | 0.04 | Affected | 0.0992 | 0.5299 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.3323G>A | S1108N 2D AIThe SynGAP1 missense variant S1108N is not 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, 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 S1108N, 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 | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -6.488 | Likely Benign | 0.250 | Likely Benign | Likely Benign | 0.070 | Likely Benign | -2.02 | Neutral | 0.611 | Possibly Damaging | 0.239 | Benign | 2.47 | Pathogenic | 0.06 | Tolerated | 0.1283 | 0.3952 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| 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.3323G>T | S1108I 2D AIThe SynGAP1 missense variant S1108I is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443875‑G‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized 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. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, has no reported result for this variant. Overall, the balance of evidence (five benign versus four pathogenic predictions) suggests the variant is most likely benign, and this conclusion does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | Uncertain | 1 | 6-33443875-G-T | -3.666 | Likely Benign | 0.292 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -3.73 | Deleterious | 0.971 | Probably Damaging | 0.604 | Possibly Damaging | 2.44 | Pathogenic | 0.10 | Tolerated | 3.77 | 5 | 0.0949 | 0.4602 | -2 | -1 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||
| c.3324C>A | S1108R 2D AISynGAP1 missense variant S1108R has no ClinVar record and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, ESM1b, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a 2‑to‑2 split and therefore unavailable; Foldetta, which would combine FoldX‑MD and Rosetta outputs, has no reported result. Consequently, the evidence is evenly divided, leaving the variant’s functional impact uncertain. The predictions do not contradict any ClinVar status, as none is available. Overall, the variant is most likely of uncertain significance rather than definitively benign or pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -5.878 | Likely Benign | 0.912 | Likely Pathogenic | Ambiguous | 0.109 | Likely Benign | -2.75 | Deleterious | 0.611 | Possibly Damaging | 0.329 | Benign | 2.54 | Benign | 0.04 | Affected | 0.0864 | 0.3492 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3324C>G | S1108R 2D AIThe SynGAP1 missense variant S1108R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, and FATHMM, while those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign). Foldetta, which would assess protein‑folding stability, has no available result for this variant. Overall, the computational evidence is balanced, providing no clear bias toward benign or pathogenic. Thus, the variant’s likely impact remains uncertain, and there is no contradiction with the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -5.878 | Likely Benign | 0.912 | Likely Pathogenic | Ambiguous | 0.108 | Likely Benign | -2.75 | Deleterious | 0.611 | Possibly Damaging | 0.329 | Benign | 2.54 | Benign | 0.04 | Affected | 0.0864 | 0.3492 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.2812G>A | G938R 2D AIThe SynGAP1 missense variant G938R is listed in ClinVar (ID 1019898.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence (seven benign versus three pathogenic predictions) supports a benign classification. This consensus does not contradict the ClinVar “Uncertain” designation, which remains unresolved. 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 | Uncertain | 1 | -5.271 | Likely Benign | 0.732 | Likely Pathogenic | Likely Benign | 0.141 | Likely Benign | -1.11 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.74 | Benign | 0.36 | Tolerated | 3.77 | 5 | 0.0924 | 0.3614 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.2812G>C | G938R 2D AIThe SynGAP1 missense variant G938R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Benign” call. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation. 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 | 0.905695 | Disordered | 0.949795 | Binding | 0.318 | 0.883 | 0.625 | -5.271 | Likely Benign | 0.732 | Likely Pathogenic | Likely Benign | 0.141 | Likely Benign | -1.11 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.74 | Benign | 0.36 | Tolerated | 3.77 | 5 | 0.0924 | 0.3614 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.2812G>T | G938W 2D AIThe SynGAP1 missense variant G938W is not 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 agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs. four benign) indicate that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar annotation exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.905695 | Disordered | 0.949795 | Binding | 0.318 | 0.883 | 0.625 | -8.763 | Likely Pathogenic | 0.604 | Likely Pathogenic | Likely Benign | 0.194 | Likely Benign | -1.71 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.70 | Benign | 0.04 | Affected | 0.0762 | 0.4008 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||||||
| c.2813G>A | G938E 2D AIThe SynGAP1 missense variant G938E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The variant’s predicted benign status does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.949795 | Binding | 0.318 | 0.883 | 0.625 | -5.394 | Likely Benign | 0.577 | Likely Pathogenic | Likely Benign | 0.112 | Likely Benign | -1.40 | Neutral | 0.997 | Probably Damaging | 0.979 | Probably Damaging | 2.75 | Benign | 0.28 | Tolerated | 0.1370 | 0.3720 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| 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.2813G>T | G938V 2D AIThe SynGAP1 missense variant G938V is not 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, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that G938V 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 | 0.905695 | Disordered | 0.949795 | Binding | 0.318 | 0.883 | 0.625 | -6.112 | Likely Benign | 0.153 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -0.81 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.83 | Benign | 0.31 | Tolerated | 0.1230 | 0.3811 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| 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.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.2995T>G | S999A 2D AIThe SynGAP1 missense variant S999A 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 | 0.834292 | Disordered | 0.950682 | Binding | 0.262 | 0.897 | 0.625 | -3.719 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -0.83 | Neutral | 0.005 | Benign | 0.016 | Benign | 2.71 | Benign | 0.81 | Tolerated | 0.4516 | 0.5434 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2996C>A | S999Y 2D AIThe SynGAP1 missense variant S999Y is not 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 S999Y, 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 | 0.834292 | Disordered | 0.950682 | Binding | 0.262 | 0.897 | 0.625 | -6.446 | Likely Benign | 0.346 | Ambiguous | Likely Benign | 0.069 | Likely Benign | -1.74 | Neutral | 0.934 | Possibly Damaging | 0.559 | Possibly Damaging | 2.64 | Benign | 0.00 | Affected | 0.0881 | 0.6249 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2996C>G | S999C 2D AIThe SynGAP1 missense variant S999C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. ESM1b is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S999C, 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 | 0.834292 | Disordered | 0.950682 | Binding | 0.262 | 0.897 | 0.625 | -7.751 | In-Between | 0.139 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -1.68 | Neutral | 0.991 | Probably Damaging | 0.873 | Possibly Damaging | 2.63 | Benign | 0.01 | Affected | 0.1131 | 0.6212 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2996C>T | S999F 2D AIThe SynGAP1 missense variant S999F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. 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 independently predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect; this 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 | 0.834292 | Disordered | 0.950682 | Binding | 0.262 | 0.897 | 0.625 | -6.206 | Likely Benign | 0.368 | Ambiguous | Likely Benign | 0.072 | Likely Benign | -1.79 | Neutral | 0.966 | Probably Damaging | 0.837 | Possibly Damaging | 2.64 | Benign | 0.01 | Affected | 0.0865 | 0.6337 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.3319C>A | Q1107K 2D AIThe SynGAP1 missense variant Q1107K is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools largely support a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. Only polyPhen‑2 HumDiv predicts a pathogenic effect, and AlphaMissense‑Default remains uncertain. High‑accuracy assessments further reinforce the 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 impact, and this conclusion is not in conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -4.066 | Likely Benign | 0.400 | Ambiguous | Likely Benign | 0.095 | Likely Benign | -1.99 | Neutral | 0.920 | Possibly Damaging | 0.425 | Benign | 2.60 | Benign | 0.30 | Tolerated | 0.1805 | 0.5276 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3319C>G | Q1107E 2D AIThe SynGAP1 missense variant Q1107E 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 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 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 | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -3.875 | Likely Benign | 0.231 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -1.54 | Neutral | 0.920 | Possibly Damaging | 0.425 | Benign | 2.59 | Benign | 0.02 | Affected | 0.1453 | 0.2932 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3320A>C | Q1107P 2D AIThe SynGAP1 missense variant Q1107P 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—including the high‑accuracy tools—points to a benign effect for Q1107P, 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 | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -2.643 | Likely Benign | 0.047 | Likely Benign | Likely Benign | 0.135 | Likely Benign | -2.35 | Neutral | 0.965 | Probably Damaging | 0.611 | Possibly Damaging | 2.57 | Benign | 0.01 | Affected | 0.2109 | 0.5767 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3320A>G | Q1107R 2D AIThe SynGAP1 missense variant Q1107R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. AlphaMissense‑Default is uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” 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 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 | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -2.837 | Likely Benign | 0.394 | Ambiguous | Likely Benign | 0.126 | Likely Benign | -1.76 | Neutral | 0.965 | Probably Damaging | 0.425 | Benign | 2.55 | Benign | 0.04 | Affected | 0.1482 | 0.3319 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.3320A>T | Q1107L 2D AIThe SynGAP1 missense variant Q1107L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, PROVEAN and SIFT predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -3.785 | Likely Benign | 0.116 | Likely Benign | Likely Benign | 0.119 | Likely Benign | -3.27 | Deleterious | 0.006 | Benign | 0.004 | Benign | 2.53 | Benign | 0.01 | Affected | 0.0820 | 0.6447 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| 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.2911C>A | P971T 2D AIThe SynGAP1 missense variant P971T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.950334 | Disordered | 0.951523 | Binding | 0.545 | 0.905 | 0.625 | -5.627 | Likely Benign | 0.053 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -0.95 | Neutral | 0.001 | Benign | 0.003 | Benign | 3.96 | Benign | 0.00 | Affected | 0.1388 | 0.5888 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2911C>G | P971A 2D AIThe SynGAP1 missense variant P971A 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 a “Likely Benign” consensus. High‑accuracy assessments confirm this: 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 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 | 0.950334 | Disordered | 0.951523 | Binding | 0.545 | 0.905 | 0.625 | -4.244 | Likely Benign | 0.049 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -0.51 | Neutral | 0.000 | Benign | 0.002 | Benign | 4.05 | Benign | 0.00 | Affected | 0.3100 | 0.5282 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2911C>T | P971S 2D AIThe SynGAP1 missense variant P971S is catalogued in gnomAD (ID 6‑33443463‑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, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all indicate a benign or likely benign outcome. Only SIFT classifies the change as pathogenic, representing a minority opinion. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise reports likely benign. No Foldetta stability analysis is available, so it does not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.950334 | Disordered | 0.951523 | Binding | 0.545 | 0.905 | 0.625 | 6-33443463-C-T | 1 | 6.20e-7 | -4.188 | Likely Benign | 0.061 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.51 | Neutral | 0.002 | Benign | 0.003 | Benign | 3.99 | Benign | 0.00 | Affected | 4.32 | 2 | 0.3009 | 0.5667 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.2912C>A | P971H 2D AIThe SynGAP1 missense variant P971H is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443464‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; a Foldetta stability prediction is not available. 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 | 0.950334 | Disordered | 0.951523 | Binding | 0.545 | 0.905 | 0.625 | Uncertain | 1 | 6-33443464-C-A | 1 | 6.20e-7 | -5.243 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -1.11 | Neutral | 0.898 | Possibly Damaging | 0.477 | Possibly Damaging | 3.89 | Benign | 0.00 | Affected | 4.32 | 2 | 0.1584 | 0.4858 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||
| c.2912C>G | P971R 2D AIThe SynGAP1 missense variant P971R is not 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 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 is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.950334 | Disordered | 0.951523 | Binding | 0.545 | 0.905 | 0.625 | -4.407 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.042 | Likely Benign | -1.01 | Neutral | 0.453 | Possibly Damaging | 0.078 | Benign | 3.91 | Benign | 0.00 | Affected | 0.1306 | 0.3818 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2912C>T | P971L 2D AIThe SynGAP1 missense variant P971L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.950334 | Disordered | 0.951523 | Binding | 0.545 | 0.905 | 0.625 | -4.892 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -1.57 | Neutral | 0.144 | Benign | 0.026 | Benign | 3.93 | Benign | 0.00 | Affected | 0.2046 | 0.5985 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2950A>C | K984Q 2D AIThe SynGAP1 missense variant K984Q is not 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 unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.951648 | Binding | 0.288 | 0.895 | 0.750 | -2.932 | Likely Benign | 0.612 | Likely Pathogenic | Likely Benign | 0.083 | Likely Benign | -0.67 | Neutral | 0.905 | Possibly Damaging | 0.637 | Possibly Damaging | 2.66 | Benign | 0.00 | Affected | 0.5054 | 0.1240 | Weaken | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||||||||||
