Table of SynGAP1 Isoform α2 (UniProt Q96PV0-1) Missense Variants.
| c.dna | Variant | SGM Consensus | Domain | IUPred2 | ANCHOR2 | AlphaFold | MobiDB | ClinVar | gnomAD | ESM1b | AlphaMissense | REVEL | PSMutPred | FoldX | Rosetta | Foldetta | PremPS | PROVEAN | PolyPhen-2 HumDiv | PolyPhen-2 HumVar | FATHMM | SIFT | PAM | Physical | SASA | Normalized B-factor backbone | Normalized B-factor sidechain | SynGAP Structural Annotation | DOI | ||||||||||||||||||||||||||||||||||||||
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| Score | Prediction | Score | Prediction | pLDDT | disorder | disorder | Clinical Status | Review | Subm. | ID | Allele count | Allele freq. | LLR score | Prediction | Pathogenicity | Class | Optimized | Score | Prediction | IP RF | SP RF | Prediction | Average ΔΔG | Prediction | StdDev | ΔΔG | Prediction | ΔΔG | Prediction | ΔΔG | Prediction | Score | Prediction | pph2_prob | Prediction | pph2_prob | Prediction | Nervous System Score | Prediction | Prediction | Status | Conservation | Sequences | 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.2945A>T | Y982F 2D  AIThe SynGAP1 missense variant Y982F 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 | 0.707965 | Disordered | 0.966717 | Binding | 0.272 | 0.895 | 0.625 | -3.431 | Likely Benign | 0.208 | Likely Benign | Likely Benign | 0.154 | Likely Benign | 0.2351 | 0.2980 | -0.36 | Neutral | 0.006 | Benign | 0.009 | Benign | 4.63 | Benign | 0.00 | Affected | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1163 | 0.3740 | -2.66 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.03 | Pathogenic | 0.00 | Affected | 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 | 0.2521 | 0.4480 | -2.22 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.17 | Pathogenic | 0.00 | Affected | 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 | 0.1657 | 0.5298 | -2.64 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.02 | Pathogenic | 0.00 | Affected | 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 | 0.1933 | 0.4069 | -1.78 | Neutral | 0.991 | Probably Damaging | 0.988 | Probably Damaging | 2.04 | Pathogenic | 0.00 | Affected | 4.32 | 1 | 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 | 0.2042 | 0.5517 | -1.65 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.08 | Pathogenic | 0.00 | Affected | 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 | 0.1380 | 0.4625 | -2.67 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 2.02 | Pathogenic | 0.00 | Affected | -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 | 0.1163 | 0.3740 | -2.66 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.03 | Pathogenic | 0.00 | Affected | 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 | 0.1163 | 0.3740 | -2.66 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.03 | Pathogenic | 0.00 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||
| 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 | 0.5054 | 0.1240 | Weaken | -0.67 | Neutral | 0.905 | Possibly Damaging | 0.637 | Possibly Damaging | 2.66 | Benign | 0.00 | Affected | 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 | 0.4353 | 0.1200 | -0.88 | Neutral | 0.798 | Possibly Damaging | 0.535 | Possibly Damaging | 2.71 | Benign | 0.00 | Affected | 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 | 0.2441 | 0.3463 | -1.10 | Neutral | 0.951 | Possibly Damaging | 0.708 | Possibly Damaging | 2.71 | Benign | 0.00 | Affected | 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 | 0.5098 | 0.1558 | Weaken | -0.41 | Neutral | 0.012 | Benign | 0.012 | Benign | 2.67 | Benign | 0.00 | Affected | 4.32 | 1 | 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 | 0.1576 | 0.4168 | -1.82 | Neutral | 0.995 | Probably Damaging | 0.944 | Probably Damaging | 2.60 | Benign | 0.00 | Affected | 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 | 0.4138 | 0.1677 | 0.52 | Neutral | 0.951 | Possibly Damaging | 0.637 | Possibly Damaging | 2.89 | Benign | 0.00 | Affected | 4.32 | 1 | 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 | 0.4138 | 0.1677 | 0.52 | Neutral | 0.951 | Possibly Damaging | 0.637 | Possibly Damaging | 2.89 | Benign | 0.00 | Affected | 4.32 | 1 | 0 | 1 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||
| 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 | 0.1213 | 0.3905 | -2.40 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.52 | Benign | 0.00 | Affected | 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 | 0.2684 | 0.4540 | -2.29 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.51 | Benign | 0.00 | Affected | 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 | 0.1531 | 0.5395 | -2.49 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 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 | 0.1812 | 0.4822 | -1.68 | Neutral | 0.991 | Probably Damaging | 0.988 | Probably Damaging | 2.65 | Benign | 0.00 | Affected | 4.32 | 1 | 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 | 0.1889 | 0.5844 | -1.62 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.54 | Benign | 0.00 | Affected | 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 | 0.1367 | 0.5206 | -2.78 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 2.50 | Benign | 0.00 | Affected | -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 | 0.1213 | 0.3905 | -2.40 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.52 | Benign | 0.00 | Affected | 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 | 0.1213 | 0.3905 | -2.40 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.52 | Benign | 0.00 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||
| 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 | 0.2760 | 0.7973 | -2.19 | Neutral | 0.924 | Possibly Damaging | 0.722 | Possibly Damaging | 2.15 | Pathogenic | 0.00 | Affected | 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 | 0.1700 | 0.7589 | -1.66 | Neutral | 0.974 | Probably Damaging | 0.842 | Possibly Damaging | 2.14 | Pathogenic | 0.00 | Affected | 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 | 0.4207 | 0.7733 | -2.32 | Neutral | 0.552 | Possibly Damaging | 0.388 | Benign | 2.14 | Pathogenic | 0.00 | Affected | 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 | 0.2866 | 0.6225 | -3.14 | Deleterious | 0.924 | Possibly Damaging | 0.784 | Possibly Damaging | 2.13 | Pathogenic | 0.00 | Affected | 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 | 0.1146 | 0.7960 | -3.48 | Deleterious | 0.018 | Benign | 0.028 | Benign | 2.10 | Pathogenic | 0.00 | Affected | -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 | 0.2081 | 0.5364 | -1.22 | Neutral | 0.974 | Probably Damaging | 0.715 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | 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 | 0.2081 | 0.5364 | -1.22 | Neutral | 0.974 | Probably Damaging | 0.715 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||
| 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 | 0.1331 | 0.7427 | -1.42 | Neutral | 0.943 | Possibly Damaging | 0.755 | Possibly Damaging | 2.41 | Pathogenic | 0.49 | Tolerated | 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 | 0.1553 | 0.7629 | -3.16 | Deleterious | 0.998 | Probably Damaging | 0.951 | Probably Damaging | 2.35 | Pathogenic | 0.02 | Affected | 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 | 0.0632 | 0.6818 | -4.41 | Deleterious | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.33 | Pathogenic | 0.01 | Affected | -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 | 0.3930 | 0.6846 | -3.72 | Deleterious | 0.943 | Possibly Damaging | 0.686 | Possibly Damaging | 2.39 | Pathogenic | 0.02 | Affected | 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 | 0.3835 | 0.6710 | -2.79 | Deleterious | 0.943 | Possibly Damaging | 0.808 | Possibly Damaging | 2.45 | Pathogenic | 0.07 | Tolerated | 4.32 | 2 | 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 | 0.0907 | 0.7202 | -4.01 | Deleterious | 0.992 | Probably Damaging | 0.913 | Probably Damaging | 2.34 | Pathogenic | 0.00 | Affected | -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 | 0.1586 | 0.7239 | -1.36 | Neutral | 0.049 | Benign | 0.044 | Benign | 2.64 | Benign | 0.04 | Affected | 4.32 | 2 | 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 | 0.1586 | 0.7239 | -1.36 | Neutral | 0.049 | Benign | 0.044 | Benign | 2.64 | Benign | 0.04 | Affected | 4.32 | 2 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||
| 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 | 0.1034 | 0.4143 | -1.08 | Neutral | 0.924 | Possibly Damaging | 0.652 | Possibly Damaging | 2.70 | Benign | 0.00 | Affected | 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 | 0.1652 | 0.3793 | -1.42 | Neutral | 0.856 | Possibly Damaging | 0.474 | Possibly Damaging | 2.73 | Benign | 0.00 | Affected | 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 | 0.0693 | 0.3592 | -1.70 | Neutral | 0.977 | Probably Damaging | 0.900 | Possibly Damaging | 2.69 | Benign | 0.00 | Affected | 4.32 | 2 | 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 | 0.1179 | 0.1414 | -2.70 | Deleterious | 0.998 | Probably Damaging | 0.947 | Probably Damaging | 2.62 | Benign | 0.00 | Affected | -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 | 0.3282 | 0.1698 | -2.96 | Deleterious | 0.977 | Probably Damaging | 0.900 | Possibly Damaging | 2.62 | Benign | 0.00 | Affected | -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 | 0.1257 | 0.1088 | -2.39 | Neutral | 0.954 | Possibly Damaging | 0.867 | Possibly Damaging | 2.69 | Benign | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||
| c.2965T>A | S989T 2D AIThe SynGAP1 missense variant S989T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest a pathogenic impact. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign outcome. No Foldetta stability data are available. Overall, the majority of evidence points to a benign effect, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.908835 | Binding | 0.296 | 0.911 | 0.750 | -3.995 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 0.059 | Likely Benign | 0.1183 | 0.5377 | -1.48 | Neutral | 0.770 | Possibly Damaging | 0.396 | Benign | 2.66 | Benign | 0.00 | Affected | 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 | 0.1690 | 0.4941 | -2.48 | Neutral | 0.010 | Benign | 0.015 | Benign | 2.67 | Benign | 0.00 | Affected | 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 | 0.4580 | 0.4221 | -1.15 | Neutral | 0.580 | Possibly Damaging | 0.253 | Benign | 2.68 | Benign | 0.00 | Affected | 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 | 0.0611 | 0.4815 | -3.32 | Deleterious | 0.986 | Probably Damaging | 0.876 | Possibly Damaging | 2.60 | Benign | 0.00 | Affected | -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 | 0.0828 | 0.5202 | -2.88 | Deleterious | 0.996 | Probably Damaging | 0.905 | Possibly Damaging | 2.59 | Benign | 0.00 | Affected | 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 | 0.0598 | 0.5103 | -3.35 | Deleterious | 0.986 | Probably Damaging | 0.876 | Possibly Damaging | 2.60 | Benign | 0.00 | Affected | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||
| 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 | 0.1524 | 0.5598 | -0.06 | Neutral | 0.001 | Benign | 0.007 | Benign | 2.89 | Benign | 1.00 | Tolerated | 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 | 0.1910 | 0.5345 | -1.95 | Neutral | 0.586 | Possibly Damaging | 0.377 | Benign | 2.74 | Benign | 0.01 | Affected | 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 | 0.4537 | 0.4509 | -0.51 | Neutral | 0.001 | Benign | 0.004 | Benign | 2.91 | Benign | 0.03 | Affected | 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 | 0.0893 | 0.5832 | -2.52 | Deleterious | 0.832 | Possibly Damaging | 0.500 | Possibly Damaging | 2.74 | Benign | 0.00 | Affected | -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 | 0.1041 | 0.5823 | -1.91 | Neutral | 0.938 | Possibly Damaging | 0.690 | Possibly Damaging | 2.73 | Benign | 0.01 | Affected | 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 | 0.0814 | 0.6021 | -2.65 | Deleterious | 0.710 | Possibly Damaging | 0.272 | Benign | 2.75 | Benign | 0.00 | Affected | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0956 | 0.4181 | -1.20 | Neutral | 0.984 | Probably Damaging | 0.772 | Possibly Damaging | 4.11 | Benign | 0.01 | Affected | 4.32 | 2 | -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 | 0.0956 | 0.4181 | -1.20 | Neutral | 0.984 | Probably Damaging | 0.772 | Possibly Damaging | 4.11 | Benign | 0.01 | Affected | 4.32 | 2 | -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 | 0.0745 | 0.3654 | -2.32 | Neutral | 0.997 | Probably Damaging | 0.975 | Probably Damaging | 4.07 | Benign | 0.00 | Affected | -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 | 0.1480 | 0.4277 | -1.30 | Neutral | 0.846 | Possibly Damaging | 0.697 | Possibly Damaging | 4.13 | Benign | 0.01 | Affected | 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 | 0.3522 | 0.4528 | -0.83 | Neutral | 0.002 | Benign | 0.026 | Benign | 4.20 | Benign | 0.62 | Tolerated | 4.32 | 2 | 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 | 0.1148 | 0.3961 | -1.61 | Neutral | 0.440 | Benign | 0.253 | Benign | 4.16 | Benign | 0.01 | Affected | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0939 | 0.4541 | -0.30 | Neutral | 0.302 | Benign | 0.089 | Benign | 4.20 | Benign | 0.29 | Tolerated | 4.32 | 2 | 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 | 0.1211 | 0.5202 | -0.50 | Neutral | 0.086 | Benign | 0.038 | Benign | 4.24 | Benign | 0.16 | Tolerated | 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 | 0.0832 | 0.4083 | -1.25 | Neutral | 0.680 | Possibly Damaging | 0.356 | Benign | 4.17 | Benign | 0.04 | Affected | -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 | 0.1645 | 0.1056 | -1.24 | Neutral | 0.302 | Benign | 0.158 | Benign | 4.21 | Benign | 0.05 | Affected | -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 | 0.3041 | 0.2668 | -0.08 | Neutral | 0.000 | Benign | 0.003 | Benign | 4.29 | Benign | 0.41 | Tolerated | 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 | 0.2114 | 0.2612 | -0.28 | Neutral | 0.056 | Benign | 0.086 | Benign | 4.21 | Benign | 0.16 | Tolerated | -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 | 0.1603 | 0.5789 | -0.65 | Neutral | 0.001 | Benign | 0.010 | Benign | 4.32 | Benign | 0.04 | Affected | 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 | 0.3487 | 0.4991 | -0.46 | Neutral | 0.001 | Benign | 0.006 | Benign | 4.26 | Benign | 0.07 | Tolerated | 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 | 0.3421 | 0.5465 | -0.13 | Neutral | 0.011 | Benign | 0.023 | Benign | 4.26 | Benign | 0.59 | Tolerated | 4.32 | 2 | -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 | 0.1799 | 0.4591 | -0.93 | Neutral | 0.938 | Possibly Damaging | 0.819 | Possibly Damaging | 4.11 | Benign | 0.00 | Affected | 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 | 0.1469 | 0.3122 | -0.85 | Neutral | 0.586 | Possibly Damaging | 0.478 | Possibly Damaging | 4.14 | Benign | 0.01 | Affected | 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 | 0.2299 | 0.6697 | -1.37 | Neutral | 0.224 | Benign | 0.138 | Benign | 4.14 | Benign | 0.01 | Affected | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||
| 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 | 0.4975 | 0.1889 | -0.45 | Neutral | 0.002 | Benign | 0.004 | Benign | 4.16 | Benign | 0.03 | Affected | 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 | 0.4148 | 0.1699 | -0.58 | Neutral | 0.036 | Benign | 0.039 | Benign | 4.14 | Benign | 0.02 | Affected | 4.32 | 2 | 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 | 0.2503 | 0.4248 | -1.22 | Neutral | 0.144 | Benign | 0.085 | Benign | 4.09 | Benign | 0.01 | Affected | 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 | 0.5064 | 0.1657 | Weaken | 0.02 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.21 | Benign | 0.47 | Tolerated | 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 | 0.1612 | 0.4395 | -1.21 | Neutral | 0.589 | Possibly Damaging | 0.187 | Benign | 4.04 | Benign | 0.00 | Affected | 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 | 0.4010 | 0.2376 | -0.73 | Neutral | 0.255 | Benign | 0.113 | Benign | 4.09 | Benign | 0.01 | Affected | 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 | 0.4010 | 0.2376 | -0.73 | Neutral | 0.255 | Benign | 0.113 | Benign | 4.09 | Benign | 0.01 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1467 | 0.5667 | -1.15 | Neutral | 0.224 | Benign | 0.096 | Benign | 4.19 | Benign | 0.00 | Affected | 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 | 0.3287 | 0.4841 | -1.02 | Neutral | 0.001 | Benign | 0.008 | Benign | 4.22 | Benign | 0.00 | Affected | 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 | 0.3204 | 0.5236 | -1.03 | Neutral | 0.011 | Benign | 0.015 | Benign | 4.24 | Benign | 0.00 | Affected | 4.32 | 1 | 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 | 0.1618 | 0.4571 | -0.75 | Neutral | 0.832 | Possibly Damaging | 0.600 | Possibly Damaging | 4.16 | Benign | 0.00 | Affected | 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 | 0.1370 | 0.3424 | -1.06 | Neutral | 0.586 | Possibly Damaging | 0.304 | Benign | 4.18 | Benign | 0.00 | Affected | 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 | 0.2294 | 0.6324 | -1.03 | Neutral | 0.411 | Benign | 0.096 | Benign | 4.16 | Benign | 0.00 | Affected | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1418 | 0.6163 | -0.71 | Neutral | 0.036 | Benign | 0.039 | Benign | 4.26 | Benign | 0.03 | Affected | 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 | 0.3242 | 0.4961 | -0.40 | Neutral | 0.000 | Benign | 0.002 | Benign | 4.30 | Benign | 0.86 | Tolerated | 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 | 0.3171 | 0.5161 | -0.58 | Neutral | 0.002 | Benign | 0.004 | Benign | 4.30 | Benign | 0.09 | Tolerated | 4.32 | 4 | -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 | 0.1585 | 0.5160 | -1.19 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.25 | Benign | 0.00 | Affected | 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 | 0.1297 | 0.3385 | -1.04 | Neutral | 0.144 | Benign | 0.085 | Benign | 4.26 | Benign | 0.01 | Affected | 4.32 | 4 | -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 | 0.2057 | 0.6631 | -1.65 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.25 | Benign | 0.02 | Affected | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1582 | 0.7182 | -0.62 | Neutral | 0.224 | Benign | 0.120 | Benign | 4.17 | Benign | 0.00 | Affected | 4.32 | 4 | 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 | 0.1938 | 0.5294 | -1.17 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.11 | Benign | 0.00 | Affected | 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 | 0.2661 | 0.5694 | -0.63 | Neutral | 0.224 | Benign | 0.066 | Benign | 4.18 | Benign | 0.00 | Affected | 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 | 0.1815 | 0.2143 | -1.09 | Neutral | 0.411 | Benign | 0.120 | Benign | 4.15 | Benign | 0.00 | Affected | 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 | 0.2145 | 0.4741 | -0.82 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.13 | Benign | 0.00 | Affected | 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 | 0.1232 | 0.6335 | -1.01 | Neutral | 0.369 | Benign | 0.120 | Benign | 4.15 | Benign | 0.00 | Affected | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1620 | 0.6994 | -0.97 | Neutral | 0.611 | Possibly Damaging | 0.321 | Benign | 4.11 | Benign | 0.00 | Affected | 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 | 0.1924 | 0.5106 | -0.40 | Neutral | 0.971 | Probably Damaging | 0.690 | Possibly Damaging | 4.31 | Benign | 0.00 | Affected | 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 | 0.2674 | 0.5506 | -0.42 | Neutral | 0.611 | Possibly Damaging | 0.237 | Benign | 4.14 | Benign | 0.00 | Affected | 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 | 0.1754 | 0.2143 | -1.55 | Neutral | 0.971 | Probably Damaging | 0.690 | Possibly Damaging | 4.09 | Benign | 0.00 | Affected | 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 | 0.2234 | 0.4741 | -1.29 | Neutral | 0.761 | Possibly Damaging | 0.396 | Benign | 4.13 | Benign | 0.00 | Affected | 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 | 0.1281 | 0.6147 | -1.09 | Neutral | 0.245 | Benign | 0.138 | Benign | 4.09 | Benign | 0.00 | Affected | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1469 | 0.6651 | -0.94 | Neutral | 0.625 | Possibly Damaging | 0.266 | Benign | 2.69 | Benign | 0.04 | Affected | 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 | 0.1963 | 0.6268 | -1.05 | Neutral | 0.966 | Probably Damaging | 0.773 | Possibly Damaging | 2.65 | Benign | 0.04 | Affected | 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 | 0.4516 | 0.5434 | -0.83 | Neutral | 0.005 | Benign | 0.016 | Benign | 2.71 | Benign | 0.81 | Tolerated | 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 | 0.0881 | 0.6249 | -1.74 | Neutral | 0.934 | Possibly Damaging | 0.559 | Possibly Damaging | 2.64 | Benign | 0.00 | Affected | -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 | 0.1131 | 0.6212 | -1.68 | Neutral | 0.991 | Probably Damaging | 0.873 | Possibly Damaging | 2.63 | Benign | 0.01 | Affected | 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 | 0.0865 | 0.6337 | -1.79 | Neutral | 0.966 | Probably Damaging | 0.837 | Possibly Damaging | 2.64 | Benign | 0.01 | Affected | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0916 | 0.4034 | -0.34 | Neutral | 0.211 | Benign | 0.108 | Benign | 2.76 | Benign | 0.70 | Tolerated | 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 | 0.1220 | 0.3404 | -0.20 | Neutral | 0.437 | Benign | 0.170 | Benign | 2.76 | Benign | 0.81 | Tolerated | 4.32 | 4 | 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 | 0.0594 | 0.3259 | -1.02 | Neutral | 0.968 | Probably Damaging | 0.713 | Possibly Damaging | 2.70 | Benign | 0.13 | Tolerated | 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 | 0.1001 | 0.0900 | -0.82 | Neutral | 0.995 | Probably Damaging | 0.913 | Probably Damaging | 2.72 | Benign | 0.16 | Tolerated | -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 | 0.1045 | 0.1594 | -0.87 | Neutral | 0.896 | Possibly Damaging | 0.596 | Possibly Damaging | 2.78 | Benign | 0.29 | Tolerated | 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 | 0.2501 | 0.1270 | -0.38 | Neutral | 0.946 | Possibly Damaging | 0.673 | Possibly Damaging | 2.80 | Benign | 0.19 | Tolerated | -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 | 0.0769 | 0.3104 | -0.32 | Neutral | 0.437 | Benign | 0.108 | Benign | 2.70 | Benign | 0.17 | Tolerated | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0994 | 0.3264 | -0.17 | Neutral | 0.022 | Benign | 0.018 | Benign | 2.69 | Benign | 0.00 | Affected | 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 | 0.1569 | 0.2714 | -0.20 | Neutral | 0.022 | Benign | 0.008 | Benign | 2.71 | Benign | 0.00 | Affected | 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 | 0.0703 | 0.2876 | -0.85 | Neutral | 0.934 | Possibly Damaging | 0.617 | Possibly Damaging | 2.65 | Benign | 0.00 | Affected | 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 | 0.1141 | 0.0958 | -1.02 | Neutral | 0.997 | Probably Damaging | 0.870 | Possibly Damaging | 2.64 | Benign | 0.00 | Affected | -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 | 0.3322 | 0.0929 | -1.02 | Neutral | 0.966 | Probably Damaging | 0.690 | Possibly Damaging | 2.65 | Benign | 0.00 | Affected | 4.32 | 4 | -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 | 0.1299 | 0.0832 | -1.09 | Neutral | 0.966 | Probably Damaging | 0.708 | Possibly Damaging | 2.67 | Benign | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||
| 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 | 0.2084 | 0.3057 | -1.41 | Neutral | 0.801 | Possibly Damaging | 0.596 | Possibly Damaging | 2.76 | Benign | 1.00 | Tolerated | 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 | 0.2597 | 0.2335 | -2.09 | Neutral | 0.891 | Possibly Damaging | 0.673 | Possibly Damaging | 2.75 | Benign | 0.89 | Tolerated | 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 | 0.1243 | 0.4427 | -1.85 | Neutral | 0.961 | Probably Damaging | 0.808 | Possibly Damaging | 2.74 | Benign | 0.14 | Tolerated | 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 | 0.2015 | 0.3738 | -2.02 | Neutral | 0.989 | Probably Damaging | 0.874 | Possibly Damaging | 2.77 | Benign | 0.28 | Tolerated | 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 | 0.2160 | 0.2978 | -1.52 | Neutral | 0.012 | Benign | 0.022 | Benign | 2.76 | Benign | 0.25 | Tolerated | 4.32 | 4 | 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 | 0.1296 | 0.5088 | -3.12 | Deleterious | 0.801 | Possibly Damaging | 0.602 | Possibly Damaging | 2.79 | Benign | 0.13 | Tolerated | -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 | 0.1927 | 0.3510 | -1.83 | Neutral | 0.801 | Possibly Damaging | 0.602 | Possibly Damaging | 2.77 | Benign | 0.23 | Tolerated | 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 | 0.1927 | 0.3510 | -1.83 | Neutral | 0.801 | Possibly Damaging | 0.602 | Possibly Damaging | 2.77 | Benign | 0.23 | Tolerated | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1151 | 0.3746 | -1.88 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 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 | 0.2730 | 0.4789 | -1.72 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 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 | 0.1442 | 0.5966 | -1.98 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 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 | 0.1798 | 0.5029 | -1.37 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 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 | 0.1864 | 0.6227 | -1.04 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.51 | Benign | 0.00 | Affected | 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 | 0.1294 | 0.5735 | -2.31 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.50 | Benign | 0.00 | Affected | -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 | 0.1151 | 0.3746 | -1.88 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 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 | 0.1151 | 0.3746 | -1.88 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||
| 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 | 0.2056 | 0.3580 | -1.18 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.88 | Benign | 0.35 | Tolerated | 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 | 0.2695 | 0.2530 | -2.16 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.78 | Benign | 0.29 | Tolerated | 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 | 0.1175 | 0.5143 | -1.67 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.72 | Benign | 0.49 | Tolerated | 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 | 0.2076 | 0.4643 | -2.69 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.72 | Benign | 0.18 | Tolerated | 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 | 0.2097 | 0.3132 | -1.88 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.77 | Benign | 0.50 | Tolerated | 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 | 0.1223 | 0.6026 | -3.14 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.75 | Benign | 0.55 | Tolerated | -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 | 0.1831 | 0.3832 | -1.55 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.78 | Benign | 0.71 | Tolerated | 3.77 | 5 | 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 | 0.1831 | 0.3832 | -1.55 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.78 | Benign | 0.71 | Tolerated | 3.77 | 5 | 0 | 3 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||
| 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 | 0.0994 | 0.2856 | -2.29 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.66 | Benign | 0.00 | Affected | 3.77 | 5 | -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 | 0.2328 | 0.3514 | -1.98 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.63 | Benign | 0.00 | Affected | 3.77 | 5 | 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 | 0.1246 | 0.4492 | -2.20 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.59 | Benign | 0.00 | Affected | 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 | 0.1520 | 0.3761 | -1.50 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.65 | Benign | 0.00 | Affected | 3.77 | 5 | 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 | 0.1600 | 0.4937 | -1.30 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.66 | Benign | 0.00 | Affected | 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 | 0.1028 | 0.4098 | -2.79 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.62 | Benign | 0.00 | Affected | -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 | 0.0994 | 0.2856 | -2.29 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.66 | Benign | 0.00 | Affected | 3.77 | 5 | -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 | 0.0994 | 0.2856 | -2.29 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.66 | Benign | 0.00 | Affected | 3.77 | 5 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||
| 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 | 0.2168 | 0.1094 | -0.75 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.73 | Benign | 0.75 | Tolerated | -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 | 0.2406 | 0.0894 | -0.42 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.70 | Benign | 0.17 | Tolerated | 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 | 0.3776 | 0.1094 | -1.53 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.73 | Benign | 0.56 | Tolerated | 3.77 | 5 | -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 | 0.4426 | 0.2274 | -0.58 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.83 | Benign | 0.90 | Tolerated | -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 | 0.3062 | 0.2358 | -1.39 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.68 | Benign | 0.08 | Tolerated | 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 | 0.2423 | 0.3339 | -1.06 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.71 | Benign | 0.10 | Tolerated | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1121 | 0.3237 | -1.93 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.65 | Benign | 0.01 | Affected | 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 | 0.2361 | 0.4341 | -1.49 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.73 | Benign | 0.05 | Affected | 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 | 0.1405 | 0.5142 | -1.91 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.61 | Benign | 0.01 | Affected | 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 | 0.1743 | 0.4342 | -1.54 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.65 | Benign | 0.01 | Affected | 3.77 | 5 | 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 | 0.1796 | 0.5550 | -1.24 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.68 | Benign | 0.03 | Affected | 3.77 | 5 | 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 | 0.1324 | 0.4769 | -2.55 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.65 | Benign | 0.00 | Affected | -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 | 0.1121 | 0.3237 | -1.93 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.65 | Benign | 0.01 | Affected | 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 | 0.1121 | 0.3237 | -1.93 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.65 | Benign | 0.01 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||
| 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 | 0.2076 | 0.7013 | -2.15 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.75 | Benign | 0.01 | Affected | 3.77 | 5 | 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 | 0.2488 | 0.7228 | -2.46 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.64 | Benign | 0.01 | Affected | 3.77 | 5 | -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 | 0.1043 | 0.6293 | -3.71 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.62 | Benign | 0.00 | Affected | -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 | 0.4014 | 0.6444 | -2.65 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.69 | Benign | 0.03 | Affected | 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 | 0.3660 | 0.6073 | -2.84 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.65 | Benign | 0.01 | Affected | 3.77 | 5 | -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 | 0.1447 | 0.6608 | -3.61 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.64 | Benign | 0.01 | Affected | -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 | 0.2315 | 0.6303 | -0.53 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.93 | Benign | 1.00 | Tolerated | 3.77 | 5 | 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 | 0.2315 | 0.6303 | -0.53 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.93 | Benign | 1.00 | Tolerated | 3.77 | 5 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||
| 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 | 0.2511 | 0.7625 | -1.90 | Neutral | 0.961 | Probably Damaging | 0.630 | Possibly Damaging | 2.41 | Pathogenic | 0.01 | Affected | 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 | 0.1577 | 0.7242 | -1.65 | Neutral | 0.980 | Probably Damaging | 0.782 | Possibly Damaging | 2.39 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 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 | 0.3959 | 0.7153 | -3.06 | Deleterious | 0.980 | Probably Damaging | 0.630 | Possibly Damaging | 2.39 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 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 | 0.2800 | 0.6003 | -3.06 | Deleterious | 0.961 | Probably Damaging | 0.721 | Possibly Damaging | 2.36 | Pathogenic | 0.01 | Affected | 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 | 0.1111 | 0.7580 | -3.81 | Deleterious | 0.998 | Probably Damaging | 0.924 | Probably Damaging | 2.34 | Pathogenic | 0.00 | Affected | -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 | 0.2077 | 0.4817 | -0.37 | Neutral | 0.011 | Benign | 0.017 | Benign | 2.50 | Benign | 0.30 | Tolerated | 3.77 | 5 | 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 | 0.2077 | 0.4817 | -0.37 | Neutral | 0.011 | Benign | 0.017 | Benign | 2.50 | Benign | 0.30 | Tolerated | 3.77 | 5 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||
| 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 | 0.2405 | 0.2464 | -1.74 | Neutral | 0.980 | Probably Damaging | 0.783 | Possibly Damaging | 2.57 | Benign | 0.05 | Affected | 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 | 0.2538 | 0.3245 | -1.51 | Neutral | 0.910 | Possibly Damaging | 0.468 | Possibly Damaging | 2.75 | Benign | 0.62 | Tolerated | 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 | 0.2351 | 0.2403 | -2.10 | Neutral | 0.961 | Probably Damaging | 0.721 | Possibly Damaging | 2.58 | Benign | 0.03 | Affected | -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 | 0.1651 | 0.2514 | -0.96 | Neutral | 0.031 | Benign | 0.064 | Benign | 2.64 | Benign | 0.05 | Affected | 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 | 0.4196 | 0.0775 | -1.97 | Neutral | 0.994 | Probably Damaging | 0.892 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 3.77 | 5 | -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 | 0.2646 | 0.1605 | -2.31 | Neutral | 1.000 | Probably Damaging | 0.961 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | -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 | 0.2538 | 0.3245 | -1.51 | Neutral | 0.910 | Possibly Damaging | 0.468 | Possibly Damaging | 2.75 | Benign | 0.62 | Tolerated | 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 | 0.2538 | 0.3245 | -1.51 | Neutral | 0.910 | Possibly Damaging | 0.468 | Possibly Damaging | 2.75 | Benign | 0.62 | Tolerated | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1041 | 0.4415 | -0.79 | Neutral | 0.642 | Possibly Damaging | 0.494 | Possibly Damaging | 2.72 | Benign | 0.01 | Affected | 3.77 | 5 | -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 | 0.1041 | 0.4415 | -0.79 | Neutral | 0.642 | Possibly Damaging | 0.494 | Possibly Damaging | 2.72 | Benign | 0.01 | Affected | 3.77 | 5 | -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 | 0.1692 | 0.4521 | -1.10 | Neutral | 0.642 | Possibly Damaging | 0.252 | Benign | 2.78 | Benign | 0.01 | Affected | 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 | 0.3641 | 0.4571 | -0.04 | Neutral | 0.139 | Benign | 0.089 | Benign | 2.89 | Benign | 0.64 | Tolerated | 3.77 | 5 | 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 | 0.1352 | 0.3434 | -1.21 | Neutral | 0.473 | Possibly Damaging | 0.192 | Benign | 2.71 | Benign | 0.01 | Affected | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1399 | 0.5730 | -0.56 | Neutral | 0.369 | Benign | 0.171 | Benign | 2.84 | Benign | 0.14 | Tolerated | 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 | 0.3272 | 0.4900 | -0.55 | Neutral | 0.112 | Benign | 0.084 | Benign | 2.81 | Benign | 0.26 | Tolerated | 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 | 0.3217 | 0.5300 | -0.23 | Neutral | 0.224 | Benign | 0.131 | Benign | 2.81 | Benign | 0.22 | Tolerated | 3.77 | 5 | -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 | 0.1553 | 0.4635 | -0.38 | Neutral | 0.832 | Possibly Damaging | 0.600 | Possibly Damaging | 2.75 | Benign | 0.08 | Tolerated | 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 | 0.1339 | 0.3083 | 1.24 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.89 | Benign | 0.88 | Tolerated | 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 | 0.2155 | 0.6388 | -0.90 | Neutral | 0.224 | Benign | 0.131 | Benign | 2.76 | Benign | 0.12 | Tolerated | -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 | 0.1812 | 0.6039 | -0.96 | Neutral | 0.069 | Benign | 0.072 | Benign | 2.70 | Benign | 0.26 | Tolerated | 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 | 0.2338 | 0.5430 | -1.27 | Neutral | 0.453 | Possibly Damaging | 0.150 | Benign | 2.66 | Benign | 0.15 | Tolerated | 3.77 | 5 | -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 | 0.4728 | 0.5131 | -0.89 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.71 | Benign | 0.30 | Tolerated | 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 | 0.0954 | 0.5629 | -1.78 | Neutral | 0.290 | Benign | 0.124 | Benign | 2.66 | Benign | 0.03 | Affected | -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 | 0.1345 | 0.5817 | -2.06 | Neutral | 0.898 | Possibly Damaging | 0.579 | Possibly Damaging | 2.64 | Benign | 0.05 | Affected | 3.77 | 5 | 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 | 0.0922 | 0.5803 | -2.54 | Deleterious | 0.453 | Possibly Damaging | 0.272 | Benign | 2.65 | Benign | 0.03 | Affected | 3.77 | 5 | -2 | -3 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||
| 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 | 0.2677 | 0.5408 | -0.60 | Neutral | 0.068 | Benign | 0.039 | Benign | 2.95 | Benign | 0.50 | Tolerated | 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 | 0.1044 | 0.4714 | -1.47 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 2.80 | Benign | 0.12 | Tolerated | -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 | 0.1401 | 0.4126 | -2.49 | Neutral | 0.997 | Probably Damaging | 0.889 | Possibly Damaging | 2.68 | Benign | 0.06 | Tolerated | -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 | 0.2003 | 0.2942 | -1.39 | Neutral | 0.818 | Possibly Damaging | 0.381 | Benign | 2.74 | Benign | 0.77 | Tolerated | 3.77 | 5 | -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 | 0.3677 | 0.4682 | -1.06 | Neutral | 0.025 | Benign | 0.022 | Benign | 2.78 | Benign | 0.36 | Tolerated | 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 | 0.1359 | 0.3533 | -2.47 | Neutral | 0.818 | Possibly Damaging | 0.377 | Benign | 2.72 | Benign | 0.06 | Tolerated | 3.77 | 5 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||