| c.2950A>G | K984E 2D AIThe SynGAP1 missense variant K984E has no ClinVar record and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, PROVEAN, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default predict it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. Overall, the majority of individual predictors lean toward benign, and the consensus score explicitly labels it benign, whereas a comparable number of tools predict pathogenicity. Based on the available evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.951648 | Binding | 0.288 | 0.895 | 0.750 | -4.909 | Likely Benign | 0.932 | Likely Pathogenic | Ambiguous | 0.086 | Likely Benign | -0.88 | Neutral | 0.798 | Possibly Damaging | 0.535 | Possibly Damaging | 2.71 | Benign | 0.00 | Affected | 0.4353 | 0.1200 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.2951A>C | K984T 2D AIThe SynGAP1 missense variant K984T is not 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, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the predictions are mixed; however, the SGM‑Consensus and the majority of benign‑predicting tools lean toward a benign interpretation. This assessment does not contradict ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.951648 | Binding | 0.288 | 0.895 | 0.750 | -3.429 | Likely Benign | 0.854 | Likely Pathogenic | Ambiguous | 0.087 | Likely Benign | -1.10 | Neutral | 0.951 | Possibly Damaging | 0.708 | Possibly Damaging | 2.71 | Benign | 0.00 | Affected | 0.2441 | 0.3463 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||||||
| c.2951A>G | K984R 2D AIThe SynGAP1 missense variant K984R is reported in gnomAD (ID 6‑33443503‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it to be pathogenic. 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 is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of tools indicates that 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 | 0.703578 | Disordered | 0.951648 | Binding | 0.288 | 0.895 | 0.750 | 6-33443503-A-G | 2 | 1.24e-6 | -2.044 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -0.41 | Neutral | 0.012 | Benign | 0.012 | Benign | 2.67 | Benign | 0.00 | Affected | 4.32 | 1 | 0.5098 | 0.1558 | Weaken | 2 | 3 | -0.6 | 28.01 | |||||||||||||||||||||||||||||||||
| c.2951A>T | K984M 2D AIThe SynGAP1 missense variant K984M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.951648 | Binding | 0.288 | 0.895 | 0.750 | -4.761 | Likely Benign | 0.934 | Likely Pathogenic | Ambiguous | 0.141 | Likely Benign | -1.82 | Neutral | 0.995 | Probably Damaging | 0.944 | Probably Damaging | 2.60 | Benign | 0.00 | Affected | 0.1576 | 0.4168 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.2952G>C | K984N 2D AIThe SynGAP1 missense variant K984N is catalogued in gnomAD (6‑33443504‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, and FATHMM, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments are mixed: AlphaMissense‑Optimized rates the variant as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it “Likely Benign,” and Foldetta (which integrates FoldX‑MD and Rosetta outputs) has no available result for this residue. Overall, the balance of evidence leans toward a benign effect, with no pathogenic ClinVar classification to contradict this inference. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.951648 | Binding | 0.288 | 0.895 | 0.750 | 6-33443504-G-C | 1 | 6.20e-7 | -3.020 | Likely Benign | 0.955 | Likely Pathogenic | Ambiguous | 0.091 | Likely Benign | 0.52 | Neutral | 0.951 | Possibly Damaging | 0.637 | Possibly Damaging | 2.89 | Benign | 0.00 | Affected | 4.32 | 1 | 0.4138 | 0.1677 | 0 | 1 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||
| c.2952G>T | K984N 2D AISynGAP1 missense variant K984N has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is Uncertain, SGM‑Consensus is Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, 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 | 0.703578 | Disordered | 0.951648 | Binding | 0.288 | 0.895 | 0.750 | -3.020 | Likely Benign | 0.955 | Likely Pathogenic | Ambiguous | 0.091 | Likely Benign | 0.52 | Neutral | 0.951 | Possibly Damaging | 0.637 | Possibly Damaging | 2.89 | Benign | 0.00 | Affected | 4.32 | 1 | 0.4138 | 0.1677 | 0 | 1 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||
| c.2992G>A | A998T 2D AIThe SynGAP1 missense variant A998T is not 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 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 conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.759478 | Disordered | 0.951758 | Binding | 0.318 | 0.902 | 0.500 | -3.909 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.97 | Neutral | 0.611 | Possibly Damaging | 0.321 | Benign | 4.11 | Benign | 0.00 | Affected | 0.1620 | 0.6994 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2992G>C | A998P 2D AIThe SynGAP1 missense variant A998P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence, including the high‑accuracy tools, points to a benign effect for A998P. 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 | 0.759478 | Disordered | 0.951758 | Binding | 0.318 | 0.902 | 0.500 | -2.220 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.171 | Likely Benign | -0.40 | Neutral | 0.971 | Probably Damaging | 0.690 | Possibly Damaging | 4.31 | Benign | 0.00 | Affected | 0.1924 | 0.5106 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2992G>T | A998S 2D AIThe SynGAP1 missense variant A998S is not reported in ClinVar and is absent from gnomAD. Functional 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 the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The variant is therefore 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 | 0.759478 | Disordered | 0.951758 | Binding | 0.318 | 0.902 | 0.500 | -2.893 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.022 | Likely Benign | -0.42 | Neutral | 0.611 | Possibly Damaging | 0.237 | Benign | 4.14 | Benign | 0.00 | Affected | 0.2674 | 0.5506 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2993C>A | A998D 2D AIThe SynGAP1 missense variant A998D is not reported in ClinVar and has no entry in gnomAD. Consensus from multiple in‑silico predictors shows a split: benign calls come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. The high‑accuracy assessment indicates that AlphaMissense‑Optimized predicts a benign effect, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely benign outcome, and Foldetta data are unavailable. Overall, the majority of robust predictors lean toward a benign impact. Therefore, 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 | 0.759478 | Disordered | 0.951758 | Binding | 0.318 | 0.902 | 0.500 | -5.481 | Likely Benign | 0.365 | Ambiguous | Likely Benign | 0.122 | Likely Benign | -1.55 | Neutral | 0.971 | Probably Damaging | 0.690 | Possibly Damaging | 4.09 | Benign | 0.00 | Affected | 0.1754 | 0.2143 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2993C>G | A998G 2D AIThe SynGAP1 missense variant A998G is not reported in ClinVar or gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the available predictions points to a benign impact, 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 | 0.759478 | Disordered | 0.951758 | Binding | 0.318 | 0.902 | 0.500 | -3.173 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.032 | Likely Benign | -1.29 | Neutral | 0.761 | Possibly Damaging | 0.396 | Benign | 4.13 | Benign | 0.00 | Affected | 0.2234 | 0.4741 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2993C>T | A998V 2D AIThe SynGAP1 missense variant A998V is not 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 | 0.759478 | Disordered | 0.951758 | Binding | 0.318 | 0.902 | 0.500 | -4.795 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -1.09 | Neutral | 0.245 | Benign | 0.138 | Benign | 4.09 | Benign | 0.00 | Affected | 0.1281 | 0.6147 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.3316C>A | Q1106K 2D AIThe SynGAP1 missense variant Q1106K is catalogued in gnomAD (ID 6‑33443868‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized; pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. AlphaMissense‑Default is uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because the votes are split (two benign, one pathogenic, one uncertain). Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence favors a benign effect, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.885302 | Disordered | 0.952043 | Binding | 0.382 | 0.870 | 0.875 | 6-33443868-C-A | -3.368 | Likely Benign | 0.527 | Ambiguous | Likely Benign | 0.115 | Likely Benign | -2.49 | Neutral | 0.963 | Probably Damaging | 0.959 | Probably Damaging | 1.82 | Pathogenic | 0.16 | Tolerated | 3.77 | 5 | 0.1827 | 0.4800 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||
| c.3316C>G | Q1106E 2D AIThe SynGAP1 missense variant Q1106E is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, PolyPhen‑2 (HumDiv and HumVar) and FATHMM predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also likely benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for Q1106E, 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 | 0.885302 | Disordered | 0.952043 | Binding | 0.382 | 0.870 | 0.875 | -5.074 | Likely Benign | 0.307 | Likely Benign | Likely Benign | 0.127 | Likely Benign | -1.60 | Neutral | 0.963 | Probably Damaging | 0.959 | Probably Damaging | 1.80 | Pathogenic | 0.15 | Tolerated | 0.1381 | 0.2663 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3317A>C | Q1106P 2D AIThe SynGAP1 missense variant Q1106P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the balance of evidence (5 benign vs 4 pathogenic predictions, with a benign high‑accuracy score and no contradictory ClinVar annotation) indicates that the variant is most likely benign. 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. | 0.885302 | Disordered | 0.952043 | Binding | 0.382 | 0.870 | 0.875 | -3.807 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.162 | Likely Benign | -3.14 | Deleterious | 0.996 | Probably Damaging | 0.988 | Probably Damaging | 1.75 | Pathogenic | 0.31 | Tolerated | 0.2029 | 0.5781 | 0 | -1 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||||||||||||
| c.3317A>G | Q1106R 2D AIThe SynGAP1 missense variant Q1106R is not 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, and FATHMM. AlphaMissense‑Default is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it contains two benign, one pathogenic, and one uncertain call. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑confidence predictors (four benign vs. three pathogenic) lean toward a benign interpretation, and this assessment does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.885302 | Disordered | 0.952043 | Binding | 0.382 | 0.870 | 0.875 | -4.211 | Likely Benign | 0.475 | Ambiguous | Likely Benign | 0.133 | Likely Benign | -2.20 | Neutral | 0.985 | Probably Damaging | 0.973 | Probably Damaging | 1.80 | Pathogenic | 0.09 | Tolerated | 0.1412 | 0.2850 | 1 | 1 | -1.0 | 28.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3317A>T | Q1106L 2D AIThe SynGAP1 missense variant Q1106L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic impact. This assessment does not contradict ClinVar status, as the variant is currently unreported in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.885302 | Disordered | 0.952043 | Binding | 0.382 | 0.870 | 0.875 | -4.219 | Likely Benign | 0.171 | Likely Benign | Likely Benign | 0.169 | Likely Benign | -4.46 | Deleterious | 0.985 | Probably Damaging | 0.973 | Probably Damaging | 1.77 | Pathogenic | 0.05 | Affected | 0.0833 | 0.6282 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||||||||||||
| 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.3130C>A | P1044T 2D AIThe SynGAP1 missense variant P1044T is catalogued in gnomAD (ID 6‑33443682‑C‑A) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized returns a benign prediction, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.979741 | Disordered | 0.952126 | Binding | 0.331 | 0.855 | 0.750 | 6-33443682-C-A | 1 | 6.20e-7 | -4.605 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.372 | Likely Benign | -1.02 | Neutral | 0.126 | Benign | 0.096 | Benign | 5.53 | Benign | 0.17 | Tolerated | 3.77 | 5 | 0.1681 | 0.6860 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||
| c.3130C>G | P1044A 2D AIThe SynGAP1 missense variant P1044A 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 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 | 0.979741 | Disordered | 0.952126 | Binding | 0.331 | 0.855 | 0.750 | -3.957 | Likely Benign | 0.059 | Likely Benign | Likely Benign | 0.359 | Likely Benign | -1.07 | Neutral | 0.059 | Benign | 0.061 | Benign | 5.50 | Benign | 0.18 | Tolerated | 0.3194 | 0.5850 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3130C>T | P1044S 2D AIThe SynGAP1 missense variant P1044S 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 | 0.979741 | Disordered | 0.952126 | Binding | 0.331 | 0.855 | 0.750 | -4.114 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.311 | Likely Benign | -0.79 | Neutral | 0.011 | Benign | 0.015 | Benign | 5.51 | Benign | 0.14 | Tolerated | 0.3194 | 0.6081 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3131C>A | P1044Q 2D AIThe SynGAP1 missense variant P1044Q is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.979741 | Disordered | 0.952126 | Binding | 0.331 | 0.855 | 0.750 | -4.439 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.338 | Likely Benign | 0.51 | Neutral | 0.004 | Benign | 0.015 | Benign | 5.43 | Benign | 0.45 | Tolerated | 0.1544 | 0.5591 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3131C>G | P1044R 2D AIThe SynGAP1 missense variant P1044R is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the collective evidence strongly supports a benign classification, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.979741 | Disordered | 0.952126 | Binding | 0.331 | 0.855 | 0.750 | -3.969 | Likely Benign | 0.242 | Likely Benign | Likely Benign | 0.368 | Likely Benign | 0.79 | Neutral | 0.259 | Benign | 0.140 | Benign | 5.45 | Benign | 1.00 | Tolerated | 0.1451 | 0.4270 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3131C>T | P1044L 2D AIThe SynGAP1 missense variant P1044L is not represented in ClinVar (no ClinVar ID) and is absent from gnomAD. All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic or likely pathogenic outcome. High‑accuracy assessments reinforce this benign prediction: AlphaMissense‑Optimized indicates benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.979741 | Disordered | 0.952126 | Binding | 0.331 | 0.855 | 0.750 | -4.327 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 0.418 | Likely Benign | -1.64 | Neutral | 0.411 | Benign | 0.187 | Benign | 5.43 | Benign | 0.15 | Tolerated | 0.2264 | 0.6586 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3190C>A | Q1064K 2D AIThe SynGAP1 missense variant Q1064K is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the collective predictions strongly support a benign classification, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation, so there is no contradiction. 