| 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 | 0.2176 | 0.4504 | -0.15 | Neutral | 0.586 | Possibly Damaging | 0.223 | Benign | 2.53 | Benign | 0.18 | Tolerated | 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 | 0.3960 | 0.3949 | -0.07 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.73 | Benign | 0.54 | Tolerated | 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 | 0.3545 | 0.4232 | 0.61 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.70 | Benign | 0.86 | Tolerated | 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 | 0.1688 | 0.4233 | 0.28 | Neutral | 0.004 | Benign | 0.002 | Benign | 2.54 | Benign | 0.24 | Tolerated | 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 | 0.3545 | 0.4232 | 0.61 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.70 | Benign | 0.86 | Tolerated | 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 | 0.1232 | 0.4871 | -2.06 | Neutral | 0.586 | Possibly Damaging | 0.172 | Benign | 2.53 | Benign | 0.07 | Tolerated | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1989 | 0.7529 | -2.12 | Neutral | 0.856 | Possibly Damaging | 0.723 | Possibly Damaging | 2.50 | Benign | 0.01 | Affected | 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 | 0.2348 | 0.7744 | -2.63 | Deleterious | 0.994 | Probably Damaging | 0.924 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -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 | 0.1111 | 0.6531 | -3.86 | Deleterious | 0.998 | Probably Damaging | 0.947 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | -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 | 0.4040 | 0.6760 | -2.71 | Deleterious | 0.856 | Possibly Damaging | 0.492 | Possibly Damaging | 2.50 | Benign | 0.02 | Affected | 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 | 0.3624 | 0.7059 | -3.40 | Deleterious | 0.924 | Possibly Damaging | 0.652 | Possibly Damaging | 2.46 | Pathogenic | 0.01 | Affected | 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 | 0.1424 | 0.7116 | -3.80 | Deleterious | 0.977 | Probably Damaging | 0.856 | Possibly Damaging | 2.45 | Pathogenic | 0.00 | Affected | -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 | 0.2237 | 0.6898 | -0.37 | Neutral | 0.008 | Benign | 0.028 | Benign | 2.64 | Benign | 0.65 | Tolerated | 3.77 | 5 | 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 | 0.2237 | 0.6898 | -0.37 | Neutral | 0.008 | Benign | 0.028 | Benign | 2.64 | Benign | 0.65 | Tolerated | 3.77 | 5 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||
| 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 | 0.2050 | 0.1969 | -2.55 | Deleterious | 0.951 | Possibly Damaging | 0.710 | Possibly Damaging | 2.50 | Benign | 0.05 | Affected | 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 | 0.2198 | 0.3027 | -2.38 | Neutral | 0.798 | Possibly Damaging | 0.373 | Benign | 2.65 | Benign | 0.72 | Tolerated | 3.77 | 5 | 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 | 0.1964 | 0.2137 | -2.97 | Deleterious | 0.905 | Possibly Damaging | 0.637 | Possibly Damaging | 2.51 | Benign | 0.03 | Affected | -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 | 0.1432 | 0.1801 | -0.75 | Neutral | 0.012 | Benign | 0.044 | Benign | 2.47 | Pathogenic | 0.05 | Affected | 3.77 | 5 | 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 | 0.4491 | 0.0000 | -3.16 | Deleterious | 0.986 | Probably Damaging | 0.848 | Possibly Damaging | 2.46 | Pathogenic | 0.00 | Affected | -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 | 0.2488 | 0.1137 | -3.71 | Deleterious | 0.999 | Probably Damaging | 0.944 | Probably Damaging | 2.42 | Pathogenic | 0.00 | Affected | -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 | 0.2198 | 0.3027 | -2.38 | Neutral | 0.798 | Possibly Damaging | 0.373 | Benign | 2.65 | Benign | 0.72 | Tolerated | 3.77 | 5 | 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 | 0.2198 | 0.3027 | -2.38 | Neutral | 0.798 | Possibly Damaging | 0.373 | Benign | 2.65 | Benign | 0.72 | Tolerated | 3.77 | 5 | 0 | 2 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||
| 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 | 0.2155 | 0.3960 | -1.39 | Neutral | 0.586 | Possibly Damaging | 0.302 | Benign | 2.24 | Pathogenic | 0.02 | Affected | 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 | 0.3859 | 0.3362 | -0.55 | Neutral | 0.001 | Benign | 0.004 | Benign | 2.34 | Pathogenic | 0.53 | Tolerated | 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 | 0.3426 | 0.3404 | -0.20 | Neutral | 0.004 | Benign | 0.008 | Benign | 2.48 | Pathogenic | 0.06 | Tolerated | 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 | 0.1537 | 0.3979 | -1.74 | Neutral | 0.411 | Benign | 0.139 | Benign | 2.25 | Pathogenic | 0.01 | Affected | 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 | 0.3426 | 0.3404 | -0.20 | Neutral | 0.004 | Benign | 0.008 | Benign | 2.48 | Pathogenic | 0.06 | Tolerated | 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 | 0.1022 | 0.4776 | -2.55 | Deleterious | 0.586 | Possibly Damaging | 0.304 | Benign | 2.24 | Pathogenic | 0.01 | Affected | 3.77 | 5 | -1 | 0 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.3055C>A | R1019S 2D  AIThe SynGAP1 missense variant R1019S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and ESM1b, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, while the SGM‑Consensus (majority vote) remains Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for R1019S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.856457 | Disordered | 0.966400 | Binding | 0.315 | 0.794 | 0.500 | -3.818 | Likely Benign | 0.871 | Likely Pathogenic | Ambiguous | 0.113 | Likely Benign | 0.2441 | 0.3979 | -2.59 | Deleterious | 0.800 | Possibly Damaging | 0.410 | Benign | 2.43 | Pathogenic | 0.01 | Affected | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||
| c.3055C>G | R1019G 2D  AIThe SynGAP1 missense variant R1019G 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, ESM1b, and AlphaMissense‑Optimized, whereas tools predicting a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and the Foldetta stability analysis is unavailable. Overall, the majority of predictions support a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation (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 | 0.856457 | Disordered | 0.966400 | Binding | 0.315 | 0.794 | 0.500 | -4.325 | Likely Benign | 0.614 | Likely Pathogenic | Likely Benign | 0.115 | Likely Benign | 0.2946 | 0.3489 | -3.34 | Deleterious | 0.800 | Possibly Damaging | 0.496 | Possibly Damaging | 2.39 | Pathogenic | 0.00 | Affected | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||
| c.3055C>T | R1019C 2D  AIThe SynGAP1 missense variant R1019C is listed in ClinVar with an “Uncertain” status (ClinVar ID 1676922.0) and is present in gnomAD (ID 6‑33443607‑C‑T). Prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact; ESM1b remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote) remains pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.856457 | Disordered | 0.966400 | Binding | 0.315 | 0.794 | 0.500 | Conflicting | 2 | 6-33443607-C-T | 10 | 6.19e-6 | -7.386 | In-Between | 0.646 | Likely Pathogenic | Likely Benign | 0.168 | Likely Benign | 0.3016 | 0.3664 | -4.00 | Deleterious | 0.999 | Probably Damaging | 0.880 | Possibly Damaging | 2.36 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -4 | -3 | 7.0 | -53.05 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||
| c.3056G>A | R1019H 2D  AIThe SynGAP1 missense variant R1019H is listed in ClinVar (ID 1195115.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443608‑G‑A). 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 and HumVar), SIFT, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) also benign; Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact for R1019H, and this conclusion does not contradict the current ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.856457 | Disordered | 0.966400 | Binding | 0.315 | 0.794 | 0.500 | Conflicting | 2 | 6-33443608-G-A | 67 | 4.15e-5 | -4.610 | Likely Benign | 0.258 | Likely Benign | Likely Benign | 0.122 | Likely Benign | 0.2400 | 0.1903 | -1.95 | Neutral | 0.995 | Probably Damaging | 0.845 | Possibly Damaging | 2.39 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 2 | 0 | 1.3 | -19.05 | ||||||||||||||||||||||||||||
| c.3056G>C | R1019P 2D  AIThe SynGAP1 missense variant R1019P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on benign impact include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized, whereas those that predict pathogenicity are polyPhen‑2 (HumDiv and HumVar), SIFT, 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 pathogenic vs. 2 benign), and Foldetta results are unavailable. Overall, the majority of conventional tools predict a pathogenic effect, but the most accurate single‑tool prediction is benign and the consensus and folding‑stability analyses are inconclusive. Thus, the variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.856457 | Disordered | 0.966400 | Binding | 0.315 | 0.794 | 0.500 | -3.737 | Likely Benign | 0.697 | Likely Pathogenic | Likely Benign | 0.143 | Likely Benign | 0.1899 | 0.4521 | -2.48 | Neutral | 0.966 | Probably Damaging | 0.811 | Possibly Damaging | 2.38 | Pathogenic | 0.01 | Affected | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||
| c.3056G>T | R1019L 2D  AIThe SynGAP1 missense variant R1019L is listed in ClinVar with an “Uncertain” status (ClinVar ID 3364537.0) and is present in gnomAD (gnomAD ID 6‑33443608‑G‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote) remains pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a pathogenic impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.856457 | Disordered | 0.966400 | Binding | 0.315 | 0.794 | 0.500 | Uncertain | 1 | 6-33443608-G-T | 2 | 1.24e-6 | -5.194 | Likely Benign | 0.752 | Likely Pathogenic | Likely Benign | 0.110 | Likely Benign | 0.1850 | 0.4886 | -3.57 | Deleterious | 0.800 | Possibly Damaging | 0.573 | Possibly Damaging | 2.40 | Pathogenic | 0.01 | Affected | 3.77 | 5 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||||||
| c.3058C>G | R1020G 2D AIThe SynGAP1 missense variant R1020G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default all indicate pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.852992 | Disordered | 0.972945 | Binding | 0.340 | 0.777 | 0.500 | -4.898 | Likely Benign | 0.868 | Likely Pathogenic | Ambiguous | 0.162 | Likely Benign | 0.3394 | 0.3721 | -4.26 | Deleterious | 0.990 | Probably Damaging | 0.894 | Possibly Damaging | 2.48 | Pathogenic | 0.00 | Affected | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||
| c.3058C>T | R1020W 2D  AIThe SynGAP1 missense variant R1020W is catalogued in gnomAD (ID 6‑33443610‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: the single benign predictor REVEL, and a consensus of pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic,” and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) is not available. Taken together, the preponderance of evidence indicates that R1020W is most likely pathogenic, and this conclusion does not contradict any ClinVar classification because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.852992 | Disordered | 0.972945 | Binding | 0.340 | 0.777 | 0.500 | 6-33443610-C-T | 6 | 3.72e-6 | -9.378 | Likely Pathogenic | 0.829 | Likely Pathogenic | Ambiguous | 0.165 | Likely Benign | 0.1420 | 0.4373 | -4.14 | Deleterious | 1.000 | Probably Damaging | 0.986 | Probably Damaging | 2.44 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||
| c.3059G>A | R1020Q 2D  AIThe SynGAP1 missense variant R1020Q is catalogued in gnomAD (6‑33443611‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus also indicates “Likely Benign.” No Foldetta stability analysis is available, so it does not influence the overall assessment. Based on the collective predictions, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.972945 | Binding | 0.340 | 0.777 | 0.500 | 6-33443611-G-A | 2 | 1.24e-6 | -3.753 | Likely Benign | 0.445 | Ambiguous | Likely Benign | 0.137 | Likely Benign | 0.3050 | 0.2997 | -2.19 | Neutral | 0.995 | Probably Damaging | 0.870 | Possibly Damaging | 2.52 | Benign | 0.00 | Affected | 3.77 | 5 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||
| c.3059G>C | R1020P 2D AIThe SynGAP1 missense variant R1020P is listed in ClinVar (ID 3700393.0) with an “Uncertain” status and is not reported 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. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves as “Likely Pathogenic” (3 pathogenic vs. 1 benign votes). High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM‑Consensus as “Likely Pathogenic,” and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.852992 | Disordered | 0.972945 | Binding | 0.340 | 0.777 | 0.500 | Uncertain | 1 | -3.491 | Likely Benign | 0.902 | Likely Pathogenic | Ambiguous | 0.205 | Likely Benign | 0.2077 | 0.5109 | -3.50 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.46 | Pathogenic | 0.00 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||
| c.3059G>T | R1020L 2D AISynGAP1 missense variant R1020L is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive; Foldetta stability analysis is unavailable. Overall, the majority of evidence points toward a pathogenic effect, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.972945 | Binding | 0.340 | 0.777 | 0.500 | Uncertain | 1 | -6.031 | Likely Benign | 0.907 | Likely Pathogenic | Ambiguous | 0.216 | Likely Benign | 0.1898 | 0.5214 | -4.03 | Deleterious | 0.990 | Probably Damaging | 0.921 | Probably Damaging | 2.50 | Benign | 0.00 | Affected | 3.77 | 5 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||
| c.3061C>A | Q1021K 2D  AIThe SynGAP1 missense variant Q1021K is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a mixed signal: 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 classification. High‑accuracy assessments are limited: AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. Given the predominance of benign calls in the consensus and the lack of a ClinVar pathogenic annotation, the variant is most likely benign, with no conflict with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | -4.276 | Likely Benign | 0.786 | Likely Pathogenic | Ambiguous | 0.175 | Likely Benign | 0.1551 | 0.4139 | -1.79 | Neutral | 0.963 | Probably Damaging | 0.973 | Probably Damaging | 2.66 | Benign | 0.03 | Affected | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||
| c.3061C>G | Q1021E 2D  AIThe SynGAP1 missense variant Q1021E is evaluated by multiple in silico tools. Benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions are reported by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The AlphaMissense‑Default tool gives an uncertain result. The consensus prediction from the SGM framework, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus also indicates a likely benign effect. No Foldetta stability analysis is available for this residue. ClinVar contains no entry for this variant, and it is absent from gnomAD, so there is no external evidence to contradict the computational assessment. Based on the collective predictions, the variant is most likely benign, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | -4.852 | Likely Benign | 0.545 | Ambiguous | Likely Benign | 0.137 | Likely Benign | 0.1317 | 0.2069 | -1.21 | Neutral | 0.963 | Probably Damaging | 0.973 | Probably Damaging | 2.65 | Benign | 0.03 | Affected | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||
| c.3062A>C | Q1021P 2D  AIThe SynGAP1 missense variant Q1021P 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 also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q1021P, 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 | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | -3.522 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.235 | Likely Benign | 0.2022 | 0.4789 | -2.11 | Neutral | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.56 | Benign | 0.02 | Affected | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||
| c.3062A>G | Q1021R 2D  AIThe SynGAP1 missense variant Q1021R is catalogued in gnomAD (ID 6‑33443614‑A‑G) 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, resolves 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, is not available for this variant. Overall, the majority of evidence points to a benign effect, 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 | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | 6-33443614-A-G | 1 | 6.20e-7 | -4.467 | Likely Benign | 0.770 | Likely Pathogenic | Likely Benign | 0.174 | Likely Benign | 0.1257 | 0.2405 | -1.80 | Neutral | 0.985 | Probably Damaging | 0.982 | Probably Damaging | 2.61 | Benign | 0.03 | Affected | 3.77 | 5 | 1 | 1 | -1.0 | 28.06 | ||||||||||||||||||||||||||||||
| c.3062A>T | Q1021L 2D  AIThe SynGAP1 missense variant Q1021L is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (5 pathogenic vs. 4 benign) indicate that the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as the variant has no existing ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | -5.780 | Likely Benign | 0.678 | Likely Pathogenic | Likely Benign | 0.226 | Likely Benign | 0.0688 | 0.5039 | -3.36 | Deleterious | 0.985 | Probably Damaging | 0.982 | Probably Damaging | 2.58 | Benign | 0.01 | Affected | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||||||||
| c.3063G>C | Q1021H 2D  AIThe SynGAP1 missense variant Q1021H is not reported 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, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, as no ClinVar status is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | -4.694 | Likely Benign | 0.664 | Likely Pathogenic | Likely Benign | 0.184 | Likely Benign | 0.1211 | 0.3601 | -1.72 | Neutral | 0.996 | Probably Damaging | 0.995 | Probably Damaging | 2.61 | Benign | 0.01 | Affected | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.3063G>T | Q1021H 2D AIThe SynGAP1 missense variant Q1021H is not reported 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, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the 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 | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | -4.694 | Likely Benign | 0.664 | Likely Pathogenic | Likely Benign | 0.184 | Likely Benign | 0.1211 | 0.3601 | -1.72 | Neutral | 0.996 | Probably Damaging | 0.995 | Probably Damaging | 2.61 | Benign | 0.01 | Affected | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.3064C>A | L1022I 2D AIThe SynGAP1 missense variant L1022I 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, has no available result for this variant. Overall, the consensus of all available predictions strongly supports a benign classification, and this conclusion is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.986981 | Binding | 0.339 | 0.752 | 0.500 | -4.624 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.025 | Likely Benign | 0.1081 | 0.4395 | -0.91 | Neutral | 0.114 | Benign | 0.072 | Benign | 2.58 | Benign | 0.11 | Tolerated | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||
| c.3064C>G | L1022V 2D AIThe SynGAP1 missense variant L1022V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags the variant as pathogenic, creating a single discordant prediction. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments confirm 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, 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 | 0.986981 | Binding | 0.339 | 0.752 | 0.500 | -3.957 | Likely Benign | 0.174 | Likely Benign | Likely Benign | 0.035 | Likely Benign | 0.1702 | 0.4045 | -1.22 | Neutral | 0.664 | Possibly Damaging | 0.260 | Benign | 2.66 | Benign | 0.07 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3064C>T | L1022F 2D AIThe SynGAP1 missense variant L1022F is reported in gnomAD (variant ID 6‑33443616‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for this variant, 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 | 0.859585 | Disordered | 0.986981 | Binding | 0.339 | 0.752 | 0.500 | 6-33443616-C-T | 2 | 1.24e-6 | -5.035 | Likely Benign | 0.351 | Ambiguous | Likely Benign | 0.072 | Likely Benign | 0.0730 | 0.4231 | -1.84 | Neutral | 0.971 | Probably Damaging | 0.801 | Possibly Damaging | 2.51 | Benign | 0.07 | Tolerated | 3.77 | 5 | 0 | 2 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||
| c.3065T>A | L1022H 2D AIThe SynGAP1 missense variant L1022H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie (2 pathogenic, 2 benign) and is therefore inconclusive. Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the majority of conventional predictors lean toward pathogenicity, whereas the single high‑accuracy tool predicts benign and the consensus is unresolved. Thus, the variant is most likely pathogenic based on the current predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.859585 | Disordered | 0.986981 | Binding | 0.339 | 0.752 | 0.500 | -2.473 | Likely Benign | 0.589 | Likely Pathogenic | Likely Benign | 0.140 | Likely Benign | 0.1165 | 0.1313 | -2.21 | Neutral | 0.999 | Probably Damaging | 0.944 | Probably Damaging | 2.49 | Pathogenic | 0.00 | Affected | -2 | -3 | -7.0 | 23.98 | ||||||||||||||||||||||||||||||||||||
| c.3065T>C | L1022P 2D AIThe SynGAP1 missense variant L1022P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic, two benign), and Foldetta data are unavailable. Overall, the balance of evidence favors a pathogenic interpretation, and this assessment does not conflict with ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.859585 | Disordered | 0.986981 | Binding | 0.339 | 0.752 | 0.500 | -2.532 | Likely Benign | 0.643 | Likely Pathogenic | Likely Benign | 0.177 | Likely Benign | 0.3332 | 0.1589 | -2.22 | Neutral | 0.995 | Probably Damaging | 0.925 | Probably Damaging | 2.49 | Pathogenic | 0.01 | Affected | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||
| c.3065T>G | L1022R 2D AIThe SynGAP1 missense variant L1022R is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict the ClinVar status, which currently contains no classification for L1022R. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.986981 | Binding | 0.339 | 0.752 | 0.500 | -2.875 | Likely Benign | 0.659 | Likely Pathogenic | Likely Benign | 0.183 | Likely Benign | 0.1279 | 0.1387 | -1.96 | Neutral | 0.986 | Probably Damaging | 0.894 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||
| c.3067T>A | S1023T 2D AIThe SynGAP1 missense variant S1023T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, and Foldetta results are unavailable. Overall, the majority of high‑confidence tools predict a benign impact, and there is no conflict with ClinVar status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.831250 | Disordered | 0.990262 | Binding | 0.322 | 0.750 | 0.500 | -5.573 | Likely Benign | 0.360 | Ambiguous | Likely Benign | 0.092 | Likely Benign | 0.1299 | 0.5370 | -1.62 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.49 | Pathogenic | 0.04 | Affected | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.3067T>C | S1023P 2D AIThe SynGAP1 missense variant S1023P is reported in gnomAD (ID 6‑33443619‑T‑C) but has no ClinVar entry (ClinVar status: not reported). Functional prediction tools are split: benign calls come from REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls come from polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, SGM Consensus remains inconclusive, and Foldetta (combining FoldX‑MD and Rosetta) has no available result. Overall, the majority of standard predictors lean toward pathogenicity, whereas the few high‑accuracy tools do not support a pathogenic verdict. Thus, the variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.831250 | Disordered | 0.990262 | Binding | 0.322 | 0.750 | 0.500 | 6-33443619-T-C | 2 | 1.24e-6 | -5.634 | Likely Benign | 0.679 | Likely Pathogenic | Likely Benign | 0.146 | Likely Benign | 0.1818 | 0.4616 | -2.11 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.43 | Pathogenic | 0.02 | Affected | 3.77 | 5 | -1 | 1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||
| c.3067T>G | S1023A 2D AIThe SynGAP1 missense variant S1023A 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 tools therefore lean toward a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus indicates likely benign, and no Foldetta data is available. 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 | 0.831250 | Disordered | 0.990262 | Binding | 0.322 | 0.750 | 0.500 | -6.031 | Likely Benign | 0.356 | Ambiguous | Likely Benign | 0.098 | Likely Benign | 0.4427 | 0.4386 | -1.59 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.53 | Benign | 0.04 | Affected | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||
| c.3068C>T | S1023L 2D  AIThe SynGAP1 missense variant S1023L is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, while the SGM‑Consensus remains Likely Pathogenic; Foldetta stability analysis is unavailable. Overall, the balance of evidence from the majority of tools and the SGM‑Consensus indicates a pathogenic effect, and this conclusion does not contradict any ClinVar annotation because none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.831250 | Disordered | 0.990262 | Binding | 0.322 | 0.750 | 0.500 | -5.735 | Likely Benign | 0.705 | Likely Pathogenic | Likely Benign | 0.204 | Likely Benign | 0.1080 | 0.4923 | -3.47 | Deleterious | 0.991 | Probably Damaging | 0.991 | Probably Damaging | 2.47 | Pathogenic | 0.01 | Affected | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||||||||
| c.3070C>A | L1024I 2D AIThe SynGAP1 missense variant L1024I is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.992699 | Binding | 0.327 | 0.753 | 0.500 | -4.794 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.062 | Likely Benign | 0.0992 | 0.3735 | -0.99 | Neutral | 0.959 | Probably Damaging | 0.642 | Possibly Damaging | 2.45 | Pathogenic | 0.11 | Tolerated | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||
| c.3070C>G | L1024V 2D AIThe SynGAP1 missense variant L1024V is 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 of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for the variant. 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 | 0.862302 | Disordered | 0.992699 | Binding | 0.327 | 0.753 | 0.500 | -3.758 | Likely Benign | 0.244 | Likely Benign | Likely Benign | 0.041 | Likely Benign | 0.1459 | 0.3185 | -1.33 | Neutral | 0.907 | Possibly Damaging | 0.642 | Possibly Damaging | 2.47 | Pathogenic | 0.08 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3070C>T | L1024F 2D AIThe SynGAP1 missense variant L1024F is not 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. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it contains both benign and pathogenic calls. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence favors a benign interpretation, and this assessment does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.862302 | Disordered | 0.992699 | Binding | 0.327 | 0.753 | 0.500 | -5.133 | Likely Benign | 0.544 | Ambiguous | Likely Benign | 0.059 | Likely Benign | 0.0706 | 0.3708 | -2.08 | Neutral | 0.994 | Probably Damaging | 0.924 | Probably Damaging | 2.40 | Pathogenic | 0.07 | Tolerated | 2 | 0 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||||||
| c.3071T>A | L1024H 2D AIThe SynGAP1 missense variant L1024H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: 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 SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized returns an Uncertain result, SGM‑Consensus indicates Likely Pathogenic, and Foldetta data are unavailable. Overall, the majority of evidence points toward a deleterious effect, suggesting the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar, which contains no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.862302 | Disordered | 0.992699 | Binding | 0.327 | 0.753 | 0.500 | -3.271 | Likely Benign | 0.868 | Likely Pathogenic | Ambiguous | 0.123 | Likely Benign | 0.1198 | 0.1483 | -3.09 | Deleterious | 1.000 | Probably Damaging | 0.981 | Probably Damaging | 2.38 | Pathogenic | 0.01 | Affected | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||
| c.3071T>C | L1024P 2D AIThe SynGAP1 missense variant L1024P is not 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, 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 standard prediction tools lean toward pathogenicity, while high‑accuracy methods are inconclusive. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.862302 | Disordered | 0.992699 | Binding | 0.327 | 0.753 | 0.500 | -4.385 | Likely Benign | 0.730 | Likely Pathogenic | Likely Benign | 0.149 | Likely Benign | 0.3187 | 0.2033 | -2.42 | Neutral | 0.999 | Probably Damaging | 0.974 | Probably Damaging | 2.43 | Pathogenic | 0.03 | Affected | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||
| c.3071T>G | L1024R 2D AIThe SynGAP1 missense variant L1024R is not 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 (5 pathogenic vs. 3 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. | 0.862302 | Disordered | 0.992699 | Binding | 0.327 | 0.753 | 0.500 | -3.434 | Likely Benign | 0.841 | Likely Pathogenic | Ambiguous | 0.148 | Likely Benign | 0.1335 | 0.1557 | -2.41 | Neutral | 0.997 | Probably Damaging | 0.962 | Probably Damaging | 2.40 | Pathogenic | 0.02 | Affected | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||
| c.3073C>A | Q1025K 2D AIThe SynGAP1 missense variant Q1025K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: benign calls come from REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, whereas the only pathogenic call is from polyPhen‑2 HumDiv. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign consensus. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Thus, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which has no pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.993410 | Binding | 0.363 | 0.746 | 0.500 | -4.510 | Likely Benign | 0.529 | Ambiguous | Likely Benign | 0.041 | Likely Benign | 0.1690 | 0.4438 | -1.09 | Neutral | 0.649 | Possibly Damaging | 0.353 | Benign | 2.78 | Benign | 0.22 | Tolerated | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||
| c.3073C>G | Q1025E 2D AIThe SynGAP1 missense variant Q1025E 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 the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm 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 available predictions 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 | 0.879233 | Disordered | 0.993410 | Binding | 0.363 | 0.746 | 0.500 | -3.010 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.077 | Likely Benign | 0.1391 | 0.2269 | -0.60 | Neutral | 0.649 | Possibly Damaging | 0.353 | Benign | 2.79 | Benign | 1.00 | Tolerated | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||
| c.3074A>C | Q1025P 2D AIThe SynGAP1 missense variant Q1025P is not reported 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 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 | 0.879233 | Disordered | 0.993410 | Binding | 0.363 | 0.746 | 0.500 | -2.151 | Likely Benign | 0.211 | Likely Benign | Likely Benign | 0.153 | Likely Benign | 0.2211 | 0.5196 | -1.22 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.72 | Benign | 0.11 | Tolerated | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||
| c.3074A>G | Q1025R 2D AIThe SynGAP1 missense variant Q1025R is not reported 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, while polyPhen‑2 (both HumDiv and HumVar) predict a pathogenic outcome. AlphaMissense‑Default remains uncertain, and 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 is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.993410 | Binding | 0.363 | 0.746 | 0.500 | -4.435 | Likely Benign | 0.480 | Ambiguous | Likely Benign | 0.101 | Likely Benign | 0.1342 | 0.2656 | -1.28 | Neutral | 0.818 | Possibly Damaging | 0.453 | Possibly Damaging | 2.72 | Benign | 0.10 | Tolerated | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||
| c.3074A>T | Q1025L 2D AIThe SynGAP1 missense variant Q1025L is not reported 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 | 0.879233 | Disordered | 0.993410 | Binding | 0.363 | 0.746 | 0.500 | -6.460 | Likely Benign | 0.463 | Ambiguous | Likely Benign | 0.117 | Likely Benign | 0.0798 | 0.5497 | -2.48 | Neutral | 0.901 | Possibly Damaging | 0.534 | Possibly Damaging | 2.70 | Benign | 0.05 | Affected | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||
| c.3075G>C | Q1025H 2D AIThe SynGAP1 missense variant Q1025H is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. 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 classify the variant as benign. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence supports a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.993410 | Binding | 0.363 | 0.746 | 0.500 | -4.976 | Likely Benign | 0.405 | Ambiguous | Likely Benign | 0.051 | Likely Benign | 0.1332 | 0.3852 | -1.43 | Neutral | 0.014 | Benign | 0.012 | Benign | 2.68 | Benign | 0.05 | Affected | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.3075G>T | Q1025H 2D AIThe SynGAP1 missense variant Q1025H is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. 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 classify the variant as benign. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence supports a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.993410 | Binding | 0.363 | 0.746 | 0.500 | -4.976 | Likely Benign | 0.405 | Ambiguous | Likely Benign | 0.051 | Likely Benign | 0.1332 | 0.3852 | -1.43 | Neutral | 0.014 | Benign | 0.012 | Benign | 2.68 | Benign | 0.05 | Affected | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.3076G>A | D1026N 2D AIThe SynGAP1 D1026N variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT 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 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 | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | -4.166 | Likely Benign | 0.608 | Likely Pathogenic | Likely Benign | 0.117 | Likely Benign | 0.1240 | 0.5060 | -2.07 | Neutral | 0.411 | Benign | 0.239 | Benign | 2.55 | Benign | 0.01 | Affected | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||
| c.3076G>C | D1026H 2D AIThe SynGAP1 missense variant D1026H is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443628‑G‑C). 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. AlphaMissense‑Optimized is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑to‑2 split. 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. Thus, the variant is most likely pathogenic based on current computational evidence, 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. | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | 6-33443628-G-C | 1 | 6.20e-7 | -4.412 | Likely Benign | 0.900 | Likely Pathogenic | Ambiguous | 0.105 | Likely Benign | 0.1470 | 0.5345 | -2.03 | Neutral | 0.832 | Possibly Damaging | 0.600 | Possibly Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -1 | 1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||
| c.3076G>T | D1026Y 2D AIThe SynGAP1 missense variant D1026Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default all classify the variant as damaging. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Based on the preponderance of pathogenic predictions and the SGM‑Consensus outcome, the variant is most likely pathogenic; this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | -6.999 | Likely Benign | 0.892 | Likely Pathogenic | Ambiguous | 0.200 | Likely Benign | 0.0676 | 0.4936 | -3.08 | Deleterious | 0.938 | Possibly Damaging | 0.596 | Possibly Damaging | 2.47 | Pathogenic | 0.00 | Affected | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||
| c.3077A>C | D1026A 2D AIThe SynGAP1 D1026A variant is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM, while those that predict a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a tie, and Foldetta results are not available. Overall, the majority of standard tools favor a benign interpretation, and no ClinVar entry contradicts this assessment. Thus, the variant is most likely benign based on current predictions, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | -4.211 | Likely Benign | 0.849 | Likely Pathogenic | Ambiguous | 0.070 | Likely Benign | 0.3392 | 0.5279 | -2.69 | Deleterious | 0.112 | Benign | 0.061 | Benign | 2.53 | Benign | 0.02 | Affected | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||||||||
| c.3077A>G | D1026G 2D AIThe SynGAP1 missense variant D1026G is not 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 (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two benign, 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 evidence 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. | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | -4.125 | Likely Benign | 0.691 | Likely Pathogenic | Likely Benign | 0.098 | Likely Benign | 0.3377 | 0.5042 | -2.84 | Deleterious | 0.001 | Benign | 0.005 | Benign | 2.67 | Benign | 0.01 | Affected | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||||||||
| c.3077A>T | D1026V 2D AIThe SynGAP1 missense variant D1026V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Tools that predict a pathogenic effect are PROVEAN, SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and therefore also indicates a likely pathogenic outcome. AlphaMissense‑Optimized is uncertain, and no Foldetta stability result is available, so it does not contribute evidence. Overall, the majority of reliable predictors classify the variant as pathogenic, 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 | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | -5.871 | Likely Benign | 0.900 | Likely Pathogenic | Ambiguous | 0.144 | Likely Benign | 0.0957 | 0.5236 | -3.13 | Deleterious | 0.004 | Benign | 0.004 | Benign | 2.48 | Pathogenic | 0.00 | Affected | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||
| c.3078C>A | D1026E 2D AIThe SynGAP1 missense variant D1026E is not reported in ClinVar and is absent from gnomAD. All available in silico predictors classify the change as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence strongly supports a benign classification, and this is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | -3.431 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.055 | Likely Benign | 0.1449 | 0.4783 | -0.37 | Neutral | 0.001 | Benign | 0.005 | Benign | 2.73 | Benign | 0.56 | Tolerated | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3078C>G | D1026E 2D AIThe SynGAP1 missense variant D1026E is not reported in ClinVar and is absent from gnomAD. All available in silico predictors classify the change as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence strongly supports a benign classification, and this is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | -3.431 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.055 | Likely Benign | 0.1449 | 0.4783 | -0.37 | Neutral | 0.001 | Benign | 0.005 | Benign | 2.73 | Benign | 0.56 | Tolerated | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3079A>C | N1027H 2D  AIThe SynGAP1 missense variant N1027H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions, including the high‑accuracy tools, indicate that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -4.185 | Likely Benign | 0.193 | Likely Benign | Likely Benign | 0.074 | Likely Benign | 0.1345 | 0.7176 | -1.44 | Neutral | 0.970 | Probably Damaging | 0.799 | Possibly Damaging | 2.74 | Benign | 0.07 | Tolerated | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||
| c.3079A>G | N1027D 2D  AIThe SynGAP1 missense variant N1027D is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all score benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also classifies it as likely benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, and AlphaMissense‑Default remains uncertain. High‑accuracy tools reinforce the benign assessment: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence supports a benign classification, and this is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -2.891 | Likely Benign | 0.458 | Ambiguous | Likely Benign | 0.073 | Likely Benign | 0.1854 | 0.4004 | -1.27 | Neutral | 0.649 | Possibly Damaging | 0.353 | Benign | 2.74 | Benign | 0.27 | Tolerated | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||
| c.3079A>T | N1027Y 2D  AIThe SynGAP1 missense variant N1027Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are 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 | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -5.799 | Likely Benign | 0.626 | Likely Pathogenic | Likely Benign | 0.074 | Likely Benign | 0.0611 | 0.6133 | -2.15 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.70 | Benign | 0.03 | Affected | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||||||||
| c.3080A>C | N1027T 2D  AIThe SynGAP1 missense variant N1027T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumDiv indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus also reports Likely Benign; Foldetta results are not available. Overall, the consensus of the available predictions points to a benign effect, and this conclusion is consistent with the absence of any ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -3.604 | Likely Benign | 0.199 | Likely Benign | Likely Benign | 0.046 | Likely Benign | 0.1239 | 0.7188 | -0.71 | Neutral | 0.481 | Possibly Damaging | 0.220 | Benign | 2.75 | Benign | 0.13 | Tolerated | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||||||