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 | -3.592 | Likely Benign | 0.234 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -0.32 | Neutral | 0.224 | Benign | 0.120 | Benign | 4.23 | Benign | 0.24 | Tolerated | 0.2758 | 0.4192 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3190C>G | Q1064E 2D AIThe SynGAP1 missense variant Q1064E is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are not available. Based on the unanimous benign predictions and lack of ClinVar evidence, the variant is most likely benign and does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978316 | Disordered | 0.953106 | Binding | 0.378 | 0.914 | 0.875 | -4.277 | Likely Benign | 0.184 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -0.48 | Neutral | 0.203 | Benign | 0.077 | Benign | 4.22 | Benign | 0.32 | Tolerated | 0.2259 | 0.2843 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3191A>C | Q1064P 2D AIThe SynGAP1 missense variant Q1064P 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 | 0.978316 | Disordered | 0.953106 | Binding | 0.378 | 0.914 | 0.875 | -2.032 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.270 | Likely Benign | 0.93 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.23 | Benign | 0.20 | Tolerated | 0.2819 | 0.4766 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3191A>G | Q1064R 2D AIThe SynGAP1 missense variant Q1064R is not 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 the variant is not yet classified there. Thus, the variant is most likely benign. 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 | -2.981 | Likely Benign | 0.202 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -0.28 | Neutral | 0.586 | Possibly Damaging | 0.159 | Benign | 4.19 | Benign | 0.16 | Tolerated | 0.2257 | 0.3654 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.3191A>T | Q1064L 2D AIThe SynGAP1 missense variant Q1064L is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the consensus of all available predictions strongly supports a benign classification, with no contradiction to ClinVar 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 | -3.492 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.133 | Likely Benign | -1.16 | Neutral | 0.224 | Benign | 0.091 | Benign | 4.20 | Benign | 0.13 | Tolerated | 0.1817 | 0.5485 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| 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.3997G>A | E1333K 2D AISynGAP1 missense variant E1333K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic impact are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and Foldetta results are unavailable. Overall, the consensus of multiple benign‑predicting tools and the SGM‑Consensus suggests a benign outcome, whereas a subset of tools indicates pathogenicity. Thus, the variant is most likely benign based on the current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.930790 | Disordered | 0.953319 | Binding | 0.347 | 0.746 | 0.750 | -5.038 | Likely Benign | 0.942 | Likely Pathogenic | Ambiguous | 0.244 | Likely Benign | -2.49 | Neutral | 0.980 | Probably Damaging | 0.956 | Probably Damaging | 2.84 | Benign | 0.00 | Affected | 0.2728 | 0.7491 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3997G>C | E1333Q 2D AIThe SynGAP1 missense variant E1333Q 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 those that predict a pathogenic impact 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, is classified as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (3 benign vs. 1 pathogenic votes) also indicates benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the preponderance of evidence points to a benign effect for E1333Q, 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 | 0.930790 | Disordered | 0.953319 | Binding | 0.347 | 0.746 | 0.750 | -4.034 | Likely Benign | 0.746 | Likely Pathogenic | Likely Benign | 0.217 | Likely Benign | -1.84 | Neutral | 0.980 | Probably Damaging | 0.968 | Probably Damaging | 2.83 | Benign | 0.00 | Affected | 0.1548 | 0.7617 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3998A>C | E1333A 2D AIThe SynGAP1 missense variant E1333A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returned an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2). Foldetta, which would assess protein‑folding stability, has no available output for this variant. Overall, more tools predict pathogenicity than benignity, and no ClinVar entry contradicts this assessment. Thus, the variant is most likely pathogenic based on the current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.930790 | Disordered | 0.953319 | Binding | 0.347 | 0.746 | 0.750 | -3.636 | Likely Benign | 0.834 | Likely Pathogenic | Ambiguous | 0.254 | Likely Benign | -3.76 | Deleterious | 0.980 | Probably Damaging | 0.956 | Probably Damaging | 2.83 | Benign | 0.00 | Affected | 0.4177 | 0.7382 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3998A>G | E1333G 2D AIThe SynGAP1 missense variant E1333G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie and therefore unavailable; Foldetta, which would evaluate protein‑folding stability, has no result for this variant. Overall, more tools predict pathogenicity than benignity, and no ClinVar entry contradicts this assessment. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.930790 | Disordered | 0.953319 | Binding | 0.347 | 0.746 | 0.750 | -4.504 | Likely Benign | 0.801 | Likely Pathogenic | Ambiguous | 0.260 | Likely Benign | -4.31 | Deleterious | 0.994 | Probably Damaging | 0.968 | Probably Damaging | 2.83 | Benign | 0.00 | Affected | 0.3101 | 0.6217 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3998A>T | E1333V 2D AIThe SynGAP1 E1333V 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 are REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (two pathogenic vs two benign votes), and Foldetta results are unavailable. Overall, the majority of evidence (six pathogenic vs three benign) points to a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.930790 | Disordered | 0.953319 | Binding | 0.347 | 0.746 | 0.750 | -4.322 | Likely Benign | 0.974 | Likely Pathogenic | Likely Pathogenic | 0.289 | Likely Benign | -4.30 | Deleterious | 0.994 | Probably Damaging | 0.981 | Probably Damaging | 2.81 | Benign | 0.00 | Affected | 0.0994 | 0.7615 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||||
| c.3999G>C | E1333D 2D AIThe SynGAP1 missense variant E1333D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for E1333D, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.930790 | Disordered | 0.953319 | Binding | 0.347 | 0.746 | 0.750 | -4.239 | Likely Benign | 0.651 | Likely Pathogenic | Likely Benign | 0.117 | Likely Benign | -1.78 | Neutral | 0.953 | Possibly Damaging | 0.935 | Probably Damaging | 2.88 | Benign | 0.00 | Affected | 0.1989 | 0.5029 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3999G>T | E1333D 2D AIThe SynGAP1 missense variant E1333D is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT classify the change as pathogenic, and AlphaMissense‑Default also predicts pathogenicity. High‑accuracy tools specifically give a benign prediction for AlphaMissense‑Optimized and a likely benign result for the SGM‑Consensus; Foldetta data are unavailable. Overall, the majority of evidence supports a benign interpretation, and this is consistent with the absence of a ClinVar pathogenic claim. Thus, the variant is most likely benign, and this is consistent with the lack of a ClinVar pathogenic claim. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.930790 | Disordered | 0.953319 | Binding | 0.347 | 0.746 | 0.750 | -4.239 | Likely Benign | 0.651 | Likely Pathogenic | Likely Benign | 0.117 | Likely Benign | -1.78 | Neutral | 0.953 | Possibly Damaging | 0.935 | Probably Damaging | 2.88 | Benign | 0.00 | Affected | 0.1989 | 0.5029 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2908G>A | E970K 2D AIThe SynGAP1 missense variant E970K is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the collective evidence strongly supports a benign interpretation, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.951925 | Disordered | 0.953422 | Binding | 0.342 | 0.902 | 0.750 | -3.344 | Likely Benign | 0.303 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -0.24 | Neutral | 0.078 | Benign | 0.042 | Benign | 4.18 | Benign | 0.17 | Tolerated | 0.3372 | 0.7361 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.2908G>C | E970Q 2D AIThe SynGAP1 missense variant E970Q is catalogued in gnomAD (6-33443460‑G‑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 reports a pathogenic outcome. Grouping by consensus, the benign‑predicting tools comprise the entire set, while no pathogenic predictions are present. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are unavailable. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.951925 | Disordered | 0.953422 | Binding | 0.342 | 0.902 | 0.750 | 6-33443460-G-C | 1 | 6.20e-7 | -2.662 | Likely Benign | 0.141 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -0.23 | Neutral | 0.007 | Benign | 0.006 | Benign | 4.13 | Benign | 0.21 | Tolerated | 4.32 | 2 | 0.2577 | 0.6899 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||
| c.2909A>C | E970A 2D AIThe SynGAP1 missense variant E970A is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments 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. Based on the consensus of all predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.951925 | Disordered | 0.953422 | Binding | 0.342 | 0.902 | 0.750 | -1.704 | Likely Benign | 0.156 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -0.89 | Neutral | 0.069 | Benign | 0.018 | Benign | 4.15 | Benign | 0.19 | Tolerated | 0.3679 | 0.6798 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2909A>G | E970G 2D AIThe SynGAP1 missense variant E970G is listed in ClinVar (ID 2013677.0) as Benign and is not reported in 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 a benign effect, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant. Overall, the computational evidence overwhelmingly supports a benign classification, which is consistent with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.951925 | Disordered | 0.953422 | Binding | 0.342 | 0.902 | 0.750 | Benign | 1 | -0.167 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.139 | Likely Benign | -0.93 | Neutral | 0.144 | Benign | 0.058 | Benign | 4.09 | Benign | 0.10 | Tolerated | 4.32 | 2 | 0.2701 | 0.5833 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||
| c.2909A>T | E970V 2D AIThe SynGAP1 missense variant E970V is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the collective evidence strongly supports a benign interpretation, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.951925 | Disordered | 0.953422 | Binding | 0.342 | 0.902 | 0.750 | -2.791 | Likely Benign | 0.208 | Likely Benign | Likely Benign | 0.245 | Likely Benign | -1.08 | Neutral | 0.002 | Benign | 0.002 | Benign | 4.11 | Benign | 0.08 | Tolerated | 0.1990 | 0.7037 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.2910G>C | E970D 2D AIThe SynGAP1 missense variant E970D 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 | 0.951925 | Disordered | 0.953422 | Binding | 0.342 | 0.902 | 0.750 | -3.381 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -0.44 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.14 | Benign | 0.33 | Tolerated | 0.2729 | 0.4610 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2910G>T | E970D 2D AIThe SynGAP1 missense variant E970D 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 | 0.951925 | Disordered | 0.953422 | Binding | 0.342 | 0.902 | 0.750 | -3.381 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -0.44 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.14 | Benign | 0.33 | Tolerated | 0.2729 | 0.4610 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3004C>A | H1002N 2D AIThe SynGAP1 missense variant H1002N is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy methods reinforce the benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign, with no Foldetta data to contradict. Overall, the preponderance of evidence points to a benign effect for H1002N, 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 | 0.784345 | Disordered | 0.953758 | Binding | 0.285 | 0.900 | 0.500 | -5.622 | Likely Benign | 0.466 | Ambiguous | Likely Benign | 0.076 | Likely Benign | -1.41 | Neutral | 0.801 | Possibly Damaging | 0.596 | Possibly Damaging | 2.76 | Benign | 1.00 | Tolerated | 0.2084 | 0.3057 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3004C>G | H1002D 2D AIThe SynGAP1 missense variant H1002D is not 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 | 0.784345 | Disordered | 0.953758 | Binding | 0.285 | 0.900 | 0.500 | -6.511 | Likely Benign | 0.852 | Likely Pathogenic | Ambiguous | 0.218 | Likely Benign | -2.09 | Neutral | 0.891 | Possibly Damaging | 0.673 | Possibly Damaging | 2.75 | Benign | 0.89 | Tolerated | 0.2597 | 0.2335 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.3004C>T | H1002Y 2D AIThe SynGAP1 missense variant H1002Y is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors indicates a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all score the change as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also classifies it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default tool remains uncertain, and no Foldetta stability assessment is available. High‑accuracy methods that are available—AlphaMissense‑Optimized and the SGM‑Consensus—both support a benign interpretation. Therefore, the variant is most likely benign based on the current predictive evidence, 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 | 0.784345 | Disordered | 0.953758 | Binding | 0.285 | 0.900 | 0.500 | -6.159 | Likely Benign | 0.489 | Ambiguous | Likely Benign | 0.181 | Likely Benign | -1.85 | Neutral | 0.961 | Probably Damaging | 0.808 | Possibly Damaging | 2.74 | Benign | 0.14 | Tolerated | 0.1243 | 0.4427 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.3005A>C | H1002P 2D AIThe SynGAP1 missense variant H1002P is not 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 likewise indicates Likely Benign. Foldetta results are unavailable, so they do not influence the overall assessment. Based on the majority of predictions and the high‑accuracy consensus, 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 | 0.784345 | Disordered | 0.953758 | Binding | 0.285 | 0.900 | 0.500 | -4.616 | Likely Benign | 0.242 | Likely Benign | Likely Benign | 0.213 | Likely Benign | -2.02 | Neutral | 0.989 | Probably Damaging | 0.874 | Possibly Damaging | 2.77 | Benign | 0.28 | Tolerated | 0.2015 | 0.3738 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3005A>G | H1002R 2D AIThe SynGAP1 missense variant H1002R is listed in gnomAD (ID 6‑33443557‑A‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Taken together, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar classification (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 | 0.784345 | Disordered | 0.953758 | Binding | 0.285 | 0.900 | 0.500 | 6-33443557-A-G | 1 | 6.20e-7 | -3.624 | Likely Benign | 0.609 | Likely Pathogenic | Likely Benign | 0.082 | Likely Benign | -1.52 | Neutral | 0.012 | Benign | 0.022 | Benign | 2.76 | Benign | 0.25 | Tolerated | 4.32 | 4 | 0.2160 | 0.2978 | 0 | 2 | -1.3 | 19.05 | ||||||||||||||||||||||||||||||||||