| c.3080A>G | N1027S 2D  AIThe SynGAP1 missense variant N1027S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the collective predictions strongly suggest that the variant is most likely benign, and this conclusion 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 | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -2.443 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.088 | Likely Benign | 0.3540 | 0.6874 | -0.35 | Neutral | 0.068 | Benign | 0.039 | Benign | 2.77 | Benign | 0.50 | Tolerated | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||||||
| c.3080A>T | N1027I 2D  AIThe SynGAP1 missense variant N1027I is not reported 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 (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. 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 | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -5.847 | Likely Benign | 0.751 | Likely Pathogenic | Likely Benign | 0.065 | Likely Benign | 0.0677 | 0.5724 | -2.36 | Neutral | 0.970 | Probably Damaging | 0.726 | Possibly Damaging | 2.71 | Benign | 0.02 | Affected | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||||||||
| c.3081C>A | N1027K 2D  AIThe SynGAP1 missense variant N1027K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and the SGM‑Consensus result is benign; Foldetta predictions are unavailable. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -3.177 | Likely Benign | 0.841 | Likely Pathogenic | Ambiguous | 0.063 | Likely Benign | 0.1808 | 0.6079 | -0.64 | Neutral | 0.481 | Possibly Damaging | 0.220 | Benign | 2.81 | Benign | 0.65 | Tolerated | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||
| c.3081C>G | N1027K 2D AIThe SynGAP1 missense variant N1027K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and AlphaMissense‑Optimized is uncertain. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -3.177 | Likely Benign | 0.841 | Likely Pathogenic | Ambiguous | 0.063 | Likely Benign | 0.1808 | 0.6079 | -0.64 | Neutral | 0.481 | Possibly Damaging | 0.220 | Benign | 2.81 | Benign | 0.65 | Tolerated | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||
| c.3082C>A | L1028M 2D  AIThe SynGAP1 missense variant L1028M is not reported 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, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for the variant, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.995137 | Binding | 0.364 | 0.730 | 0.500 | -4.591 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.082 | Likely Benign | 0.0776 | 0.3124 | -0.07 | Neutral | 0.986 | Probably Damaging | 0.825 | Possibly Damaging | 2.70 | Benign | 0.18 | Tolerated | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||
| c.3082C>G | L1028V 2D AIThe SynGAP1 missense variant L1028V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. Foldetta results are not available, so they do not influence the assessment. Overall, the majority of computational 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 | 0.899122 | Disordered | 0.995137 | Binding | 0.364 | 0.730 | 0.500 | -3.992 | Likely Benign | 0.217 | Likely Benign | Likely Benign | 0.042 | Likely Benign | 0.1328 | 0.2715 | -0.68 | Neutral | 0.737 | Possibly Damaging | 0.376 | Benign | 2.74 | Benign | 0.26 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3083T>A | L1028Q 2D  AIThe SynGAP1 missense variant L1028Q is not reported 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 because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.995137 | Binding | 0.364 | 0.730 | 0.500 | -2.718 | Likely Benign | 0.612 | Likely Pathogenic | Likely Benign | 0.179 | Likely Benign | 0.1110 | 0.1403 | -0.19 | Neutral | 0.986 | Probably Damaging | 0.825 | Possibly Damaging | 2.80 | Benign | 0.38 | Tolerated | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||
| c.3083T>C | L1028P 2D AIThe SynGAP1 missense variant L1028P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, 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 this variant, and there is no ClinVar annotation to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.995137 | Binding | 0.364 | 0.730 | 0.500 | -3.080 | Likely Benign | 0.594 | Likely Pathogenic | Likely Benign | 0.215 | Likely Benign | 0.2846 | 0.1763 | -0.42 | Neutral | 0.004 | Benign | 0.010 | Benign | 2.70 | Benign | 0.25 | Tolerated | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||
| c.3083T>G | L1028R 2D AIThe SynGAP1 missense variant L1028R is not reported 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 (three benign votes versus one pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, 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 | 0.899122 | Disordered | 0.995137 | Binding | 0.364 | 0.730 | 0.500 | -2.204 | Likely Benign | 0.793 | Likely Pathogenic | Ambiguous | 0.167 | Likely Benign | 0.1328 | 0.1603 | -0.24 | Neutral | 0.960 | Probably Damaging | 0.761 | Possibly Damaging | 2.75 | Benign | 0.84 | Tolerated | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||
| c.3085C>A | Q1029K 2D AIThe SynGAP1 missense variant Q1029K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. AlphaMissense‑Default remains uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while Foldetta data is missing. Overall, the majority of evidence points to a benign impact for Q1029K, 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 | 0.995643 | Binding | 0.375 | 0.734 | 0.500 | -3.698 | Likely Benign | 0.516 | Ambiguous | Likely Benign | 0.075 | Likely Benign | 0.1656 | 0.4196 | -1.18 | Neutral | 0.771 | Possibly Damaging | 0.482 | Possibly Damaging | 2.79 | Benign | 1.00 | Tolerated | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||
| c.3085C>G | Q1029E 2D AIThe SynGAP1 missense variant Q1029E is reported in gnomAD (ID 6‑33443637‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags it as pathogenic, creating a single discordant call. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates 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 | 0.852992 | Disordered | 0.995643 | Binding | 0.375 | 0.734 | 0.500 | 6-33443637-C-G | 17 | 1.05e-5 | -3.660 | Likely Benign | 0.281 | Likely Benign | Likely Benign | 0.044 | Likely Benign | 0.1327 | 0.2433 | -0.92 | Neutral | 0.625 | Possibly Damaging | 0.258 | Benign | 2.83 | Benign | 0.26 | Tolerated | 3.77 | 5 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.3086A>C | Q1029P 2D AIThe SynGAP1 missense variant Q1029P 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 for this variant. Overall, the consensus of all available predictions strongly supports a benign impact, 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 | 0.852992 | Disordered | 0.995643 | Binding | 0.375 | 0.734 | 0.500 | -2.940 | Likely Benign | 0.124 | Likely Benign | Likely Benign | 0.105 | Likely Benign | 0.1966 | 0.4986 | -1.23 | Neutral | 0.005 | Benign | 0.015 | Benign | 2.68 | Benign | 0.15 | Tolerated | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||
| c.3086A>G | Q1029R 2D AIThe SynGAP1 missense variant Q1029R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (both HumDiv and HumVar) predict a pathogenic outcome. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign; 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 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 | 0.852992 | Disordered | 0.995643 | Binding | 0.375 | 0.734 | 0.500 | -3.437 | Likely Benign | 0.420 | Ambiguous | Likely Benign | 0.073 | Likely Benign | 0.1377 | 0.2420 | -0.72 | Neutral | 0.961 | Probably Damaging | 0.677 | Possibly Damaging | 2.73 | Benign | 0.88 | Tolerated | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||
| c.3086A>T | Q1029L 2D AIThe SynGAP1 missense variant Q1029L 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, and polyPhen‑2 HumVar. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome (2 benign vs. 1 pathogenic, with one uncertain). AlphaMissense‑Default remains uncertain, and Foldetta results are unavailable. High‑accuracy predictions therefore point to a benign impact: AlphaMissense‑Optimized is benign, SGM Consensus is benign, and no Foldetta data are available. Overall, the computational evidence indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.995643 | Binding | 0.375 | 0.734 | 0.500 | -3.984 | Likely Benign | 0.364 | Ambiguous | Likely Benign | 0.067 | Likely Benign | 0.0685 | 0.5866 | -2.65 | Deleterious | 0.891 | Possibly Damaging | 0.587 | Possibly Damaging | 2.70 | Benign | 0.16 | Tolerated | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||||||||
| c.3087G>C | Q1029H 2D AIThe SynGAP1 missense variant Q1029H is not reported 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 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 classification, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.995643 | Binding | 0.375 | 0.734 | 0.500 | -3.984 | Likely Benign | 0.308 | Likely Benign | Likely Benign | 0.041 | Likely Benign | 0.1268 | 0.4184 | -0.83 | Neutral | 0.989 | Probably Damaging | 0.879 | Possibly Damaging | 2.74 | Benign | 0.15 | Tolerated | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.3087G>T | Q1029H 2D AIThe SynGAP1 missense variant Q1029H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the consensus of the available predictions 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 | 0.852992 | Disordered | 0.995643 | Binding | 0.375 | 0.734 | 0.500 | -3.984 | Likely Benign | 0.308 | Likely Benign | Likely Benign | 0.041 | Likely Benign | 0.1268 | 0.4184 | -0.83 | Neutral | 0.989 | Probably Damaging | 0.879 | Possibly Damaging | 2.74 | Benign | 0.15 | Tolerated | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.3088C>A | H1030N 2D AIThe SynGAP1 missense variant H1030N is not reported in ClinVar and is absent from gnomAD. Consensus prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized returns a benign prediction, 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 that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign classification, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -3.454 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.1553 | 0.3195 | -0.88 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.78 | Benign | 0.04 | Affected | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||
| c.3088C>G | H1030D 2D AIThe SynGAP1 missense variant H1030D is reported in gnomAD (variant ID 6‑33443640‑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, and AlphaMissense‑Optimized all predict benign. Only SIFT predicts a pathogenic effect, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support 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, 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 | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | 6-33443640-C-G | 1 | 6.19e-7 | -3.500 | Likely Benign | 0.424 | Ambiguous | Likely Benign | 0.189 | Likely Benign | 0.2273 | 0.2422 | -0.85 | Neutral | 0.126 | Benign | 0.066 | Benign | 2.78 | Benign | 0.05 | Affected | 3.77 | 5 | -1 | 1 | -0.3 | -22.05 | ||||||||||||||||||||||||||||||
| c.3088C>T | H1030Y 2D AIThe SynGAP1 missense variant H1030Y is not reported 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 for H1030Y, 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 | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -5.365 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.026 | Likely Benign | 0.0874 | 0.4236 | -1.73 | Neutral | 0.812 | Possibly Damaging | 0.298 | Benign | 2.73 | Benign | 0.01 | Affected | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||
| c.3089A>C | H1030P 2D AIThe SynGAP1 missense variant H1030P 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 they do not influence the assessment. Overall, the consensus of available predictions indicates that H1030P 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 | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -2.185 | Likely Benign | 0.148 | Likely Benign | Likely Benign | 0.154 | Likely Benign | 0.1872 | 0.4225 | -0.78 | Neutral | 0.812 | Possibly Damaging | 0.298 | Benign | 2.77 | Benign | 0.02 | Affected | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||
| c.3089A>G | H1030R 2D AIThe SynGAP1 missense variant H1030R is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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 | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -2.312 | Likely Benign | 0.340 | Likely Benign | Likely Benign | 0.031 | Likely Benign | 0.1872 | 0.2955 | -1.08 | Neutral | 0.224 | Benign | 0.066 | Benign | 2.85 | Benign | 0.06 | Tolerated | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||
| c.3089A>T | H1030L 2D AIThe SynGAP1 missense variant H1030L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, 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 majority of prediction tools and the high‑accuracy methods indicates that H1030L is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -3.513 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.108 | Likely Benign | 0.0968 | 0.5710 | -2.35 | Neutral | 0.224 | Benign | 0.120 | Benign | 2.76 | Benign | 0.02 | Affected | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||
| c.3090C>A | H1030Q 2D AIThe SynGAP1 missense variant H1030Q 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 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 | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -2.548 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.1538 | 0.4001 | 0.01 | Neutral | 0.004 | Benign | 0.004 | Benign | 2.88 | Benign | 0.53 | Tolerated | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||
| c.3090C>G | H1030Q 2D AIThe SynGAP1 missense variant H1030Q 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 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 | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -2.548 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.1538 | 0.4001 | 0.01 | Neutral | 0.004 | Benign | 0.004 | Benign | 2.88 | Benign | 0.53 | Tolerated | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||
| c.3091A>C | M1031L 2D  AIThe SynGAP1 missense variant M1031L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | -2.213 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.056 | Likely Benign | 0.1220 | 0.4050 | -0.82 | Neutral | 0.044 | Benign | 0.018 | Benign | 2.84 | Benign | 0.33 | Tolerated | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||
| c.3091A>G | M1031V 2D  AIThe SynGAP1 missense variant M1031V is catalogued in gnomAD (ID 6‑33443643‑A‑G) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool listed—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently scores the variant as benign. No pathogenic predictions are reported. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the uniform benign predictions and the lack of any ClinVar pathogenic classification, the variant is most likely benign and does not contradict existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | 6-33443643-A-G | 7 | 4.34e-6 | -2.815 | Likely Benign | 0.198 | Likely Benign | Likely Benign | 0.054 | Likely Benign | 0.2305 | 0.3388 | -0.81 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.72 | Benign | 0.44 | Tolerated | 3.77 | 5 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||||||||||
| c.3091A>T | M1031L 2D AIThe SynGAP1 missense variant M1031L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | -2.213 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.056 | Likely Benign | 0.1220 | 0.4050 | -0.82 | Neutral | 0.044 | Benign | 0.018 | Benign | 2.84 | Benign | 0.33 | Tolerated | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||
| c.3092T>A | M1031K 2D  AIThe SynGAP1 missense variant M1031K is not reported 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 (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, 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 | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | -1.940 | Likely Benign | 0.709 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | 0.1224 | 0.1412 | -0.80 | Neutral | 0.325 | Benign | 0.098 | Benign | 2.66 | Benign | 0.18 | Tolerated | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||
| c.3092T>C | M1031T 2D  AIThe SynGAP1 missense variant M1031T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443644‑T‑C). In silico prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts a pathogenic outcome; the only inconclusive result is AlphaMissense‑Default, which is treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus is “Likely Benign,” and Foldetta data are not available. **Thus, 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. | Likely Benign | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | Uncertain | 1 | 6-33443644-T-C | 2 | 1.24e-6 | -1.863 | Likely Benign | 0.540 | Ambiguous | Likely Benign | 0.085 | Likely Benign | 0.1587 | 0.2264 | -0.24 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.67 | Benign | 1.00 | Tolerated | 3.77 | 5 | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||||||||||
| c.3092T>G | M1031R 2D  AIThe SynGAP1 missense variant M1031R is not reported 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 M1031R, 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 | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | -1.365 | Likely Benign | 0.673 | Likely Pathogenic | Likely Benign | 0.117 | Likely Benign | 0.1368 | 0.1212 | -0.85 | Neutral | 0.325 | Benign | 0.129 | Benign | 2.64 | Benign | 0.12 | Tolerated | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||
| c.3093G>A | M1031I 2D  AIThe SynGAP1 missense variant M1031I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Taken together, the overwhelming majority of evidence points to a benign impact for M1031I. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | -3.312 | Likely Benign | 0.739 | Likely Pathogenic | Likely Benign | 0.026 | Likely Benign | 0.1128 | 0.3324 | -0.99 | Neutral | 0.095 | Benign | 0.027 | Benign | 2.71 | Benign | 0.25 | Tolerated | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||
| c.3093G>C | M1031I 2D AIThe SynGAP1 missense variant M1031I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Taken together, the overwhelming majority of evidence points to a benign impact for M1031I. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | -3.312 | Likely Benign | 0.739 | Likely Pathogenic | Likely Benign | 0.025 | Likely Benign | 0.1128 | 0.3324 | -0.99 | Neutral | 0.095 | Benign | 0.027 | Benign | 2.71 | Benign | 0.25 | Tolerated | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||
| c.3093G>T | M1031I 2D AIThe SynGAP1 missense variant M1031I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Taken together, the overwhelming majority of evidence points to a benign impact for M1031I. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | -3.312 | Likely Benign | 0.739 | Likely Pathogenic | Likely Benign | 0.026 | Likely Benign | 0.1128 | 0.3324 | -0.99 | Neutral | 0.095 | Benign | 0.027 | Benign | 2.71 | Benign | 0.25 | Tolerated | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||
| c.3094C>A | L1032M 2D AIThe SynGAP1 missense variant L1032M 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. In contrast, polyPhen‑2 (HumDiv and HumVar) predict 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 likely benign; Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this 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 | 0.865454 | Disordered | 0.995318 | Binding | 0.365 | 0.735 | 0.500 | -4.353 | Likely Benign | 0.219 | Likely Benign | Likely Benign | 0.064 | Likely Benign | 0.0935 | 0.4719 | -0.09 | Neutral | 0.995 | Probably Damaging | 0.892 | Possibly Damaging | 2.66 | Benign | 0.10 | Tolerated | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||