| c.3005A>T | H1002L 2D AIThe SynGAP1 H1002L 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, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and 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 and the absence of the variant in population databases, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.784345 | Disordered | 0.953758 | Binding | 0.285 | 0.900 | 0.500 | -6.448 | Likely Benign | 0.556 | Ambiguous | Likely Benign | 0.157 | Likely Benign | -3.12 | Deleterious | 0.801 | Possibly Damaging | 0.602 | Possibly Damaging | 2.79 | Benign | 0.13 | Tolerated | 0.1296 | 0.5088 | -2 | -3 | 7.0 | -23.98 | ||||||||||||||||||||||||||||||||||||||||
| c.3006T>A | H1002Q 2D AIThe SynGAP1 missense variant H1002Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.953758 | Binding | 0.285 | 0.900 | 0.500 | -5.071 | Likely Benign | 0.650 | Likely Pathogenic | Likely Benign | 0.140 | Likely Benign | -1.83 | Neutral | 0.801 | Possibly Damaging | 0.602 | Possibly Damaging | 2.77 | Benign | 0.23 | Tolerated | 0.1927 | 0.3510 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3006T>G | H1002Q 2D AIThe SynGAP1 missense variant H1002Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this conclusion, so the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.953758 | Binding | 0.285 | 0.900 | 0.500 | -5.071 | Likely Benign | 0.650 | Likely Pathogenic | Likely Benign | 0.140 | Likely Benign | -1.83 | Neutral | 0.801 | Possibly Damaging | 0.602 | Possibly Damaging | 2.77 | Benign | 0.23 | Tolerated | 0.1927 | 0.3510 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3127A>G | R1043G 2D AIThe SynGAP1 missense variant R1043G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), 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, 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). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978672 | Disordered | 0.954069 | Binding | 0.299 | 0.853 | 0.625 | -2.168 | Likely Benign | 0.201 | Likely Benign | Likely Benign | 0.383 | Likely Benign | -3.17 | Deleterious | 0.130 | Benign | 0.049 | Benign | 5.94 | Benign | 0.00 | Affected | 0.3179 | 0.3697 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3127A>T | R1043W 2D AIThe SynGAP1 missense variant R1043W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign prediction; Foldetta results are unavailable. Overall, the majority of high‑confidence tools predict a benign impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.978672 | Disordered | 0.954069 | Binding | 0.299 | 0.853 | 0.625 | -6.382 | Likely Benign | 0.523 | Ambiguous | Likely Benign | 0.444 | Likely Benign | -3.43 | Deleterious | 0.971 | Probably Damaging | 0.729 | Possibly Damaging | 5.38 | Benign | 0.00 | Affected | 0.1403 | 0.3696 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3128G>A | R1043K 2D AIThe SynGAP1 missense variant R1043K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar or gnomAD entries—there is no contradiction with existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978672 | Disordered | 0.954069 | Binding | 0.299 | 0.853 | 0.625 | -4.038 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.376 | Likely Benign | -1.41 | Neutral | 0.069 | Benign | 0.033 | Benign | 5.39 | Benign | 0.00 | Affected | 0.5141 | 0.4070 | Weaken | 3 | 2 | 0.6 | -28.01 | ||||||||||||||||||||||||||||||||||||||
| c.3128G>C | R1043T 2D AIThe SynGAP1 missense variant R1043T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978672 | Disordered | 0.954069 | Binding | 0.299 | 0.853 | 0.625 | -3.928 | Likely Benign | 0.298 | Likely Benign | Likely Benign | 0.463 | Likely Benign | -1.77 | Neutral | 0.001 | Benign | 0.003 | Benign | 5.39 | Benign | 0.00 | Affected | 0.1975 | 0.5513 | -1 | -1 | 3.8 | -55.08 | |||||||||||||||||||||||||||||||||||||||
| c.3128G>T | R1043M 2D AIThe SynGAP1 missense variant R1043M is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Consensus predictions from multiple in‑silico tools cluster around a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign, while polyPhen‑2 HumDiv and SIFT predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus also indicates Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for R1043M, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978672 | Disordered | 0.954069 | Binding | 0.299 | 0.853 | 0.625 | -4.800 | Likely Benign | 0.510 | Ambiguous | Likely Benign | 0.471 | Likely Benign | -1.98 | Neutral | 0.744 | Possibly Damaging | 0.229 | Benign | 5.38 | Benign | 0.00 | Affected | 0.1982 | 0.4468 | 0 | -1 | 6.4 | -24.99 | |||||||||||||||||||||||||||||||||||||||
| c.3129G>C | R1043S 2D AIThe SynGAP1 missense variant R1043S is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into two groups: benign predictions include PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from REVEL and SIFT. AlphaMissense‑Default is uncertain, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores benign, SGM‑Consensus is likely benign, and Foldetta results are unavailable. Taken together, the majority of evidence points to a benign impact for R1043S. This conclusion is consistent with the absence of a ClinVar assertion, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978672 | Disordered | 0.954069 | Binding | 0.299 | 0.853 | 0.625 | -3.223 | Likely Benign | 0.457 | Ambiguous | Likely Benign | 0.509 | Likely Pathogenic | -2.10 | Neutral | 0.036 | Benign | 0.018 | Benign | 5.42 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2727 | 0.4628 | -1 | 0 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||
| c.3129G>T | R1043S 2D AIThe SynGAP1 missense variant R1043S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443681‑G‑T). Prediction tools that agree on a benign effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are REVEL and SIFT. AlphaMissense‑Default remains uncertain, and no Foldetta stability result is available. High‑accuracy assessments: AlphaMissense‑Optimized classifies the variant as benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome; Foldetta data are missing, so it does not contribute to the evaluation. Based on the collective predictions, the variant is most likely benign, which is consistent with its ClinVar “Uncertain” classification and does not contradict the available evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978672 | Disordered | 0.954069 | Binding | 0.299 | 0.853 | 0.625 | Uncertain | 1 | 6-33443681-G-T | 2 | 1.24e-6 | -3.223 | Likely Benign | 0.457 | Ambiguous | Likely Benign | 0.509 | Likely Pathogenic | -2.10 | Neutral | 0.036 | Benign | 0.018 | Benign | 5.42 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2727 | 0.4628 | -1 | 0 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||
| c.2914C>A | P972T 2D AIThe SynGAP1 missense variant P972T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.954150 | Binding | 0.472 | 0.904 | 0.625 | -5.144 | Likely Benign | 0.057 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -1.01 | Neutral | 0.078 | Benign | 0.042 | Benign | 4.29 | Benign | 0.03 | Affected | 0.1802 | 0.5726 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2914C>G | P972A 2D AIThe SynGAP1 missense variant P972A is listed in ClinVar with an uncertain significance (ClinVar ID 3172763.0) and is present in the gnomAD database (gnomAD ID 6‑33443466‑C‑G). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the computational evidence strongly suggests 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 | 0.891961 | Disordered | 0.954150 | Binding | 0.472 | 0.904 | 0.625 | Uncertain | 1 | 6-33443466-C-G | 1 | 6.20e-7 | -0.167 | Likely Benign | 0.045 | Likely Benign | Likely Benign | 0.046 | Likely Benign | -0.89 | Neutral | 0.016 | Benign | 0.011 | Benign | 4.29 | Benign | 0.07 | Tolerated | 4.32 | 2 | 0.3212 | 0.4753 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||
| c.2914C>T | P972S 2D AIThe SynGAP1 missense variant P972S (ClinVar ID 3361353.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33443466‑C‑T). Consensus among most in silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as benign. Only SIFT classifies it as pathogenic, representing the sole discordant prediction. 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) reports “Likely Benign.” No Foldetta stability analysis is available for this residue. Overall, the preponderance of computational evidence points to a benign effect, which is consistent with the ClinVar designation of uncertainty rather than pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.954150 | Binding | 0.472 | 0.904 | 0.625 | Uncertain | 1 | 6-33443466-C-T | 4 | 2.48e-6 | -4.008 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -0.38 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.28 | Benign | 0.05 | Affected | 4.32 | 2 | 0.3168 | 0.4822 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||
| c.2915C>A | P972H 2D AIThe SynGAP1 missense variant P972H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools (polyPhen‑2 HumDiv and SIFT) predict pathogenicity, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments 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 | 0.891961 | Disordered | 0.954150 | Binding | 0.472 | 0.904 | 0.625 | -4.791 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -1.62 | Neutral | 0.589 | Possibly Damaging | 0.229 | Benign | 4.19 | Benign | 0.02 | Affected | 0.1930 | 0.4798 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2915C>G | P972R 2D AIThe SynGAP1 missense variant P972R is reported in gnomAD (ID 6‑33443467‑C‑G) but has no ClinVar entry. All evaluated in silico predictors classify it as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Based on the unanimous benign predictions and lack of ClinVar pathogenic annotation, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.954150 | Binding | 0.472 | 0.904 | 0.625 | 6-33443467-C-G | -4.483 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -1.44 | Neutral | 0.290 | Benign | 0.114 | Benign | 4.23 | Benign | 0.12 | Tolerated | 4.32 | 2 | 0.1379 | 0.3931 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||
| c.2915C>T | P972L 2D AIThe SynGAP1 missense variant P972L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.954150 | Binding | 0.472 | 0.904 | 0.625 | -4.399 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.020 | Likely Benign | -1.73 | Neutral | 0.036 | Benign | 0.026 | Benign | 4.24 | Benign | 0.02 | Affected | 0.2107 | 0.5447 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3049T>A | F1017I 2D AIThe SynGAP1 missense variant F1017I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of conventional tools (5 pathogenic vs 4 benign) lean toward pathogenicity, but the single high‑accuracy benign prediction introduces uncertainty. The variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | -3.244 | Likely Benign | 0.584 | Likely Pathogenic | Likely Benign | 0.113 | Likely Benign | -2.55 | Deleterious | 0.951 | Possibly Damaging | 0.710 | Possibly Damaging | 2.50 | Benign | 0.05 | Affected | 0.2050 | 0.1969 | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.3049T>C | F1017L 2D AIThe SynGAP1 missense variant F1017L is listed in ClinVar (ID 3719654.0) as benign and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM‑Consensus score (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus (majority vote) is benign. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence points to a benign impact, aligning with the ClinVar classification and showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | Benign | 1 | -2.048 | Likely Benign | 0.934 | Likely Pathogenic | Ambiguous | 0.157 | Likely Benign | -2.38 | Neutral | 0.798 | Possibly Damaging | 0.373 | Benign | 2.65 | Benign | 0.72 | Tolerated | 3.77 | 5 | 0.2198 | 0.3027 | 0 | 2 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||
| c.3049T>G | F1017V 2D AIThe SynGAP1 missense variant F1017V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for F1017V, and this conclusion does not contradict any ClinVar annotation because the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | -2.517 | Likely Benign | 0.497 | Ambiguous | Likely Benign | 0.161 | Likely Benign | -2.97 | Deleterious | 0.905 | Possibly Damaging | 0.637 | Possibly Damaging | 2.51 | Benign | 0.03 | Affected | 0.1964 | 0.2137 | -1 | -1 | 1.4 | -48.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3050T>A | F1017Y 2D AIThe SynGAP1 missense variant F1017Y is reported in gnomAD (6‑33443602‑T‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic outcome are SIFT and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | 6-33443602-T-A | -3.583 | Likely Benign | 0.186 | Likely Benign | Likely Benign | 0.042 | Likely Benign | -0.75 | Neutral | 0.012 | Benign | 0.044 | Benign | 2.47 | Pathogenic | 0.05 | Affected | 3.77 | 5 | 0.1432 | 0.1801 | 3 | 7 | -4.1 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.3050T>C | F1017S 2D AIThe SynGAP1 missense variant F1017S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains Likely Pathogenic; Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | -1.804 | Likely Benign | 0.782 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | -3.16 | Deleterious | 0.986 | Probably Damaging | 0.848 | Possibly Damaging | 2.46 | Pathogenic | 0.00 | Affected | 0.4491 | 0.0000 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||||||||||||
| c.3050T>G | F1017C 2D AIThe SynGAP1 missense variant F1017C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Pathogenic, and the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | -5.769 | Likely Benign | 0.706 | Likely Pathogenic | Likely Benign | 0.133 | Likely Benign | -3.71 | Deleterious | 0.999 | Probably Damaging | 0.944 | Probably Damaging | 2.42 | Pathogenic | 0.00 | Affected | 0.2488 | 0.1137 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||||||||||||
| c.3051C>A | F1017L 2D AIThe SynGAP1 missense variant F1017L is catalogued in gnomAD (ID 6‑33443603‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM; pathogenic predictions come from polyPhen‑2 HumDiv 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 a likely benign outcome. AlphaMissense‑Optimized yields an uncertain result, and no Foldetta stability data are available. Overall, the preponderance of evidence points to a benign effect. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | 6-33443603-C-A | -2.048 | Likely Benign | 0.934 | Likely Pathogenic | Ambiguous | 0.140 | Likely Benign | -2.38 | Neutral | 0.798 | Possibly Damaging | 0.373 | Benign | 2.65 | Benign | 0.72 | Tolerated | 3.77 | 5 | 0.2198 | 0.3027 | 0 | 2 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||