| c.3094C>G | L1032V 2D AIThe SynGAP1 missense variant L1032V 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 polyPhen‑2 HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for the variant, 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 | 0.865454 | Disordered | 0.995318 | Binding | 0.365 | 0.735 | 0.500 | -4.123 | Likely Benign | 0.176 | Likely Benign | Likely Benign | 0.075 | Likely Benign | 0.1637 | 0.4353 | 0.16 | Neutral | 0.889 | Possibly Damaging | 0.514 | Possibly Damaging | 2.78 | Benign | 0.78 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3095T>A | L1032Q 2D AIThe SynGAP1 missense variant L1032Q is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the aggregate evidence, the variant is most likely benign, 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 | 0.865454 | Disordered | 0.995318 | Binding | 0.365 | 0.735 | 0.500 | -2.992 | Likely Benign | 0.467 | Ambiguous | Likely Benign | 0.134 | Likely Benign | 0.1217 | 0.1677 | -0.78 | Neutral | 0.995 | Probably Damaging | 0.892 | Possibly Damaging | 2.66 | Benign | 0.03 | Affected | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||
| c.3095T>C | L1032P 2D AIThe SynGAP1 missense variant L1032P has no ClinVar entry and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and the SGM‑Consensus score all classify the change as benign or likely benign. AlphaMissense‑Optimized also predicts a benign outcome, whereas SIFT uniquely flags the variant as pathogenic. The AlphaMissense‑Default assessment is uncertain, and no Foldetta stability data are available. High‑accuracy analyses reinforce the benign consensus: AlphaMissense‑Optimized reports a benign effect, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign. Foldetta results are missing, so they do not influence the interpretation. Overall, the majority of computational evidence supports a benign classification, which is consistent with the absence of a ClinVar pathogenic annotation. Thus, the variant is most likely benign, and this conclusion does not contradict ClinVar status, as no ClinVar pathogenic claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995318 | Binding | 0.365 | 0.735 | 0.500 | -2.560 | Likely Benign | 0.449 | Ambiguous | Likely Benign | 0.142 | Likely Benign | 0.3024 | 0.2330 | -0.71 | Neutral | 0.012 | Benign | 0.017 | Benign | 2.64 | Benign | 0.05 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||
| c.3095T>G | L1032R 2D AIThe SynGAP1 missense variant L1032R is not reported 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 (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. 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 | 0.865454 | Disordered | 0.995318 | Binding | 0.365 | 0.735 | 0.500 | -2.658 | Likely Benign | 0.707 | Likely Pathogenic | Likely Benign | 0.099 | Likely Benign | 0.1350 | 0.1919 | -1.03 | Neutral | 0.995 | Probably Damaging | 0.892 | Possibly Damaging | 2.66 | Benign | 0.02 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||
| c.3097T>A | S1033T 2D AIThe SynGAP1 missense variant S1033T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.993473 | Binding | 0.294 | 0.737 | 0.625 | -3.702 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.029 | Likely Benign | 0.1379 | 0.6089 | -0.05 | Neutral | 0.568 | Possibly Damaging | 0.171 | Benign | 2.73 | Benign | 0.58 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3097T>C | S1033P 2D AIThe SynGAP1 missense variant S1033P is not reported in ClinVar and is absent from gnomAD, indicating no documented population frequency. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are not available, so they do not influence the overall assessment. Based on the consensus of all available predictions, the variant is most likely benign, and this conclusion is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.993473 | Binding | 0.294 | 0.737 | 0.625 | -2.046 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.068 | Likely Benign | 0.1889 | 0.5486 | 0.05 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.68 | Benign | 0.27 | Tolerated | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.3097T>G | S1033A 2D AIThe SynGAP1 missense variant S1033A 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 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 | 0.993473 | Binding | 0.294 | 0.737 | 0.625 | -3.107 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.4387 | 0.5282 | 0.06 | Neutral | 0.220 | Benign | 0.085 | Benign | 2.81 | Benign | 1.00 | Tolerated | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||
| c.3098C>A | S1033Y 2D AIThe SynGAP1 missense variant S1033Y is reported in gnomAD (ID 6‑33443650‑C‑A) but has no ClinVar entry. 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 is benign and the SGM‑Consensus is 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 | 0.910643 | Disordered | 0.993473 | Binding | 0.294 | 0.737 | 0.625 | 6-33443650-C-A | 1 | 6.19e-7 | -4.857 | Likely Benign | 0.564 | Ambiguous | Likely Benign | 0.034 | Likely Benign | 0.0708 | 0.5262 | -1.01 | Neutral | 0.021 | Benign | 0.008 | Benign | 2.69 | Benign | 0.04 | Affected | 3.77 | 5 | -2 | -3 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||
| c.3098C>G | S1033C 2D AIThe SynGAP1 missense variant S1033C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for S1033C, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.993473 | Binding | 0.294 | 0.737 | 0.625 | -6.263 | Likely Benign | 0.198 | Likely Benign | Likely Benign | 0.044 | Likely Benign | 0.1031 | 0.5704 | -0.39 | Neutral | 0.992 | Probably Damaging | 0.750 | Possibly Damaging | 2.68 | Benign | 0.12 | Tolerated | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.3098C>T | S1033F 2D AIThe SynGAP1 missense variant S1033F is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus is Likely 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 (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.993473 | Binding | 0.294 | 0.737 | 0.625 | -5.013 | Likely Benign | 0.555 | Ambiguous | Likely Benign | 0.022 | Likely Benign | 0.0699 | 0.5546 | -1.02 | Neutral | 0.440 | Benign | 0.185 | Benign | 2.70 | Benign | 0.05 | Affected | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||
| c.3100C>A | P1034T 2D AIThe SynGAP1 missense variant P1034T is not reported in ClinVar and has no entry in gnomAD, indicating it is not catalogued in these databases. Prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only two tools predict a pathogenic outcome: SIFT and FATHMM. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions support 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 | 0.926919 | Disordered | 0.991713 | Binding | 0.343 | 0.752 | 0.625 | -4.367 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.026 | Likely Benign | 0.1518 | 0.6620 | -2.00 | Neutral | 0.126 | Benign | 0.096 | Benign | 2.44 | Pathogenic | 0.03 | Affected | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||
| c.3100C>G | P1034A 2D AIThe SynGAP1 missense variant P1034A is listed in ClinVar as Benign (ClinVar ID 1901716.0) 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, representing the sole discordant signal. 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 status, with no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.926919 | Disordered | 0.991713 | Binding | 0.343 | 0.752 | 0.625 | Benign | 1 | -4.174 | Likely Benign | 0.178 | Likely Benign | Likely Benign | 0.060 | Likely Benign | 0.3028 | 0.5622 | -2.44 | Neutral | 0.059 | Benign | 0.061 | Benign | 2.47 | Pathogenic | 0.06 | Tolerated | 3.77 | 5 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||
| c.3100C>T | P1034S 2D AIThe SynGAP1 missense variant P1034S 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 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 P1034S, 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 | 0.926919 | Disordered | 0.991713 | Binding | 0.343 | 0.752 | 0.625 | -3.730 | Likely Benign | 0.262 | Likely Benign | Likely Benign | 0.054 | Likely Benign | 0.3044 | 0.5853 | -2.28 | Neutral | 0.011 | Benign | 0.015 | Benign | 2.44 | Pathogenic | 0.05 | Affected | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||
| c.3101C>A | P1034H 2D AIThe SynGAP1 missense variant P1034H 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 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, and PROVEAN) predicts pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (five pathogenic vs. three benign) lean toward pathogenicity, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.926919 | Disordered | 0.991713 | Binding | 0.343 | 0.752 | 0.625 | -4.634 | Likely Benign | 0.540 | Ambiguous | Likely Benign | 0.083 | Likely Benign | 0.1776 | 0.5451 | -3.17 | Deleterious | 0.938 | Possibly Damaging | 0.750 | Possibly Damaging | 2.38 | Pathogenic | 0.02 | Affected | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||
| c.3101C>G | P1034R 2D AIThe SynGAP1 P1034R variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic; Foldetta stability analysis is unavailable. Overall, the predictions are mixed, with a slight tilt toward pathogenicity due to the SGM Consensus result and the number of pathogenic calls. The variant is most likely pathogenic based on the current computational evidence, and this assessment does not contradict ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.926919 | Disordered | 0.991713 | Binding | 0.343 | 0.752 | 0.625 | -3.666 | Likely Benign | 0.676 | Likely Pathogenic | Likely Benign | 0.073 | Likely Benign | 0.1366 | 0.4182 | -3.04 | Deleterious | 0.002 | Benign | 0.005 | Benign | 2.40 | Pathogenic | 0.02 | Affected | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.3101C>T | P1034L 2D AIThe SynGAP1 missense variant P1034L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN and SIFT, while AlphaMissense‑Default is uncertain. The high‑accuracy AlphaMissense‑Optimized model classifies the variant as 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). 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 P1034L is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.926919 | Disordered | 0.991713 | Binding | 0.343 | 0.752 | 0.625 | -4.204 | Likely Benign | 0.449 | Ambiguous | Likely Benign | 0.067 | Likely Benign | 0.2267 | 0.6937 | -3.24 | Deleterious | 0.001 | Benign | 0.005 | Benign | 2.53 | Benign | 0.01 | Affected | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||
| c.3103C>A | P1035T 2D AIThe SynGAP1 missense variant P1035T is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default remains uncertain, and no Foldetta stability assessment is available. High‑accuracy evidence from AlphaMissense‑Optimized and the SGM‑Consensus both support a benign classification, while the absence of a Foldetta result does not alter this view. Overall, the majority of predictions indicate a benign effect, 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 | 0.945666 | Disordered | 0.989572 | Binding | 0.300 | 0.756 | 0.625 | Uncertain | 1 | -4.447 | Likely Benign | 0.426 | Ambiguous | Likely Benign | 0.087 | Likely Benign | 0.1628 | 0.7220 | -0.96 | Neutral | 0.901 | Possibly Damaging | 0.537 | Possibly Damaging | 2.72 | Benign | 0.23 | Tolerated | 3.77 | 5 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||
| c.3103C>G | P1035A 2D AIThe SynGAP1 missense variant P1035A 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 | 0.945666 | Disordered | 0.989572 | Binding | 0.300 | 0.756 | 0.625 | -4.293 | Likely Benign | 0.241 | Likely Benign | Likely Benign | 0.041 | Likely Benign | 0.3188 | 0.6022 | -1.02 | Neutral | 0.481 | Possibly Damaging | 0.222 | Benign | 2.74 | Benign | 0.41 | Tolerated | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| c.3103C>T | P1035S 2D AIThe SynGAP1 missense variant P1035S 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 view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are unavailable. Taken together, the preponderance of evidence points to a benign impact for P1035S, 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 | 0.945666 | Disordered | 0.989572 | Binding | 0.300 | 0.756 | 0.625 | -3.678 | Likely Benign | 0.341 | Ambiguous | Likely Benign | 0.059 | Likely Benign | 0.3257 | 0.6253 | -0.97 | Neutral | 0.818 | Possibly Damaging | 0.355 | Benign | 2.79 | Benign | 0.28 | Tolerated | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||
| c.3104C>A | P1035H 2D AIThe SynGAP1 missense variant P1035H is not reported in ClinVar and has no entries in gnomAD. Consensus predictions from multiple in‑silico tools are mixed: benign calls come from SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign effect, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. No Foldetta stability analysis is available 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 | 0.945666 | Disordered | 0.989572 | Binding | 0.300 | 0.756 | 0.625 | -5.333 | Likely Benign | 0.608 | Likely Pathogenic | Likely Benign | 0.058 | Likely Benign | 0.1893 | 0.5669 | -0.76 | Neutral | 0.997 | Probably Damaging | 0.889 | Possibly Damaging | 2.68 | Benign | 0.15 | Tolerated | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||
| c.3104C>G | P1035R 2D AIThe SynGAP1 missense variant P1035R is not 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 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 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. | Likely Benign | 0.945666 | Disordered | 0.989572 | Binding | 0.300 | 0.756 | 0.625 | -4.534 | Likely Benign | 0.604 | Likely Pathogenic | Likely Benign | 0.119 | Likely Benign | 0.1424 | 0.4201 | 1.07 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 2.89 | Benign | 0.93 | Tolerated | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.3104C>T | P1035L 2D AIThe SynGAP1 missense variant P1035L 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, SIFT, ESM1b, 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; 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 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 | 0.945666 | Disordered | 0.989572 | Binding | 0.300 | 0.756 | 0.625 | -5.694 | Likely Benign | 0.675 | Likely Pathogenic | Likely Benign | 0.071 | Likely Benign | 0.2444 | 0.7354 | -2.11 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 2.70 | Benign | 0.21 | Tolerated | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||
| c.3106C>A | Q1036K 2D AIThe SynGAP1 missense variant Q1036K is not reported in ClinVar and has no entry in gnomAD. 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 reinforce the benign prediction: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. No Foldetta stability analysis is available for this variant. Overall, the majority of computational 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 | 0.948786 | Disordered | 0.987955 | Binding | 0.275 | 0.765 | 0.625 | -3.757 | Likely Benign | 0.646 | Likely Pathogenic | Likely Benign | 0.079 | Likely Benign | 0.2096 | 0.5220 | -1.72 | Neutral | 0.011 | Benign | 0.005 | Benign | 2.58 | Benign | 0.05 | Affected | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||
| c.3106C>G | Q1036E 2D AIThe SynGAP1 missense variant Q1036E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only SIFT predicts a pathogenic outcome. When predictions are grouped by consensus, the benign group contains nine tools, while the pathogenic group contains one (SIFT). High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable, so they do not influence the assessment. Overall, the evidence strongly suggests 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 | 0.948786 | Disordered | 0.987955 | Binding | 0.275 | 0.765 | 0.625 | -3.797 | Likely Benign | 0.313 | Likely Benign | Likely Benign | 0.056 | Likely Benign | 0.1629 | 0.3484 | -1.22 | Neutral | 0.264 | Benign | 0.062 | Benign | 2.59 | Benign | 0.03 | Affected | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||
| c.3107A>C | Q1036P 2D AIThe SynGAP1 missense variant Q1036P 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 substitution 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 unavailable. Overall, the preponderance of evidence from multiple prediction algorithms and the consensus score indicates that the variant is most likely benign, 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 | 0.948786 | Disordered | 0.987955 | Binding | 0.275 | 0.765 | 0.625 | -2.491 | Likely Benign | 0.135 | Likely Benign | Likely Benign | 0.104 | Likely Benign | 0.2018 | 0.5564 | -2.00 | Neutral | 0.802 | Possibly Damaging | 0.238 | Benign | 2.57 | Benign | 0.01 | Affected | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||
| c.3107A>G | Q1036R 2D AIThe SynGAP1 missense variant Q1036R is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from 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 (majority of the four 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 collective evidence points to a benign effect for Q1036R, 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 | 0.948786 | Disordered | 0.987955 | Binding | 0.275 | 0.765 | 0.625 | -3.816 | Likely Benign | 0.596 | Likely Pathogenic | Likely Benign | 0.083 | Likely Benign | 0.1710 | 0.3071 | -1.32 | Neutral | 0.292 | Benign | 0.071 | Benign | 2.54 | Benign | 0.04 | Affected | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||
| c.3107A>T | Q1036L 2D AIThe SynGAP1 missense variant Q1036L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors a benign outcome, with two benign votes versus one pathogenic and 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 evidence points to a benign 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. | 0.948786 | Disordered | 0.987955 | Binding | 0.275 | 0.765 | 0.625 | -4.389 | Likely Benign | 0.435 | Ambiguous | Likely Benign | 0.092 | Likely Benign | 0.1069 | 0.5996 | -2.92 | Deleterious | 0.152 | Benign | 0.045 | Benign | 2.52 | Benign | 0.01 | Affected | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||||||||
| c.3108G>C | Q1036H 2D AIThe SynGAP1 missense variant Q1036H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.948786 | Disordered | 0.987955 | Binding | 0.275 | 0.765 | 0.625 | -4.189 | Likely Benign | 0.536 | Ambiguous | Likely Benign | 0.065 | Likely Benign | 0.1641 | 0.4835 | -1.18 | Neutral | 0.977 | Probably Damaging | 0.615 | Possibly Damaging | 2.50 | Benign | 0.29 | Tolerated | 3.77 | 5 | 0 | 3 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||
| c.3108G>T | Q1036H 2D AIThe SynGAP1 missense variant Q1036H is listed in gnomAD (ID 6‑33443660‑G‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and Foldetta (FoldX‑MD/Rosetta stability assessment) has no available result. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta data are missing. Overall, the majority of reliable predictors indicate a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.948786 | Disordered | 0.987955 | Binding | 0.275 | 0.765 | 0.625 | 6-33443660-G-T | 1 | 6.20e-7 | -4.189 | Likely Benign | 0.536 | Ambiguous | Likely Benign | 0.065 | Likely Benign | 0.1641 | 0.4835 | -1.18 | Neutral | 0.977 | Probably Damaging | 0.615 | Possibly Damaging | 2.50 | Benign | 0.29 | Tolerated | 3.77 | 5 | 0 | 3 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||
| c.3109A>C | I1037L 2D AIThe SynGAP1 missense variant I1037L is not reported in ClinVar and is absent from gnomAD, indicating no known clinical or population evidence. Functional prediction tools uniformly favor a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity, and the only uncertain call comes from AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as “Likely Benign.” High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates 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 available predictions indicates that I1037L 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 | 0.939629 | Disordered | 0.986140 | Binding | 0.309 | 0.774 | 0.625 | -2.563 | Likely Benign | 0.448 | Ambiguous | Likely Benign | 0.074 | Likely Benign | 0.0939 | 0.4302 | -0.46 | Neutral | 0.421 | Benign | 0.128 | Benign | 2.82 | Benign | 0.81 | Tolerated | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||
| c.3109A>G | I1037V 2D AIThe SynGAP1 missense variant I1037V 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, 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, 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 I1037V is most likely benign, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.939629 | Disordered | 0.986140 | Binding | 0.309 | 0.774 | 0.625 | -2.326 | Likely Benign | 0.461 | Ambiguous | Likely Benign | 0.085 | Likely Benign | 0.1229 | 0.3985 | -0.09 | Neutral | 0.421 | Benign | 0.128 | Benign | 2.76 | Benign | 0.93 | Tolerated | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3109A>T | I1037F 2D AIThe SynGAP1 missense variant I1037F is not reported in ClinVar and has no entries in gnomAD. Consensus from multiple in‑silico predictors shows a split: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy tools further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the majority of evidence points to a benign effect, and this assessment is consistent with the absence of a ClinVar pathogenic claim. Thus, the variant is most likely benign, and this conclusion does not contradict ClinVar, which has no pathogenic assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.939629 | Disordered | 0.986140 | Binding | 0.309 | 0.774 | 0.625 | -3.517 | Likely Benign | 0.653 | Likely Pathogenic | Likely Benign | 0.115 | Likely Benign | 0.0653 | 0.3722 | -0.97 | Neutral | 0.977 | Probably Damaging | 0.632 | Possibly Damaging | 2.71 | Benign | 0.16 | Tolerated | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||
| c.3110T>A | I1037N 2D AIThe SynGAP1 missense variant I1037N is not reported 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) yields a Likely Benign classification, while AlphaMissense‑Optimized remains uncertain. Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.939629 | Disordered | 0.986140 | Binding | 0.309 | 0.774 | 0.625 | -3.955 | Likely Benign | 0.832 | Likely Pathogenic | Ambiguous | 0.131 | Likely Benign | 0.1022 | 0.1140 | 1.56 | Neutral | 0.666 | Possibly Damaging | 0.211 | Benign | 2.81 | Benign | 0.34 | Tolerated | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||||||||
| c.3110T>C | I1037T 2D AIThe SynGAP1 missense variant I1037T is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33443662‑T‑C). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are AlphaMissense‑Default and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the majority of predictions (seven benign vs. two pathogenic) indicate that the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.939629 | Disordered | 0.986140 | Binding | 0.309 | 0.774 | 0.625 | 6-33443662-T-C | 1 | 6.21e-7 | -2.565 | Likely Benign | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.066 | Likely Benign | 0.1071 | 0.2175 | 0.40 | Neutral | 0.292 | Benign | 0.110 | Benign | 2.79 | Benign | 0.34 | Tolerated | 3.77 | 5 | -1 | 0 | -5.2 | -12.05 | ||||||||||||||||||||||||||||||
| c.3110T>G | I1037S 2D AIThe SynGAP1 missense variant I1037S is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which classifies the variant as Likely Benign. Only AlphaMissense‑Default predicts a pathogenic outcome, while AlphaMissense‑Optimized is uncertain and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Based on the overall consensus of the majority of tools, 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 | 0.939629 | Disordered | 0.986140 | Binding | 0.309 | 0.774 | 0.625 | -2.247 | Likely Benign | 0.935 | Likely Pathogenic | Ambiguous | 0.120 | Likely Benign | 0.2634 | 0.1110 | 0.43 | Neutral | 0.032 | Benign | 0.017 | Benign | 2.83 | Benign | 0.27 | Tolerated | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||||||||
| c.3111C>G | I1037M 2D AIThe SynGAP1 missense variant I1037M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Only two tools, polyPhen‑2 HumDiv and polyPhen‑2 HumVar, 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 majority of evidence 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 | 0.939629 | Disordered | 0.986140 | Binding | 0.309 | 0.774 | 0.625 | -3.849 | Likely Benign | 0.333 | Likely Benign | Likely Benign | 0.093 | Likely Benign | 0.0775 | 0.3885 | -0.40 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 2.71 | Benign | 0.18 | Tolerated | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||
| c.3112A>C | T1038P 2D AIThe SynGAP1 missense variant T1038P is not reported 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, while polyPhen‑2 (both HumDiv and HumVar) predict a pathogenic outcome. AlphaMissense‑Default remains uncertain, and 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 is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.938133 | Disordered | 0.982911 | Binding | 0.279 | 0.794 | 0.625 | -2.196 | Likely Benign | 0.390 | Ambiguous | Likely Benign | 0.116 | Likely Benign | 0.1856 | 0.4680 | -1.10 | Neutral | 0.965 | Probably Damaging | 0.611 | Possibly Damaging | 2.66 | Benign | 0.26 | Tolerated | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||
| c.3112A>G | T1038A 2D AIThe SynGAP1 missense variant T1038A 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, whereas 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 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 | 0.938133 | Disordered | 0.982911 | Binding | 0.279 | 0.794 | 0.625 | -3.544 | Likely Benign | 0.265 | Likely Benign | Likely Benign | 0.047 | Likely Benign | 0.3429 | 0.3983 | -0.79 | Neutral | 0.649 | Possibly Damaging | 0.209 | Benign | 2.81 | Benign | 0.15 | Tolerated | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.3112A>T | T1038S 2D AIThe SynGAP1 missense variant T1038S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence supports a benign classification, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.938133 | Disordered | 0.982911 | Binding | 0.279 | 0.794 | 0.625 | -2.693 | Likely Benign | 0.198 | Likely Benign | Likely Benign | 0.101 | Likely Benign | 0.2879 | 0.4035 | -0.17 | Neutral | 0.649 | Possibly Damaging | 0.209 | Benign | 2.98 | Benign | 0.74 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3113C>A | T1038N 2D AIThe SynGAP1 missense variant T1038N is not reported in ClinVar and has no entries in gnomAD, indicating it has not been catalogued in these databases. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the substitution as benign, while the majority‑vote consensus from SGM (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, and AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates likely benign. No Foldetta stability analysis is available, so folding‑stability evidence is lacking. Overall, the preponderance of computational evidence supports a benign classification for T1038N, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Thus, the variant is most likely benign, and this is not contradicted by ClinVar, which has no pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.938133 | Disordered | 0.982911 | Binding | 0.279 | 0.794 | 0.625 | -3.837 | Likely Benign | 0.390 | Ambiguous | Likely Benign | 0.054 | Likely Benign | 0.1184 | 0.4490 | -1.36 | Neutral | 0.818 | Possibly Damaging | 0.355 | Benign | 2.68 | Benign | 0.10 | Tolerated | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||||||||
| c.3113C>G | T1038S 2D AIThe SynGAP1 missense variant T1038S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence supports a benign classification, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.938133 | Disordered | 0.982911 | Binding | 0.279 | 0.794 | 0.625 | -2.693 | Likely Benign | 0.198 | Likely Benign | Likely Benign | 0.102 | Likely Benign | 0.2879 | 0.4035 | -0.17 | Neutral | 0.649 | Possibly Damaging | 0.209 | Benign | 2.98 | Benign | 0.74 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3113C>T | T1038I 2D AIThe SynGAP1 T1038I missense variant has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which classifies the variant as Likely Benign. Tools that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is Uncertain, and the Foldetta protein‑folding stability assessment is unavailable. Overall, the balance of evidence leans toward a benign interpretation, with one high‑accuracy tool inconclusive and no conflicting ClinVar annotation. Thus, the variant is most likely benign, and there is no ClinVar status that contradicts this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.938133 | Disordered | 0.982911 | Binding | 0.279 | 0.794 | 0.625 | -4.552 | Likely Benign | 0.877 | Likely Pathogenic | Ambiguous | 0.093 | Likely Benign | 0.1012 | 0.5036 | -2.02 | Neutral | 0.990 | Probably Damaging | 0.637 | Possibly Damaging | 2.69 | Benign | 0.04 | Affected | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||
| c.3115A>C | I1039L 2D AIThe SynGAP1 missense variant I1039L 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 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 | 0.969315 | Disordered | 0.979204 | Binding | 0.292 | 0.806 | 0.625 | -2.035 | Likely Benign | 0.269 | Likely Benign | Likely Benign | 0.083 | Likely Benign | 0.1057 | 0.4605 | -0.14 | Neutral | 0.264 | Benign | 0.048 | Benign | 2.82 | Benign | 0.98 | Tolerated | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||
| c.3115A>G | I1039V 2D AIThe SynGAP1 missense variant I1039V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.969315 | Disordered | 0.979204 | Binding | 0.292 | 0.806 | 0.625 | -2.455 | Likely Benign | 0.164 | Likely Benign | Likely Benign | 0.060 | Likely Benign | 0.1405 | 0.4112 | 0.21 | Neutral | 0.264 | Benign | 0.048 | Benign | 2.76 | Benign | 0.41 | Tolerated | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3115A>T | I1039F 2D AIThe SynGAP1 missense variant I1039F is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign interpretation: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign, while the majority of other predictors (polyPhen‑2 HumDiv and HumVar) indicate pathogenic. When predictions are grouped by agreement, the benign‑oriented tools outnumber the pathogenic ones, and the single uncertain call from AlphaMissense‑Default does not alter this balance. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Benign. Foldetta data are unavailable. Overall, the computational evidence overwhelmingly supports 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 | 0.969315 | Disordered | 0.979204 | Binding | 0.292 | 0.806 | 0.625 | -2.872 | Likely Benign | 0.545 | Ambiguous | Likely Benign | 0.124 | Likely Benign | 0.0710 | 0.4368 | -1.16 | Neutral | 0.925 | Possibly Damaging | 0.510 | Possibly Damaging | 2.68 | Benign | 0.13 | Tolerated | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||
| c.3116T>A | I1039N 2D AIThe SynGAP1 missense variant I1039N has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar status (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 | 0.969315 | Disordered | 0.979204 | Binding | 0.292 | 0.806 | 0.625 | -3.469 | Likely Benign | 0.951 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | 0.1151 | 0.1311 | -1.24 | Neutral | 0.011 | Benign | 0.010 | Benign | 2.67 | Benign | 0.02 | Affected | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||||||||
| c.3116T>C | I1039T 2D AIThe SynGAP1 missense variant I1039T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443668‑T‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM; the SGM‑Consensus score (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Only AlphaMissense‑Default predicts a pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM‑Consensus remains benign; a Foldetta stability analysis is not available. Overall, the majority of computational evidence supports a benign impact, and this is consistent with the ClinVar “Uncertain” 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 | 0.979204 | Binding | 0.292 | 0.806 | 0.625 | Uncertain | 1 | 6-33443668-T-C | 12 | 7.43e-6 | -2.465 | Likely Benign | 0.645 | Likely Pathogenic | Likely Benign | 0.193 | Likely Benign | 0.1248 | 0.2293 | 0.45 | Neutral | 0.004 | Benign | 0.008 | Benign | 2.75 | Benign | 0.10 | Tolerated | 3.77 | 5 | -1 | 0 | -5.2 | -12.05 | ||||||||||||||||||||||||||||
| c.3116T>G | I1039S 2D AIThe SynGAP1 missense variant I1039S 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, and FATHMM all classify the substitution as benign. In contrast, SIFT and AlphaMissense‑Default predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. No Foldetta stability assessment is available. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.969315 | Disordered | 0.979204 | Binding | 0.292 | 0.806 | 0.625 | -1.688 | Likely Benign | 0.829 | Likely Pathogenic | Ambiguous | 0.171 | Likely Benign | 0.2917 | 0.1294 | -0.20 | Neutral | 0.032 | Benign | 0.008 | Benign | 2.76 | Benign | 0.03 | Affected | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||||||||
| c.3117T>G | I1039M 2D AIThe SynGAP1 missense variant I1039M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. 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, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for I1039M, 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 | 0.969315 | Disordered | 0.979204 | Binding | 0.292 | 0.806 | 0.625 | -3.444 | Likely Benign | 0.292 | Likely Benign | Likely Benign | 0.116 | Likely Benign | 0.0926 | 0.4392 | -0.38 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 2.68 | Benign | 0.16 | Tolerated | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||
| c.3118G>A | G1040S 2D AIThe SynGAP1 missense variant G1040S is 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 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, 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. Overall, the majority of evidence (six benign versus four pathogenic predictions) points to a benign impact for G1040S. 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 | 0.964893 | Disordered | 0.973805 | Binding | 0.332 | 0.816 | 0.625 | -2.179 | Likely Benign | 0.307 | Likely Benign | Likely Benign | 0.653 | Likely Pathogenic | 0.2332 | 0.5298 | -1.81 | Neutral | 0.827 | Possibly Damaging | 0.375 | Benign | -0.74 | Pathogenic | 0.02 | Affected | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.3118G>C | G1040R 2D AIThe SynGAP1 missense variant G1040R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Benign predictions are limited to polyPhen‑2 HumVar and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus remains pathogenic. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Taken together, the majority of evidence supports a pathogenic classification, 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 | 0.964893 | Disordered | 0.973805 | Binding | 0.332 | 0.816 | 0.625 | -2.901 | Likely Benign | 0.949 | Likely Pathogenic | Ambiguous | 0.704 | Likely Pathogenic | 0.0924 | 0.4415 | -3.00 | Deleterious | 0.463 | Possibly Damaging | 0.194 | Benign | -0.74 | Pathogenic | 0.00 | Affected | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.3118G>T | G1040C 2D AIThe SynGAP1 missense variant G1040C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all predict pathogenicity, while ESM1b and AlphaMissense‑Optimized predict a benign outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized reports a benign prediction, whereas the SGM‑Consensus remains Likely Pathogenic; the Foldetta stability analysis is unavailable. Overall, the preponderance of evidence from multiple in silico tools indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.964893 | Disordered | 0.973805 | Binding | 0.332 | 0.816 | 0.625 | -6.272 | Likely Benign | 0.620 | Likely Pathogenic | Likely Benign | 0.744 | Likely Pathogenic | 0.1155 | 0.4556 | -3.04 | Deleterious | 0.999 | Probably Damaging | 0.917 | Probably Damaging | -0.74 | Pathogenic | 0.00 | Affected | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||
| c.3119G>A | G1040D 2D AIThe SynGAP1 missense variant G1040D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only ESM1b, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic impact. The high‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it likely pathogenic, and the Foldetta stability analysis is unavailable. Overall, the preponderance of evidence indicates that G1040D 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 | 0.964893 | Disordered | 0.973805 | Binding | 0.332 | 0.816 | 0.625 | -4.154 | Likely Benign | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.761 | Likely Pathogenic | 0.1677 | 0.2042 | -2.82 | Deleterious | 0.986 | Probably Damaging | 0.787 | Possibly Damaging | -0.74 | Pathogenic | 0.00 | Affected | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||
| c.3119G>C | G1040A 2D AIThe SynGAP1 missense variant G1040A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL and FATHMM, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign prediction (2 benign vs. 1 pathogenic). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.964893 | Disordered | 0.973805 | Binding | 0.332 | 0.816 | 0.625 | -2.625 | Likely Benign | 0.409 | Ambiguous | Likely Benign | 0.606 | Likely Pathogenic | 0.3246 | 0.5331 | -1.65 | Neutral | 0.114 | Benign | 0.030 | Benign | -0.74 | Pathogenic | 0.30 | Tolerated | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.3119G>T | G1040V 2D AIThe SynGAP1 missense variant G1040V is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443671‑G‑T). Prediction tools that agree on a benign effect are ESM1b and AlphaMissense‑Optimized; those that predict a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta results are unavailable. Overall, the majority of predictions indicate a pathogenic impact, and this is not in conflict with the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.964893 | Disordered | 0.973805 | Binding | 0.332 | 0.816 | 0.625 | Uncertain | 1 | 6-33443671-G-T | 4 | 2.48e-6 | -3.453 | Likely Benign | 0.645 | Likely Pathogenic | Likely Benign | 0.774 | Likely Pathogenic | 0.1239 | 0.4213 | -2.89 | Deleterious | 0.827 | Possibly Damaging | 0.456 | Possibly Damaging | -0.74 | Pathogenic | 0.01 | Affected | 3.77 | 5 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||
| c.3121C>A | P1041T 2D AIThe SynGAP1 missense variant P1041T 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 | 0.962114 | Disordered | 0.967463 | Binding | 0.345 | 0.833 | 0.625 | -5.009 | Likely Benign | 0.187 | Likely Benign | Likely Benign | 0.361 | Likely Benign | 0.1632 | 0.6699 | -2.45 | Neutral | 0.051 | Benign | 0.025 | Benign | 5.50 | Benign | 0.10 | Tolerated | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||
| c.3121C>G | P1041A 2D AIThe SynGAP1 missense variant P1041A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv. 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 stability analysis is unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.962114 | Disordered | 0.967463 | Binding | 0.345 | 0.833 | 0.625 | -4.597 | Likely Benign | 0.157 | Likely Benign | Likely Benign | 0.331 | Likely Benign | 0.3154 | 0.5939 | -2.73 | Deleterious | 0.798 | Possibly Damaging | 0.283 | Benign | 5.53 | Benign | 0.24 | Tolerated | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| c.3121C>T | P1041S 2D AIThe SynGAP1 missense variant P1041S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443673‑C‑T). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.962114 | Disordered | 0.967463 | Binding | 0.345 | 0.833 | 0.625 | Conflicting | 2 | 6-33443673-C-T | 1 | 6.20e-7 | -4.246 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.344 | Likely Benign | 0.3199 | 0.6120 | -2.72 | Deleterious | 0.664 | Possibly Damaging | 0.283 | Benign | 5.48 | Benign | 0.11 | Tolerated | 3.77 | 5 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||
| c.3122C>A | P1041H 2D AIThe SynGAP1 missense variant P1041H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, and Foldetta’s protein‑folding stability result is unavailable. Overall, the majority of high‑confidence tools predict a benign impact, and there is no conflict with ClinVar status because the variant has not been reported there. Thus, based on current predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.962114 | Disordered | 0.967463 | Binding | 0.345 | 0.833 | 0.625 | -5.312 | Likely Benign | 0.377 | Ambiguous | Likely Benign | 0.476 | Likely Benign | 0.1883 | 0.5434 | -3.32 | Deleterious | 0.999 | Probably Damaging | 0.917 | Probably Damaging | 5.45 | Benign | 0.03 | Affected | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||
| c.3122C>G | P1041R 2D AIThe SynGAP1 missense variant P1041R is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The AlphaMissense‑Default result is uncertain, and no Foldetta stability data are available, so these are treated as unavailable. Overall, six tools support a benign classification while three support pathogenicity, and the high‑accuracy AlphaMissense‑Optimized and SGM Consensus both predict benign. Therefore, the variant is most likely benign based on the current predictions, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.962114 | Disordered | 0.967463 | Binding | 0.345 | 0.833 | 0.625 | -4.808 | Likely Benign | 0.545 | Ambiguous | Likely Benign | 0.443 | Likely Benign | 0.1401 | 0.4292 | -3.33 | Deleterious | 0.986 | Probably Damaging | 0.787 | Possibly Damaging | 5.46 | Benign | 0.07 | Tolerated | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||