| c.3051C>G | F1017L 2D AIThe SynGAP1 missense variant F1017L is not 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 polyPhen‑2 HumDiv and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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 majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign based on current predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | -2.048 | Likely Benign | 0.934 | Likely Pathogenic | Ambiguous | 0.140 | Likely Benign | -2.38 | Neutral | 0.798 | Possibly Damaging | 0.373 | Benign | 2.65 | Benign | 0.72 | Tolerated | 3.77 | 5 | 0.2198 | 0.3027 | 0 | 2 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||
| c.3313C>G | R1105G 2D AIThe SynGAP1 missense variant R1105G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Consensus from standard in silico predictors shows a split: benign calls come from REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessment gives a benign prediction from AlphaMissense‑Optimized, a pathogenic consensus from the SGM method (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and no result from Foldetta, so its stability impact is unavailable. Overall, the majority of tools lean toward a benign effect, but the high‑accuracy consensus is conflicted. Thus, the variant is most likely benign based on the bulk of predictions, 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. | 0.901269 | Disordered | 0.954396 | Binding | 0.330 | 0.863 | 0.875 | -4.900 | Likely Benign | 0.438 | Ambiguous | Likely Benign | 0.146 | Likely Benign | -3.48 | Deleterious | 0.677 | Possibly Damaging | 0.168 | Benign | 2.45 | Pathogenic | 0.09 | Tolerated | 0.3293 | 0.4269 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3313C>T | R1105W 2D AIThe SynGAP1 missense variant R1105W is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443865‑C‑T). Prediction tools show mixed results: benign calls come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The AlphaMissense‑Default tool remains uncertain. A consensus analysis (SGM) that aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic majority. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, whereas the SGM Consensus predicts pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for R1105W, which does not conflict with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.901269 | Disordered | 0.954396 | Binding | 0.330 | 0.863 | 0.875 | Uncertain | 1 | 6-33443865-C-T | 6 | 3.93e-6 | -6.911 | Likely Benign | 0.488 | Ambiguous | Likely Benign | 0.133 | Likely Benign | -4.34 | Deleterious | 0.999 | Probably Damaging | 0.696 | Possibly Damaging | 2.42 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.1154 | 0.4117 | -3 | 2 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||
| c.3314G>A | R1105Q 2D AIThe SynGAP1 missense variant R1105Q is listed in ClinVar (ID 1803693.0) with an uncertain significance status and is present in gnomAD (variant ID 6‑33443866‑G‑A). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all 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 further support this: 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, 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 | 0.901269 | Disordered | 0.954396 | Binding | 0.330 | 0.863 | 0.875 | Uncertain | 2 | 6-33443866-G-A | 3 | 1.96e-6 | -3.666 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -1.21 | Neutral | 0.958 | Probably Damaging | 0.194 | Benign | 2.50 | Benign | 0.16 | Tolerated | 3.77 | 5 | 0.2942 | 0.3174 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.3314G>C | R1105P 2D AIThe SynGAP1 missense variant R1105P is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN 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, PROVEAN) leans pathogenic. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of predictions (six benign vs. two pathogenic) suggest a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. 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. | 0.901269 | Disordered | 0.954396 | Binding | 0.330 | 0.863 | 0.875 | -3.325 | Likely Benign | 0.425 | Ambiguous | Likely Benign | 0.149 | Likely Benign | -3.22 | Deleterious | 0.007 | Benign | 0.006 | Benign | 2.44 | Pathogenic | 0.08 | Tolerated | 0.2031 | 0.5101 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3314G>T | R1105L 2D AIThe SynGAP1 missense variant R1105L is not reported in ClinVar and is present in gnomAD (ID 6‑33443866‑G‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, and FATHMM. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized classifies the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this residue, so its stability impact is unavailable. Overall, the balance of evidence leans toward a benign effect, 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. | 0.901269 | Disordered | 0.954396 | Binding | 0.330 | 0.863 | 0.875 | 6-33443866-G-T | -4.031 | Likely Benign | 0.459 | Ambiguous | Likely Benign | 0.125 | Likely Benign | -3.51 | Deleterious | 0.677 | Possibly Damaging | 0.168 | Benign | 2.46 | Pathogenic | 0.19 | Tolerated | 3.77 | 5 | 0.1734 | 0.5373 | -2 | -3 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||
| c.3310C>A | P1104T 2D AIThe SynGAP1 missense variant P1104T is reported in gnomAD (variant ID 6‑33443862‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. No Foldetta stability analysis is available, so it does not influence the conclusion. Overall, the majority of evidence points to a benign impact, and this assessment 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 | 0.936162 | Disordered | 0.954801 | Binding | 0.440 | 0.863 | 0.875 | 6-33443862-C-A | -3.995 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -0.14 | Neutral | 0.770 | Possibly Damaging | 0.481 | Possibly Damaging | 2.76 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.1549 | 0.6700 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3310C>G | P1104A 2D AIThe SynGAP1 missense variant P1104A 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 indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.936162 | Disordered | 0.954801 | Binding | 0.440 | 0.863 | 0.875 | -3.677 | Likely Benign | 0.059 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -0.54 | Neutral | 0.409 | Benign | 0.184 | Benign | 2.74 | Benign | 0.22 | Tolerated | 0.3289 | 0.5315 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3310C>T | P1104S 2D AIThe SynGAP1 missense variant P1104S is listed in ClinVar (ID 2912797.0) as Benign and is present in gnomAD (variant ID 6‑33443862‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign, and AlphaMissense‑Optimized also reports Benign. Foldetta results are not available. Overall, the majority of computational evidence supports a benign classification, which is consistent with the ClinVar status. Thus, the variant is most likely benign and does not contradict the ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.936162 | Disordered | 0.954801 | Binding | 0.440 | 0.863 | 0.875 | Benign | 1 | 6-33443862-C-T | 1 | 6.54e-7 | -2.330 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -0.30 | Neutral | 0.770 | Possibly Damaging | 0.404 | Benign | 2.77 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.3271 | 0.5746 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||
| c.3311C>A | P1104Q 2D AIThe SynGAP1 missense variant P1104Q is reported in gnomAD (ID 6‑33443863‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign likelihood. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.936162 | Disordered | 0.954801 | Binding | 0.440 | 0.863 | 0.875 | 6-33443863-C-A | -3.161 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.114 | Likely Benign | -0.64 | Neutral | 0.986 | Probably Damaging | 0.825 | Possibly Damaging | 2.68 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0.1498 | 0.5063 | -1 | 0 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||
| c.3311C>G | P1104R 2D AIThe SynGAP1 missense variant P1104R 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 further support a benign classification: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus likewise indicates Likely Benign. No Foldetta stability analysis is available for this variant. 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 | 0.936162 | Disordered | 0.954801 | Binding | 0.440 | 0.863 | 0.875 | -3.864 | Likely Benign | 0.328 | Likely Benign | Likely Benign | 0.099 | Likely Benign | -0.64 | Neutral | 0.986 | Probably Damaging | 0.761 | Possibly Damaging | 2.68 | Benign | 0.06 | Tolerated | 0.1387 | 0.3703 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3311C>T | P1104L 2D AIThe SynGAP1 missense variant P1104L 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 (majority vote) also predicts Likely Benign; Foldetta results are unavailable. Overall, the consensus of the majority of tools, including the high‑accuracy predictors, points 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 | 0.936162 | Disordered | 0.954801 | Binding | 0.440 | 0.863 | 0.875 | -3.846 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.146 | Likely Benign | -0.33 | Neutral | 0.626 | Possibly Damaging | 0.168 | Benign | 2.81 | Benign | 1.00 | Tolerated | 0.2264 | 0.6795 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2764C>G | R922G 2D AIThe SynGAP1 missense variant R922G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the change is benign: REVEL, PROVEAN, SIFT, 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) predict a pathogenic effect. AlphaMissense‑Default remains uncertain, and no Foldetta stability assessment is available. High‑accuracy tools reinforce the benign prediction: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta data are missing. Overall, the preponderance of evidence points to a benign impact for R922G, 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 | 0.549308 | Disordered | 0.955308 | Binding | 0.277 | 0.845 | 0.375 | -2.490 | Likely Benign | 0.472 | Ambiguous | Likely Benign | 0.104 | Likely Benign | -1.48 | Neutral | 0.967 | Probably Damaging | 0.626 | Possibly Damaging | 2.55 | Benign | 0.10 | Tolerated | 0.3473 | 0.3768 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2765G>A | R922Q 2D AIThe SynGAP1 missense variant R922Q is listed in ClinVar as Benign (ClinVar ID 2917638.0) and is present in gnomAD (ID 6‑33443317‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (derived from the same set of high‑confidence predictors) also 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, aligning with the ClinVar classification and indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.955308 | Binding | 0.277 | 0.845 | 0.375 | Benign | 1 | 6-33443317-G-A | 7 | 4.34e-6 | -3.295 | Likely Benign | 0.189 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -0.27 | Neutral | 0.992 | Probably Damaging | 0.736 | Possibly Damaging | 2.57 | Benign | 0.20 | Tolerated | 3.77 | 5 | 0.3444 | 0.2602 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.2765G>C | R922P 2D AIThe SynGAP1 missense variant R922P is 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 results are unavailable. Overall, the majority of evidence points to a benign impact for R922P, 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 | 0.955308 | Binding | 0.277 | 0.845 | 0.375 | -2.502 | Likely Benign | 0.578 | Likely Pathogenic | Likely Benign | 0.124 | Likely Benign | -1.36 | Neutral | 0.998 | Probably Damaging | 0.942 | Probably Damaging | 2.54 | Benign | 0.10 | Tolerated | 0.2391 | 0.4966 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2765G>T | R922L 2D AIThe SynGAP1 missense variant R922L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the substitution as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy methods that are available—AlphaMissense‑Optimized and the SGM‑Consensus—both support a benign interpretation. Therefore, the variant is most likely benign according to the consensus of predictive tools, 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 | 0.549308 | Disordered | 0.955308 | Binding | 0.277 | 0.845 | 0.375 | -3.714 | Likely Benign | 0.546 | Ambiguous | Likely Benign | 0.150 | Likely Benign | 0.84 | Neutral | 0.983 | Probably Damaging | 0.828 | Possibly Damaging | 3.04 | Benign | 1.00 | Tolerated | 0.2033 | 0.5022 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2905G>A | G969R 2D AIThe SynGAP1 missense variant G969R is not 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 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 is present). 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 | -4.783 | Likely Benign | 0.316 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -0.70 | Neutral | 0.611 | Possibly Damaging | 0.305 | Benign | 4.20 | Benign | 0.01 | Affected | 0.1039 | 0.5473 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2905G>C | G969R 2D AIThe SynGAP1 missense variant G969R is not 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 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 is present). 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 | -4.783 | Likely Benign | 0.316 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -0.70 | Neutral | 0.611 | Possibly Damaging | 0.305 | Benign | 4.20 | Benign | 0.01 | Affected | 0.1039 | 0.5473 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2906G>A | G969E 2D AIThe SynGAP1 missense variant G969E is not 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 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 is present). 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 | -4.721 | Likely Benign | 0.167 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -0.10 | Neutral | 0.611 | Possibly Damaging | 0.171 | Benign | 4.28 | Benign | 0.01 | Affected | 0.1663 | 0.5399 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| 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.2906G>T | G969V 2D AIThe SynGAP1 missense variant G969V is not 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 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 is present). 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 | -5.946 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -0.92 | Neutral | 0.761 | Possibly Damaging | 0.239 | Benign | 4.18 | Benign | 0.01 | Affected | 0.1497 | 0.3847 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.2998A>C | I1000L 2D AIThe SynGAP1 missense variant I1000L 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 | 0.745909 | Disordered | 0.957020 | Binding | 0.293 | 0.904 | 0.625 | -2.103 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -0.34 | Neutral | 0.211 | Benign | 0.108 | Benign | 2.76 | Benign | 0.70 | Tolerated | 0.0916 | 0.4034 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.2998A>G | I1000V 2D AIThe SynGAP1 missense variant I1000V is listed in ClinVar (ID 2572013.0) with an “Uncertain” clinical significance and is not reported in gnomAD. Functional prediction tools that assess evolutionary conservation and structural impact (REVEL, SIFT, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default) all converge on a benign outcome. No tool in the dataset predicts pathogenicity. High‑accuracy predictors reinforce this consensus: AlphaMissense‑Optimized reports a benign effect, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.745909 | Disordered | 0.957020 | Binding | 0.293 | 0.904 | 0.625 | Uncertain | 2 | -4.102 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.086 | Likely Benign | -0.20 | Neutral | 0.437 | Benign | 0.170 | Benign | 2.76 | Benign | 0.81 | Tolerated | 4.32 | 4 | 0.1220 | 0.3404 | 3 | 4 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.2998A>T | I1000F 2D AIThe SynGAP1 missense variant I1000F is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of predictions indicates that I1000F 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 | 0.745909 | Disordered | 0.957020 | Binding | 0.293 | 0.904 | 0.625 | -3.801 | Likely Benign | 0.201 | Likely Benign | Likely Benign | 0.147 | Likely Benign | -1.02 | Neutral | 0.968 | Probably Damaging | 0.713 | Possibly Damaging | 2.70 | Benign | 0.13 | Tolerated | 0.0594 | 0.3259 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2999T>A | I1000N 2D AIThe SynGAP1 missense variant I1000N is not 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, 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 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, and this conclusion does not contradict any ClinVar annotation (none is present). 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 | 0.745909 | Disordered | 0.957020 | Binding | 0.293 | 0.904 | 0.625 | -5.246 | Likely Benign | 0.677 | Likely Pathogenic | Likely Benign | 0.145 | Likely Benign | -0.82 | Neutral | 0.995 | Probably Damaging | 0.913 | Probably Damaging | 2.72 | Benign | 0.16 | Tolerated | 0.1001 | 0.0900 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.2999T>C | I1000T 2D AIThe SynGAP1 missense variant I1000T is not 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, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote from 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 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 | 0.745909 | Disordered | 0.957020 | Binding | 0.293 | 0.904 | 0.625 | -4.748 | Likely Benign | 0.721 | Likely Pathogenic | Likely Benign | 0.131 | Likely Benign | -0.87 | Neutral | 0.896 | Possibly Damaging | 0.596 | Possibly Damaging | 2.78 | Benign | 0.29 | Tolerated | 0.1045 | 0.1594 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||||||||||||
| c.2999T>G | I1000S 2D AIThe SynGAP1 missense variant I1000S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) 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 (seven benign vs. three pathogenic predictions) supports a benign classification. 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 | 0.745909 | Disordered | 0.957020 | Binding | 0.293 | 0.904 | 0.625 | -3.694 | Likely Benign | 0.587 | Likely Pathogenic | Likely Benign | 0.151 | Likely Benign | -0.38 | Neutral | 0.946 | Possibly Damaging | 0.673 | Possibly Damaging | 2.80 | Benign | 0.19 | Tolerated | 0.2501 | 0.1270 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||||||||||||
| c.3000C>G | I1000M 2D AIThe SynGAP1 missense variant I1000M 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 | 0.745909 | Disordered | 0.957020 | Binding | 0.293 | 0.904 | 0.625 | -3.541 | Likely Benign | 0.161 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -0.32 | Neutral | 0.437 | Benign | 0.108 | Benign | 2.70 | Benign | 0.17 | Tolerated | 0.0769 | 0.3104 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| 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.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.2866T>G | S956A 2D AIThe SynGAP1 missense variant S956A is not reported in ClinVar or gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely benign. Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta stability analysis is unavailable. Overall, the collective evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984871 | Disordered | 0.957345 | Binding | 0.364 | 0.917 | 0.750 | -4.468 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -0.47 | Neutral | 0.112 | Benign | 0.039 | Benign | 2.18 | Pathogenic | 0.13 | Tolerated | 0.4239 | 0.4838 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2867C>A | S956Y 2D AIThe SynGAP1 missense variant S956Y 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 of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the lack of ClinVar annotation. Thus, 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 | 0.984871 | Disordered | 0.957345 | Binding | 0.364 | 0.917 | 0.750 | -4.920 | Likely Benign | 0.233 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -0.90 | Neutral | 0.411 | Benign | 0.097 | Benign | 1.93 | Pathogenic | 0.22 | Tolerated | 0.1449 | 0.4932 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2867C>G | S956C 2D AIThe SynGAP1 missense variant S956C is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs. two pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (five pathogenic vs. four benign) indicate a likely pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant has no existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.984871 | Disordered | 0.957345 | Binding | 0.364 | 0.917 | 0.750 | -9.292 | Likely Pathogenic | 0.108 | Likely Benign | Likely Benign | 0.107 | Likely Benign | -0.34 | Neutral | 0.938 | Possibly Damaging | 0.665 | Possibly Damaging | 1.94 | Pathogenic | 0.03 | Affected | 0.1833 | 0.5470 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.2867C>T | S956F 2D AIThe SynGAP1 missense variant S956F is not 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, 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 predictions do not contradict any 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 | 0.984871 | Disordered | 0.957345 | Binding | 0.364 | 0.917 | 0.750 | -6.654 | Likely Benign | 0.226 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -1.04 | Neutral | 0.832 | Possibly Damaging | 0.398 | Benign | 1.93 | Pathogenic | 0.39 | Tolerated | 0.1315 | 0.4943 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.3307C>A | R1103S 2D AIThe SynGAP1 missense variant R1103S is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta results are unavailable. Overall, the majority of evidence (six benign versus two pathogenic predictions) indicates that R1103S is most likely benign, 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. | 0.945666 | Disordered | 0.957363 | Binding | 0.328 | 0.862 | 0.875 | -3.611 | Likely Benign | 0.464 | Ambiguous | Likely Benign | 0.111 | Likely Benign | -1.94 | Neutral | 0.511 | Possibly Damaging | 0.187 | Benign | 2.48 | Pathogenic | 0.28 | Tolerated | 0.3025 | 0.4224 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3307C>G | R1103G 2D AIThe SynGAP1 missense variant R1103G is not 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the balance of evidence—five benign predictions versus four pathogenic, with a benign high‑accuracy tool and no conflicting ClinVar annotation—suggests that the variant is most likely benign. This conclusion does not contradict any ClinVar status, as the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.945666 | Disordered | 0.957363 | Binding | 0.328 | 0.862 | 0.875 | -3.516 | Likely Benign | 0.221 | Likely Benign | Likely Benign | 0.132 | Likely Benign | -2.65 | Deleterious | 0.911 | Possibly Damaging | 0.308 | Benign | 2.44 | Pathogenic | 0.03 | Affected | 0.3429 | 0.4077 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3307C>T | R1103C 2D AISynGAP1 missense variant R1103C is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443859‑C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic). AlphaMissense‑Optimized reports a benign outcome, while Foldetta results are unavailable. Overall, the balance of evidence favors a pathogenic interpretation, which is in contrast to the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.945666 | Disordered | 0.957363 | Binding | 0.328 | 0.862 | 0.875 | Uncertain | 1 | 6-33443859-C-T | 6 | 3.92e-6 | -2.440 | Likely Benign | 0.246 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -3.01 | Deleterious | 0.996 | Probably Damaging | 0.787 | Possibly Damaging | 2.41 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.3376 | 0.4121 | -3 | -4 | 7.0 | -53.05 | |||||||||||||||||||||||||||||||||
| c.3308G>A | R1103H 2D AIThe SynGAP1 missense variant R1103H is listed in ClinVar (ID 577408.0) as benign and is present in gnomAD (variant ID 6‑33443860‑G‑A). Prediction tools that classify the variant as benign include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as benign, while Foldetta results are unavailable. Overall, the majority of predictions support a benign impact, and this conclusion aligns with the ClinVar benign classification, indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.945666 | Disordered | 0.957363 | Binding | 0.328 | 0.862 | 0.875 | Benign/Likely benign | 3 | 6-33443860-G-A | 31 | 2.03e-5 | -3.622 | Likely Benign | 0.156 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -1.97 | Neutral | 0.996 | Probably Damaging | 0.733 | Possibly Damaging | 2.49 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.2977 | 0.2380 | 2 | 0 | 1.3 | -19.05 | ||||||||||||||||||||||||||||||||
| c.3308G>C | R1103P 2D AIThe SynGAP1 missense variant R1103P is 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 from 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 | 0.945666 | Disordered | 0.957363 | Binding | 0.328 | 0.862 | 0.875 | -2.149 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.098 | Likely Benign | -2.48 | Neutral | 0.969 | Probably Damaging | 0.659 | Possibly Damaging | 2.43 | Pathogenic | 0.02 | Affected | 0.2288 | 0.5109 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3308G>T | R1103L 2D AIThe SynGAP1 missense variant R1103L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443860‑G‑T). 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, reports a “Likely Benign” outcome (3 benign vs. 1 pathogenic votes). High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as benign; Foldetta results are not 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 | 0.945666 | Disordered | 0.957363 | Binding | 0.328 | 0.862 | 0.875 | Uncertain | 1 | 6-33443860-G-T | -2.330 | Likely Benign | 0.205 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -2.35 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.44 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.2098 | 0.5181 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||
| c.3001C>A | L1001I 2D AIThe SynGAP1 missense variant L1001I is not 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), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence from both general and high‑accuracy tools 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 | 0.754692 | Disordered | 0.958507 | Binding | 0.269 | 0.902 | 0.375 | -4.486 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.034 | Likely Benign | -0.17 | Neutral | 0.022 | Benign | 0.018 | Benign | 2.69 | Benign | 0.00 | Affected | 0.0994 | 0.3264 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3001C>G | L1001V 2D AIThe SynGAP1 missense variant L1001V 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also 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 available predictions points to a benign impact, 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 | 0.754692 | Disordered | 0.958507 | Binding | 0.269 | 0.902 | 0.375 | -3.865 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -0.20 | Neutral | 0.022 | Benign | 0.008 | Benign | 2.71 | Benign | 0.00 | Affected | 0.1569 | 0.2714 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3001C>T | L1001F 2D AIThe SynGAP1 missense variant L1001F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (derived from the majority of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (majority vote of the four high‑confidence tools) is benign; Foldetta data are unavailable. Overall, the preponderance of evidence supports a benign classification for L1001F, and this conclusion does not conflict with ClinVar, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.958507 | Binding | 0.269 | 0.902 | 0.375 | -4.712 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.026 | Likely Benign | -0.85 | Neutral | 0.934 | Possibly Damaging | 0.617 | Possibly Damaging | 2.65 | Benign | 0.00 | Affected | 0.0703 | 0.2876 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3002T>A | L1001H 2D AIThe SynGAP1 missense variant L1001H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.958507 | Binding | 0.269 | 0.902 | 0.375 | -3.119 | Likely Benign | 0.258 | Likely Benign | Likely Benign | 0.109 | Likely Benign | -1.02 | Neutral | 0.997 | Probably Damaging | 0.870 | Possibly Damaging | 2.64 | Benign | 0.00 | Affected | 0.1141 | 0.0958 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||||||
| c.3002T>C | L1001P 2D AIThe SynGAP1 missense variant L1001P 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 ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.958507 | Binding | 0.269 | 0.902 | 0.375 | Uncertain | 1 | -3.071 | Likely Benign | 0.209 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -1.02 | Neutral | 0.966 | Probably Damaging | 0.690 | Possibly Damaging | 2.65 | Benign | 0.00 | Affected | 4.32 | 4 | 0.3322 | 0.0929 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||
| c.3002T>G | L1001R 2D AIThe SynGAP1 missense variant L1001R 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 is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.958507 | Binding | 0.269 | 0.902 | 0.375 | -2.285 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -1.09 | Neutral | 0.966 | Probably Damaging | 0.708 | Possibly Damaging | 2.67 | Benign | 0.00 | Affected | 0.1299 | 0.0832 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3928A>C | T1310P 2D AIThe SynGAP1 missense variant T1310P 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 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 indicates a benign outcome. Foldetta results are unavailable, so no additional stability evidence is present. Overall, the consensus of available predictions indicates that T1310P 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 | 0.812494 | Disordered | 0.959076 | Binding | 0.398 | 0.904 | 0.750 | -1.807 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.209 | Likely Benign | -1.48 | Neutral | 0.594 | Possibly Damaging | 0.298 | Benign | 2.75 | Benign | 0.04 | Affected | 0.1667 | 0.3604 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3928A>G | T1310A 2D AIThe SynGAP1 missense variant T1310A is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.959076 | Binding | 0.398 | 0.904 | 0.750 | -2.883 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.084 | Likely Benign | -0.21 | Neutral | 0.041 | Benign | 0.039 | Benign | 2.83 | Benign | 0.13 | Tolerated | 0.3238 | 0.3177 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3928A>T | T1310S 2D AIThe SynGAP1 missense variant T1310S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.959076 | Binding | 0.398 | 0.904 | 0.750 | -2.809 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -0.23 | Neutral | 0.089 | Benign | 0.120 | Benign | 2.80 | Benign | 0.17 | Tolerated | 0.2629 | 0.3418 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3929C>A | T1310K 2D AIThe SynGAP1 missense variant T1310K is not 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 | 0.812494 | Disordered | 0.959076 | Binding | 0.398 | 0.904 | 0.750 | -4.388 | Likely Benign | 0.318 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -0.64 | Neutral | 0.111 | Benign | 0.116 | Benign | 2.80 | Benign | 0.04 | Affected | 0.0992 | 0.2978 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||||
| c.3929C>G | T1310R 2D AIThe SynGAP1 missense variant T1310R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as tolerated or benign. Only SIFT predicts a damaging outcome, labeling it pathogenic. 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 this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are unavailable. Consequently, the aggregate evidence indicates that T1310R is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.959076 | Binding | 0.398 | 0.904 | 0.750 | -3.632 | Likely Benign | 0.226 | Likely Benign | Likely Benign | 0.231 | Likely Benign | -0.59 | Neutral | 0.001 | Benign | 0.006 | Benign | 2.78 | Benign | 0.03 | Affected | 0.0844 | 0.2501 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||||||||||||
| c.3929C>T | T1310M 2D AIThe SynGAP1 missense variant T1310M is listed in ClinVar (ID 2160201.0) as Benign and is present in gnomAD (gnomAD ID 6‑33451803‑C‑T). All evaluated in‑silico predictors report a benign outcome: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign classification, which aligns with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.959076 | Binding | 0.398 | 0.904 | 0.750 | Benign | 1 | 6-33451803-C-T | 17 | 1.05e-5 | -4.822 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.069 | Likely Benign | 2.19 | Neutral | 0.021 | Benign | 0.005 | Benign | 2.98 | Benign | 0.93 | Tolerated | 3.77 | 5 | 0.1144 | 0.5397 | -1 | -1 | 2.6 | 30.09 | ||||||||||||||||||||||||||||||||
| c.3124C>A | Q1042K 2D AIThe SynGAP1 missense variant Q1042K 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, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the collective predictions strongly suggest that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.969315 | Disordered | 0.959333 | Binding | 0.310 | 0.846 | 0.625 | -4.331 | Likely Benign | 0.498 | Ambiguous | Likely Benign | 0.304 | Likely Benign | -1.52 | Neutral | 0.224 | Benign | 0.091 | Benign | 5.44 | Benign | 0.13 | Tolerated | 0.2338 | 0.5202 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3124C>G | Q1042E 2D AIThe SynGAP1 missense variant Q1042E 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 | 0.969315 | Disordered | 0.959333 | Binding | 0.310 | 0.846 | 0.625 | -4.231 | Likely Benign | 0.262 | Likely Benign | Likely Benign | 0.267 | Likely Benign | -1.12 | Neutral | 0.224 | Benign | 0.077 | Benign | 5.44 | Benign | 0.15 | Tolerated | 0.2042 | 0.3276 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3125A>C | Q1042P 2D AIThe SynGAP1 missense variant Q1042P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumDiv indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Overall, the consensus of the available predictions points to a benign effect, and this conclusion is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.969315 | Disordered | 0.959333 | Binding | 0.310 | 0.846 | 0.625 | -2.085 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.461 | Likely Benign | -0.73 | Neutral | 0.586 | Possibly Damaging | 0.223 | Benign | 5.42 | Benign | 0.31 | Tolerated | 0.2336 | 0.5762 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3125A>G | Q1042R 2D AIThe SynGAP1 missense variant Q1042R is listed in ClinVar (ID 2662705.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33443677‑A‑G). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are unavailable. Overall, the majority of evidence supports a benign impact for Q1042R, and this conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.969315 | Disordered | 0.959333 | Binding | 0.310 | 0.846 | 0.625 | Uncertain | 2 | 6-33443677-A-G | 2 | 1.24e-6 | -2.928 | Likely Benign | 0.413 | Ambiguous | Likely Benign | 0.300 | Likely Benign | -1.39 | Neutral | 0.586 | Possibly Damaging | 0.120 | Benign | 5.48 | Benign | 0.12 | Tolerated | 3.77 | 5 | 0.1929 | 0.3887 | 1 | 1 | -1.0 | 28.06 | ||||||||||||||||||||||||||||||||
| c.3125A>T | Q1042L 2D AIThe SynGAP1 missense variant Q1042L is not 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 | 0.969315 | Disordered | 0.959333 | Binding | 0.310 | 0.846 | 0.625 | -3.796 | Likely Benign | 0.203 | Likely Benign | Likely Benign | 0.338 | Likely Benign | -2.47 | Neutral | 0.369 | Benign | 0.120 | Benign | 5.47 | Benign | 0.05 | Affected | 0.1469 | 0.6276 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| 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.2917G>A | G973R 2D AIThe SynGAP1 missense variant G973R 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, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.959498 | Binding | 0.390 | 0.897 | 0.625 | -3.950 | Likely Benign | 0.329 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -0.37 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.16 | Benign | 0.01 | Affected | 0.0930 | 0.4532 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2917G>C | G973R 2D AIThe SynGAP1 missense variant G973R 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 reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta results are not available 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. | Likely Benign | 0.887230 | Disordered | 0.959498 | Binding | 0.390 | 0.897 | 0.625 | -3.950 | Likely Benign | 0.329 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -0.37 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.16 | Benign | 0.01 | Affected | 0.0930 | 0.4532 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2917G>T | G973W 2D AIThe SynGAP1 missense variant G973W 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 reports 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 assessment. Overall, the majority of evidence points to a benign effect for G973W, 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 | 0.887230 | Disordered | 0.959498 | Binding | 0.390 | 0.897 | 0.625 | -6.896 | Likely Benign | 0.329 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -1.53 | Neutral | 0.983 | Probably Damaging | 0.813 | Possibly Damaging | 4.10 | Benign | 0.00 | Affected | 0.0846 | 0.4046 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.2918G>A | G973E 2D AIThe SynGAP1 missense variant G973E 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 likewise 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 | 0.887230 | Disordered | 0.959498 | Binding | 0.390 | 0.897 | 0.625 | -3.712 | Likely Benign | 0.210 | Likely Benign | Likely Benign | 0.079 | Likely Benign | -0.72 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.19 | Benign | 0.01 | Affected | 0.1463 | 0.4258 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| 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.2918G>T | G973V 2D AIThe SynGAP1 missense variant G973V 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. Grouping by consensus, the benign‑predicting tools outnumber the single pathogenic prediction. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a benign classification. Foldetta results are unavailable, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.959498 | Binding | 0.390 | 0.897 | 0.625 | -4.688 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -0.76 | Neutral | 0.224 | Benign | 0.091 | Benign | 4.18 | Benign | 0.01 | Affected | 0.1392 | 0.3684 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3193C>A | P1065T 2D AIThe SynGAP1 missense variant P1065T is 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 from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign classification. There is no ClinVar status 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 | 0.979741 | Disordered | 0.959518 | Binding | 0.424 | 0.917 | 0.875 | -5.392 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -1.23 | Neutral | 0.770 | Possibly Damaging | 0.481 | Possibly Damaging | 2.04 | Pathogenic | 0.00 | Affected | 0.1577 | 0.6788 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3193C>G | P1065A 2D AIThe SynGAP1 missense variant P1065A is not 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, 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 P1065A, 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 | 0.979741 | Disordered | 0.959518 | Binding | 0.424 | 0.917 | 0.875 | -4.043 | Likely Benign | 0.054 | Likely Benign | Likely Benign | 0.050 | Likely Benign | -1.85 | Neutral | 0.580 | Possibly Damaging | 0.184 | Benign | 2.19 | Pathogenic | 0.00 | Affected | 0.3140 | 0.5790 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3193C>T | P1065S 2D AIThe SynGAP1 missense variant P1065S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, 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; 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 | 0.979741 | Disordered | 0.959518 | Binding | 0.424 | 0.917 | 0.875 | -5.512 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -2.07 | Neutral | 0.770 | Possibly Damaging | 0.255 | Benign | 2.06 | Pathogenic | 0.00 | Affected | 0.3172 | 0.6021 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3194C>A | P1065Q 2D AIThe SynGAP1 missense variant P1065Q 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, 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 | 0.979741 | Disordered | 0.959518 | Binding | 0.424 | 0.917 | 0.875 | -3.928 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.026 | Likely Benign | -2.44 | Neutral | 0.102 | Benign | 0.057 | Benign | 2.00 | Pathogenic | 0.00 | Affected | 0.1487 | 0.5478 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3194C>G | P1065R 2D AIThe SynGAP1 missense variant P1065R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence from multiple independent predictors indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.979741 | Disordered | 0.959518 | Binding | 0.424 | 0.917 | 0.875 | -3.237 | Likely Benign | 0.228 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -2.46 | Neutral | 0.102 | Benign | 0.052 | Benign | 2.00 | Pathogenic | 0.00 | Affected | 0.1439 | 0.4369 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3194C>T | P1065L 2D AIThe SynGAP1 missense variant P1065L is listed in ClinVar as Benign and is present in gnomAD (ID 6‑33443746‑C‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized 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. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no reported result for this variant. Overall, the balance of evidence (5 benign vs. 4 pathogenic predictions) and the high‑accuracy benign call support a benign classification, aligning with the ClinVar status and indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.979741 | Disordered | 0.959518 | Binding | 0.424 | 0.917 | 0.875 | Likely Benign | 1 | 6-33443746-C-T | 14 | 8.71e-6 | -5.085 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -2.94 | Deleterious | 0.950 | Possibly Damaging | 0.419 | Benign | 2.01 | Pathogenic | 0.00 | Affected | 4.32 | 2 | 0.2286 | 0.6922 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||
| c.3052A>C | T1018P 2D AIThe SynGAP1 missense variant T1018P is not 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, 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. There is no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.959985 | Binding | 0.348 | 0.801 | 0.500 | -2.046 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.218 | Likely Benign | -1.39 | Neutral | 0.586 | Possibly Damaging | 0.302 | Benign | 2.24 | Pathogenic | 0.02 | Affected | 0.2155 | 0.3960 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3052A>G | T1018A 2D AIThe SynGAP1 missense variant T1018A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, 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 as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.959985 | Binding | 0.348 | 0.801 | 0.500 | -3.289 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -0.55 | Neutral | 0.001 | Benign | 0.004 | Benign | 2.34 | Pathogenic | 0.53 | Tolerated | 0.3859 | 0.3362 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3052A>T | T1018S 2D AIThe SynGAP1 missense variant T1018S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, 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 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 contains no classification for this variant. 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 | -2.897 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.090 | Likely Benign | -0.20 | Neutral | 0.004 | Benign | 0.008 | Benign | 2.48 | Pathogenic | 0.06 | Tolerated | 0.3426 | 0.3404 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| 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.3053C>G | T1018S 2D AIThe SynGAP1 missense variant T1018S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, 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 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 contains no classification for this variant. 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 | -2.897 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.026 | Likely Benign | -0.20 | Neutral | 0.004 | Benign | 0.008 | Benign | 2.48 | Pathogenic | 0.06 | Tolerated | 0.3426 | 0.3404 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| 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.2947A>C | S983R 2D AIThe SynGAP1 missense variant S983R is reported in ClinVar as “Not submitted” and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and also indicates a likely pathogenic outcome. AlphaMissense‑Optimized independently predicts pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple in silico predictors points to a pathogenic effect for S983R, and this conclusion does not contradict any ClinVar annotation, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.707965 | Disordered | 0.960212 | Binding | 0.277 | 0.889 | 0.625 | -4.733 | Likely Benign | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.156 | Likely Benign | -2.66 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.03 | Pathogenic | 0.00 | Affected | 0.1163 | 0.3740 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2947A>G | S983G 2D AIThe SynGAP1 missense variant S983G is not 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 vs 2). High‑accuracy methods show AlphaMissense‑Optimized as benign; the SGM Consensus is unavailable, and Foldetta results are not provided, so no folding‑stability evidence is available. Overall, the balance of evidence (five pathogenic vs four benign predictions) suggests the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant has not yet been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.707965 | Disordered | 0.960212 | Binding | 0.277 | 0.889 | 0.625 | -5.206 | Likely Benign | 0.638 | Likely Pathogenic | Likely Benign | 0.109 | Likely Benign | -2.22 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.17 | Pathogenic | 0.00 | Affected | 0.2521 | 0.4480 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2947A>T | S983C 2D AIThe SynGAP1 missense variant S983C 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 AlphaMissense‑Optimized, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points toward a pathogenic impact. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.707965 | Disordered | 0.960212 | Binding | 0.277 | 0.889 | 0.625 | -7.083 | In-Between | 0.741 | Likely Pathogenic | Likely Benign | 0.162 | Likely Benign | -2.64 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.02 | Pathogenic | 0.00 | Affected | 0.1657 | 0.5298 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2948G>A | S983N 2D AISynGAP1 missense variant S983N is listed as Benign in ClinVar (ID 469153) and is present in gnomAD (6‑33443500‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive; Foldetta results are not available. Overall, the majority of available predictions (five pathogenic vs. three benign) suggest a pathogenic impact, which contradicts the ClinVar benign classification. 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 | Likely Benign | 1 | 6-33443500-G-A | 6 | 3.72e-6 | -5.604 | Likely Benign | 0.909 | Likely Pathogenic | Ambiguous | 0.136 | Likely Benign | -1.78 | Neutral | 0.991 | Probably Damaging | 0.988 | Probably Damaging | 2.04 | Pathogenic | 0.00 | Affected | 4.32 | 1 | 0.1933 | 0.4069 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||
| 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.2948G>T | S983I 2D AIThe SynGAP1 missense variant S983I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). In silico predictors that agree on a benign effect are REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 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 (3 pathogenic vs. 1 benign) is likely pathogenic. Foldetta results are unavailable. Overall, the preponderance of evidence indicates that S983I 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 | 0.707965 | Disordered | 0.960212 | Binding | 0.277 | 0.889 | 0.625 | -6.259 | Likely Benign | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.190 | Likely Benign | -2.67 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 2.02 | Pathogenic | 0.00 | Affected | 0.1380 | 0.4625 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2949C>A | S983R 2D AIThe SynGAP1 missense variant S983R is reported in ClinVar as “Not submitted” and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, 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 (3 pathogenic vs. 1 benign) is likely pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that S983R is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently lacks a classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.707965 | Disordered | 0.960212 | Binding | 0.277 | 0.889 | 0.625 | -4.733 | Likely Benign | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.190 | Likely Benign | -2.66 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.03 | Pathogenic | 0.00 | Affected | 0.1163 | 0.3740 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2949C>G | S983R 2D AIThe SynGAP1 missense variant S983R is reported in ClinVar as “Not submitted” and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, 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 (3 pathogenic vs. 1 benign) is likely pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that S983R is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently lacks a pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.707965 | Disordered | 0.960212 | Binding | 0.277 | 0.889 | 0.625 | -4.733 | Likely Benign | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.190 | Likely Benign | -2.66 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.03 | Pathogenic | 0.00 | Affected | 0.1163 | 0.3740 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.4000A>C | N1334H 2D AIThe SynGAP1 missense variant N1334H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also 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 reliable tools and the high‑accuracy consensus predict a benign impact. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.915074 | Disordered | 0.960403 | Binding | 0.406 | 0.734 | 0.875 | -4.954 | Likely Benign | 0.496 | Ambiguous | Likely Benign | 0.164 | Likely Benign | -2.99 | Deleterious | 0.985 | Probably Damaging | 0.927 | Probably Damaging | 3.50 | Benign | 0.00 | Affected | 0.1963 | 0.6246 | 2 | 1 | 0.3 | 23.04 | ||||||||||||||||||||||||||||||||||||||||
| c.4000A>G | N1334D 2D AIThe SynGAP1 missense variant N1334D (ClinVar ID 3653769.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33451874‑A‑G). Functional prediction tools show a split: benign calls come from REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, an inconclusive SGM Consensus (a 2‑vs‑2 majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and no available Foldetta stability data. Overall, the majority of predictions (5/10) indicate pathogenicity, and the high‑accuracy tools do not overturn this trend. Therefore, the variant is most likely pathogenic, which does not contradict its ClinVar status of Uncertain. 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 | Uncertain | 1 | 6-33451874-A-G | -4.584 | Likely Benign | 0.674 | Likely Pathogenic | Likely Benign | 0.126 | Likely Benign | -3.06 | Deleterious | 0.886 | Possibly Damaging | 0.522 | Possibly Damaging | 3.55 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2444 | 0.3307 | 1 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||
| c.4000A>T | N1334Y 2D AIThe SynGAP1 missense variant N1334Y is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive; Foldetta results are unavailable. Overall, the majority of conventional tools predict a pathogenic impact, but the single high‑accuracy benign prediction and the inconclusive consensus suggest uncertainty. Consequently, the variant is most likely pathogenic based on the prevailing evidence, and this assessment does not contradict any ClinVar annotation because the variant has not yet been reported there. 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 | -5.916 | Likely Benign | 0.770 | Likely Pathogenic | Likely Benign | 0.249 | Likely Benign | -4.62 | Deleterious | 0.985 | Probably Damaging | 0.852 | Possibly Damaging | 3.49 | Benign | 0.00 | Affected | 0.0716 | 0.5447 | -2 | -2 | 2.2 | 49.07 | ||||||||||||||||||||||||||||||||||||||||
| c.4001A>C | N1334T 2D AIThe SynGAP1 missense variant N1334T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (two pathogenic vs. two benign votes). Foldetta, which evaluates protein‑folding stability, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and there is no ClinVar entry 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. | 0.915074 | Disordered | 0.960403 | Binding | 0.406 | 0.734 | 0.875 | -4.249 | Likely Benign | 0.576 | Likely Pathogenic | Likely Benign | 0.103 | Likely Benign | -3.45 | Deleterious | 0.047 | Benign | 0.063 | Benign | 3.59 | Benign | 0.00 | Affected | 0.1600 | 0.5519 | 0 | 0 | 2.8 | -13.00 | ||||||||||||||||||||||||||||||||||||||||
| c.4001A>G | N1334S 2D AIThe SynGAP1 missense variant N1334S is not 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. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a benign consensus (2 benign vs. 1 pathogenic, 1 uncertain). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.915074 | Disordered | 0.960403 | Binding | 0.406 | 0.734 | 0.875 | -3.989 | Likely Benign | 0.409 | Ambiguous | Likely Benign | 0.107 | Likely Benign | -2.94 | Deleterious | 0.557 | Possibly Damaging | 0.348 | Benign | 3.56 | Benign | 0.00 | Affected | 0.3542 | 0.4708 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||||||||||||||||
| c.4001A>T | N1334I 2D AIThe SynGAP1 missense variant N1334I is not 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, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign), and Foldetta results are unavailable. Overall, the balance of evidence (seven pathogenic vs. three benign predictions) indicates that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, as the variant has no existing ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.915074 | Disordered | 0.960403 | Binding | 0.406 | 0.734 | 0.875 | -5.880 | Likely Benign | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.193 | Likely Benign | -5.06 | Deleterious | 0.985 | Probably Damaging | 0.721 | Possibly Damaging | 3.50 | Benign | 0.00 | Affected | 0.0861 | 0.5491 | -2 | -3 | 8.0 | -0.94 | ||||||||||||||||||||||||||||||||||||||||
| 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.3955G>A | A1319T 2D AIThe SynGAP1 missense variant A1319T is reported in gnomAD (variant ID 6‑33451829‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts a benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT each predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, SGM‑Consensus is benign, and the Foldetta stability analysis is unavailable. Overall, the majority of evidence supports a benign impact for A1319T, 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 | 0.842060 | Disordered | 0.960481 | Binding | 0.454 | 0.851 | 0.750 | 6-33451829-G-A | -4.861 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.30 | Neutral | 0.917 | Possibly Damaging | 0.500 | Possibly Damaging | 4.13 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1944 | 0.7174 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||
| c.3955G>C | A1319P 2D AIThe SynGAP1 missense variant A1319P is reported in ClinVar as “Not submitted” and is present in gnomAD (ID 6‑33451829‑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 (majority vote from 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 the ClinVar status, which currently contains no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.960481 | Binding | 0.454 | 0.851 | 0.750 | 6-33451829-G-C | 3 | 1.95e-6 | -2.783 | Likely Benign | 0.057 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -0.81 | Neutral | 0.992 | Probably Damaging | 0.878 | Possibly Damaging | 4.06 | Benign | 0.03 | Affected | 3.77 | 5 | 0.2360 | 0.5715 | -1 | 1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||||||
| c.3955G>T | A1319S 2D AIThe SynGAP1 missense variant A1319S is catalogued in gnomAD (ID 6‑33451829‑G‑T) but has no ClinVar entry. Functional prediction tools uniformly classify it as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign effects. No tool predicts pathogenicity. Grouping by consensus, all listed predictors fall into the benign category, with no pathogenic predictions to counterbalance. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign outcome. Foldetta results are not available for this variant. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.960481 | Binding | 0.454 | 0.851 | 0.750 | 6-33451829-G-T | -4.557 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.094 | Likely Benign | 0.79 | Neutral | 0.174 | Benign | 0.112 | Benign | 4.17 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2957 | 0.5676 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.3956C>A | A1319D 2D AIThe SynGAP1 missense variant A1319D is reported in gnomAD (ID 6‑33451830‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict 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 (majority of the same four tools) is benign. Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for A1319D, 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 | 0.842060 | Disordered | 0.960481 | Binding | 0.454 | 0.851 | 0.750 | 6-33451830-C-A | -5.156 | Likely Benign | 0.297 | Likely Benign | Likely Benign | 0.208 | Likely Benign | -0.85 | Neutral | 0.971 | Probably Damaging | 0.813 | Possibly Damaging | 4.08 | Benign | 0.01 | Affected | 3.77 | 5 | 0.2290 | 0.2702 | -2 | 0 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||
| c.3956C>G | A1319G 2D AIThe SynGAP1 missense variant A1319G is listed in ClinVar (ID 1690510.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451830‑C‑G). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this is consistent with the ClinVar “Uncertain” status rather than contradicting it. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.960481 | Binding | 0.454 | 0.851 | 0.750 | Uncertain | 2 | 6-33451830-C-G | -3.927 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.128 | Likely Benign | -0.74 | Neutral | 0.819 | Possibly Damaging | 0.581 | Possibly Damaging | 4.07 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0.2423 | 0.4541 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.3956C>T | A1319V 2D AIThe SynGAP1 missense variant A1319V is reported in gnomAD (ID 6‑33451830‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict 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 (majority of the same four tools) is benign. Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for A1319V, 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 | 0.842060 | Disordered | 0.960481 | Binding | 0.454 | 0.851 | 0.750 | 6-33451830-C-T | 1 | 7.16e-7 | -5.015 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.167 | Likely Benign | -0.17 | Neutral | 0.971 | Probably Damaging | 0.757 | Possibly Damaging | 4.14 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1583 | 0.6127 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||
| c.2902G>A | G968S 2D AIThe SynGAP1 missense variant G968S 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 (none is available). 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 | -4.484 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -0.35 | Neutral | 0.058 | Benign | 0.023 | Benign | 4.22 | Benign | 0.37 | Tolerated | 0.2482 | 0.5699 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2902G>C | G968R 2D AIThe SynGAP1 missense variant G968R is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the evidence strongly supports a benign classification, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978316 | Disordered | 0.961360 | Binding | 0.327 | 0.896 | 0.750 | -4.492 | Likely Benign | 0.332 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -0.63 | Neutral | 0.005 | Benign | 0.012 | Benign | 4.19 | Benign | 0.08 | Tolerated | 0.0972 | 0.5017 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
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