| c.3122C>T | P1041L 2D AIThe SynGAP1 missense variant P1041L is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also resolves to benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact. This conclusion does not contradict ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.962114 | Disordered | 0.967463 | Binding | 0.345 | 0.833 | 0.625 | -4.901 | Likely Benign | 0.399 | Ambiguous | Likely Benign | 0.403 | Likely Benign | 0.2357 | 0.6664 | -3.14 | Deleterious | 0.905 | Possibly Damaging | 0.375 | Benign | 5.46 | Benign | 1.00 | Tolerated | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||
| 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 | 0.2338 | 0.5202 | -1.52 | Neutral | 0.224 | Benign | 0.091 | Benign | 5.44 | Benign | 0.13 | Tolerated | 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 | 0.2042 | 0.3276 | -1.12 | Neutral | 0.224 | Benign | 0.077 | Benign | 5.44 | Benign | 0.15 | Tolerated | 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 | 0.2336 | 0.5762 | -0.73 | Neutral | 0.586 | Possibly Damaging | 0.223 | Benign | 5.42 | Benign | 0.31 | Tolerated | 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 | 0.1929 | 0.3887 | -1.39 | Neutral | 0.586 | Possibly Damaging | 0.120 | Benign | 5.48 | Benign | 0.12 | Tolerated | 3.77 | 5 | 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 | 0.1469 | 0.6276 | -2.47 | Neutral | 0.369 | Benign | 0.120 | Benign | 5.47 | Benign | 0.05 | Affected | -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 | 0.2207 | 0.4671 | -1.54 | Neutral | 0.938 | Possibly Damaging | 0.596 | Possibly Damaging | 5.42 | Benign | 0.03 | Affected | 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 | 0.2207 | 0.4671 | -1.54 | Neutral | 0.938 | Possibly Damaging | 0.596 | Possibly Damaging | 5.42 | Benign | 0.03 | Affected | 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 | 0.3179 | 0.3697 | -3.17 | Deleterious | 0.130 | Benign | 0.049 | Benign | 5.94 | Benign | 0.00 | Affected | -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 | 0.1403 | 0.3696 | -3.43 | Deleterious | 0.971 | Probably Damaging | 0.729 | Possibly Damaging | 5.38 | Benign | 0.00 | Affected | 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 | 0.5141 | 0.4070 | Weaken | -1.41 | Neutral | 0.069 | Benign | 0.033 | Benign | 5.39 | Benign | 0.00 | Affected | 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 | 0.1975 | 0.5513 | -1.77 | Neutral | 0.001 | Benign | 0.003 | Benign | 5.39 | Benign | 0.00 | Affected | -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 | 0.1982 | 0.4468 | -1.98 | Neutral | 0.744 | Possibly Damaging | 0.229 | Benign | 5.38 | Benign | 0.00 | Affected | 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 | 0.2727 | 0.4628 | -2.10 | Neutral | 0.036 | Benign | 0.018 | Benign | 5.42 | Benign | 0.00 | Affected | 3.77 | 5 | -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 | 0.2727 | 0.4628 | -2.10 | Neutral | 0.036 | Benign | 0.018 | Benign | 5.42 | Benign | 0.00 | Affected | 3.77 | 5 | -1 | 0 | 3.7 | -69.11 | ||||||||||||||||||||||||||||
| 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 | 0.1681 | 0.6860 | -1.02 | Neutral | 0.126 | Benign | 0.096 | Benign | 5.53 | Benign | 0.17 | Tolerated | 3.77 | 5 | -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 | 0.3194 | 0.5850 | -1.07 | Neutral | 0.059 | Benign | 0.061 | Benign | 5.50 | Benign | 0.18 | Tolerated | 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 | 0.3194 | 0.6081 | -0.79 | Neutral | 0.011 | Benign | 0.015 | Benign | 5.51 | Benign | 0.14 | Tolerated | 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 | 0.1544 | 0.5591 | 0.51 | Neutral | 0.004 | Benign | 0.015 | Benign | 5.43 | Benign | 0.45 | Tolerated | 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 | 0.1451 | 0.4270 | 0.79 | Neutral | 0.259 | Benign | 0.140 | Benign | 5.45 | Benign | 1.00 | Tolerated | 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 | 0.2264 | 0.6586 | -1.64 | Neutral | 0.411 | Benign | 0.187 | Benign | 5.43 | Benign | 0.15 | Tolerated | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1857 | 0.6682 | 0.03 | Neutral | 0.004 | Benign | 0.010 | Benign | 2.68 | Benign | 0.52 | Tolerated | 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 | 0.2130 | 0.5332 | 1.09 | Neutral | 0.586 | Possibly Damaging | 0.223 | Benign | 2.64 | Benign | 0.24 | Tolerated | 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 | 0.2648 | 0.5493 | -0.11 | Neutral | 0.011 | Benign | 0.010 | Benign | 2.66 | Benign | 0.46 | Tolerated | 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 | 0.1954 | 0.2102 | -1.00 | Neutral | 0.411 | Benign | 0.172 | Benign | 2.64 | Benign | 0.16 | Tolerated | 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 | 0.2246 | 0.4798 | -1.21 | Neutral | 0.224 | Benign | 0.066 | Benign | 2.64 | Benign | 0.33 | Tolerated | 3.77 | 5 | 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 | 0.1487 | 0.5474 | -0.35 | Neutral | 0.011 | Benign | 0.017 | Benign | 3.06 | Benign | 1.00 | Tolerated | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1430 | 0.5934 | -1.18 | Neutral | 0.411 | Benign | 0.131 | Benign | 2.37 | Pathogenic | 0.21 | Tolerated | 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 | 0.2976 | 0.5358 | -1.67 | Neutral | 0.001 | Benign | 0.008 | Benign | 2.39 | Pathogenic | 0.29 | Tolerated | 3.77 | 5 | -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 | 0.2929 | 0.5744 | -0.72 | Neutral | 0.126 | Benign | 0.096 | Benign | 2.39 | Pathogenic | 0.70 | Tolerated | 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 | 0.1585 | 0.5250 | -1.64 | Neutral | 0.832 | Possibly Damaging | 0.670 | Possibly Damaging | 2.33 | Pathogenic | 0.07 | Tolerated | 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 | 0.1267 | 0.3841 | -1.79 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.38 | Pathogenic | 0.07 | Tolerated | 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 | 0.2036 | 0.6442 | -2.11 | Neutral | 0.001 | Benign | 0.005 | Benign | 2.35 | Pathogenic | 0.05 | Affected | 3.77 | 5 | -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 | 0.1796 | 0.6265 | 0.23 | Neutral | 0.069 | Benign | 0.049 | Benign | 2.63 | Benign | 0.63 | Tolerated | 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 | 0.2373 | 0.5656 | 0.52 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.62 | Benign | 0.03 | Affected | 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 | 0.4460 | 0.5548 | -0.50 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.65 | Benign | 0.07 | Tolerated | 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 | 0.1575 | 0.5555 | -0.63 | Neutral | 0.144 | Benign | 0.058 | Benign | 2.60 | Benign | 0.02 | Affected | 3.77 | 5 | -2 | -3 | 4.6 | 26.08 | ||||||||||||||||||||||||||||
| 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 | 0.0956 | 0.4332 | -0.54 | Neutral | 0.919 | Possibly Damaging | 0.728 | Possibly Damaging | 2.54 | Benign | 0.10 | Tolerated | 3.77 | 5 | -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 | 0.0956 | 0.4332 | -0.54 | Neutral | 0.919 | Possibly Damaging | 0.728 | Possibly Damaging | 2.54 | Benign | 0.10 | Tolerated | 3.77 | 5 | -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 | 0.0852 | 0.4046 | -1.52 | Neutral | 0.996 | Probably Damaging | 0.961 | Probably Damaging | 2.54 | Benign | 0.02 | Affected | -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 | 0.1444 | 0.4063 | -0.62 | Neutral | 0.018 | Benign | 0.030 | Benign | 2.54 | Benign | 0.10 | Tolerated | 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 | 0.3301 | 0.5138 | -0.14 | Neutral | 0.573 | Possibly Damaging | 0.358 | Benign | 2.57 | Benign | 0.64 | Tolerated | 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 | 0.1312 | 0.3688 | -0.59 | Neutral | 0.958 | Probably Damaging | 0.787 | Possibly Damaging | 2.54 | Benign | 0.11 | Tolerated | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1791 | 0.5514 | -1.18 | Neutral | 0.519 | Possibly Damaging | 0.222 | Benign | 2.74 | Benign | 0.02 | Affected | 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 | 0.3306 | 0.4897 | -1.43 | Neutral | 0.180 | Benign | 0.171 | Benign | 2.81 | Benign | 0.06 | Tolerated | 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 | 0.3144 | 0.5083 | -1.53 | Neutral | 0.519 | Possibly Damaging | 0.303 | Benign | 2.76 | Benign | 0.04 | Affected | 3.77 | 5 | -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 | 0.1800 | 0.5070 | -2.06 | Neutral | 0.978 | Probably Damaging | 0.750 | Possibly Damaging | 2.76 | Benign | 0.01 | Affected | 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 | 0.1376 | 0.3769 | -1.90 | Neutral | 0.791 | Possibly Damaging | 0.500 | Possibly Damaging | 2.74 | Benign | 0.03 | Affected | 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 | 0.2267 | 0.5838 | -2.37 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.71 | Benign | 0.02 | Affected | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0939 | 0.4532 | -0.68 | Neutral | 0.009 | Benign | 0.008 | Benign | 2.48 | Pathogenic | 0.06 | Tolerated | 3.77 | 5 | -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 | 0.0939 | 0.4532 | -0.68 | Neutral | 0.009 | Benign | 0.008 | Benign | 2.48 | Pathogenic | 0.06 | Tolerated | 3.77 | 5 | -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 | 0.1418 | 0.4258 | -0.28 | Neutral | 0.411 | Benign | 0.171 | Benign | 2.50 | Benign | 0.08 | Tolerated | 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 | 0.3349 | 0.5133 | 0.18 | Neutral | 0.000 | Benign | 0.004 | Benign | 2.68 | Benign | 1.00 | Tolerated | 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 | 0.1260 | 0.3684 | -0.83 | Neutral | 0.126 | Benign | 0.096 | Benign | 2.49 | Pathogenic | 0.13 | Tolerated | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||
| 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 | 0.2446 | 0.4911 | 0.10 | Neutral | 0.245 | Benign | 0.096 | Benign | -0.74 | Pathogenic | 0.61 | Tolerated | 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 | 0.0956 | 0.4342 | 0.20 | Neutral | 0.761 | Possibly Damaging | 0.305 | Benign | -0.74 | Pathogenic | 0.20 | Tolerated | -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 | 0.1322 | 0.4612 | -0.90 | Neutral | 0.971 | Probably Damaging | 0.750 | Possibly Damaging | -0.74 | Pathogenic | 0.10 | Tolerated | 3.77 | 5 | -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 | 0.1872 | 0.2235 | -0.31 | Neutral | 0.761 | Possibly Damaging | 0.239 | Benign | -0.74 | Pathogenic | 0.39 | Tolerated | 3.77 | 5 | -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 | 0.3353 | 0.4944 | -0.14 | Neutral | 0.009 | Benign | 0.004 | Benign | -0.74 | Pathogenic | 1.00 | Tolerated | 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 | 0.1274 | 0.3680 | -0.62 | Neutral | 0.245 | Benign | 0.096 | Benign | -0.74 | Pathogenic | 0.17 | Tolerated | 3.77 | 5 | -3 | -1 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||
| c.3154G>A | G1052R 2D AISynGAP1 missense variant G1052R is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores the variant as benign, and the SGM consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar uncertain status but provides additional support toward a likely benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | Uncertain | 1 | -9.050 | Likely Pathogenic | 0.383 | Ambiguous | Likely Benign | 0.497 | Likely Benign | 0.0976 | 0.4142 | -0.41 | Neutral | 0.990 | Probably Damaging | 0.798 | Possibly Damaging | 3.90 | Benign | 0.10 | Tolerated | 3.77 | 5 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||
| c.3154G>C | G1052R 2D AIThe SynGAP1 missense variant G1052R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and ESM1b predict a pathogenic outcome; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | -9.050 | Likely Pathogenic | 0.383 | Ambiguous | Likely Benign | 0.497 | Likely Benign | 0.0976 | 0.4142 | -0.41 | Neutral | 0.990 | Probably Damaging | 0.798 | Possibly Damaging | 3.90 | Benign | 0.10 | Tolerated | 3.77 | 5 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||
| c.3154G>T | G1052W 2D AIThe SynGAP1 missense variant G1052W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | -11.322 | Likely Pathogenic | 0.309 | Likely Benign | Likely Benign | 0.457 | Likely Benign | 0.0872 | 0.4046 | -0.90 | Neutral | 0.997 | Probably Damaging | 0.946 | Probably Damaging | 3.90 | Benign | 0.02 | Affected | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||
| c.3155G>A | G1052E 2D AIThe SynGAP1 missense variant G1052E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral impact. In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign effect. Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign classification, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | -9.869 | Likely Pathogenic | 0.287 | Likely Benign | Likely Benign | 0.448 | Likely Benign | 0.1405 | 0.3873 | -0.64 | Neutral | 0.901 | Possibly Damaging | 0.537 | Possibly Damaging | 3.90 | Benign | 0.12 | Tolerated | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||
| c.3155G>C | G1052A 2D AIThe SynGAP1 missense variant G1052A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic outcome, creating a single discordant signal. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence supports a benign classification, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | -6.945 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.382 | Likely Benign | 0.3259 | 0.4949 | -0.14 | Neutral | 0.649 | Possibly Damaging | 0.287 | Benign | 3.93 | Benign | 1.00 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3155G>T | G1052V 2D AIThe SynGAP1 missense variant G1052V is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign, while the high‑accuracy AlphaMissense‑Optimized score is benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign. In contrast, polyPhen‑2 HumDiv and HumVar both predict pathogenic, and ESM1b remains uncertain. No Foldetta stability assessment is available, so it does not influence the overall interpretation. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | -7.717 | In-Between | 0.094 | Likely Benign | Likely Benign | 0.452 | Likely Benign | 0.1329 | 0.3499 | -0.12 | Neutral | 0.901 | Possibly Damaging | 0.619 | Possibly Damaging | 3.90 | Benign | 0.19 | Tolerated | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||
| c.3157A>C | S1053R 2D AIThe SynGAP1 missense variant S1053R 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‑vote SGM‑Consensus also reports a likely benign outcome. In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy analyses reinforce the benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely benign, with no contradictory Foldetta data. Overall, the preponderance of evidence points to a benign effect for S1053R, 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 | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | -6.421 | Likely Benign | 0.359 | Ambiguous | Likely Benign | 0.225 | Likely Benign | 0.1321 | 0.3820 | 0.43 | Neutral | 0.969 | Probably Damaging | 0.581 | Possibly Damaging | 5.33 | Benign | 0.59 | Tolerated | 3.77 | 5 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||
| c.3157A>G | S1053G 2D AIThe SynGAP1 missense variant S1053G 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, has no available result for this variant. Overall, the consensus of all available predictions strongly suggests that S1053G 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 | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | -1.016 | Likely Benign | 0.050 | Likely Benign | Likely Benign | 0.220 | Likely Benign | 0.2724 | 0.5046 | -0.57 | Neutral | 0.001 | Benign | 0.002 | Benign | 5.32 | Benign | 0.59 | Tolerated | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.3157A>T | S1053C 2D AIThe SynGAP1 missense variant S1053C is catalogued in gnomAD (ID 6‑33443709‑A‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, 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 ESM1b score is uncertain, providing no clear direction. 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 reported result for this variant. Overall, the majority of reliable predictors classify S1053C as 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 | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | 6-33443709-A-T | -7.574 | In-Between | 0.095 | Likely Benign | Likely Benign | 0.220 | Likely Benign | 0.1675 | 0.5895 | -0.61 | Neutral | 0.977 | Probably Damaging | 0.777 | Possibly Damaging | 5.30 | Benign | 0.11 | Tolerated | 3.77 | 5 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||
| c.3158G>A | S1053N 2D AIThe SynGAP1 missense variant S1053N is reported in gnomAD (variant ID 6‑33443710‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, while the consensus score from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus also indicates a likely benign outcome. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, 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 | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | 6-33443710-G-A | 1 | 6.21e-7 | -6.282 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.208 | Likely Benign | 0.1953 | 0.4605 | -0.54 | Neutral | 0.625 | Possibly Damaging | 0.193 | Benign | 5.30 | Benign | 0.34 | Tolerated | 3.77 | 5 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||
| c.3158G>C | S1053T 2D AIThe SynGAP1 missense variant S1053T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the preponderance of evidence points to a benign impact for S1053T, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | -6.209 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.223 | Likely Benign | 0.2055 | 0.5976 | -0.25 | Neutral | 0.625 | Possibly Damaging | 0.249 | Benign | 5.32 | Benign | 0.70 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3158G>T | S1053I 2D AIThe SynGAP1 missense variant S1053I is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that S1053I 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 | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | -6.572 | Likely Benign | 0.177 | Likely Benign | Likely Benign | 0.250 | Likely Benign | 0.1536 | 0.4780 | -0.46 | Neutral | 0.925 | Possibly Damaging | 0.413 | Benign | 5.32 | Benign | 0.10 | Tolerated | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||
| c.3159C>A | S1053R 2D AIThe SynGAP1 missense variant S1053R is reported in gnomAD (variant ID 6‑33443711‑C‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. Overall, the majority of high‑accuracy predictors and consensus analyses indicate a benign impact. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | 6-33443711-C-A | 1 | 1.10e-6 | -6.421 | Likely Benign | 0.359 | Ambiguous | Likely Benign | 0.303 | Likely Benign | 0.1321 | 0.3820 | 0.43 | Neutral | 0.969 | Probably Damaging | 0.581 | Possibly Damaging | 5.33 | Benign | 0.59 | Tolerated | 3.77 | 5 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||
| c.3159C>G | S1053R 2D AIThe SynGAP1 missense variant S1053R is reported in gnomAD (ID 6‑33443711‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the high‑accuracy consensus methods give a benign verdict: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely 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 impact. The predictions do 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 | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | 6-33443711-C-G | -6.421 | Likely Benign | 0.359 | Ambiguous | Likely Benign | 0.304 | Likely Benign | 0.1321 | 0.3820 | 0.43 | Neutral | 0.969 | Probably Damaging | 0.581 | Possibly Damaging | 5.33 | Benign | 0.59 | Tolerated | 3.77 | 5 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||
| c.3160G>A | G1054S 2D AIThe SynGAP1 missense variant G1054S is listed in ClinVar (ID 699126.0) as Benign and is present in gnomAD (variant ID 6‑33443712‑G‑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 reports a pathogenic or likely pathogenic outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts Benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the computational evidence strongly supports a benign effect, consistent with the ClinVar designation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.878015 | Binding | 0.389 | 0.936 | 0.875 | Benign | 1 | 6-33443712-G-A | 32 | 1.99e-5 | -5.294 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.160 | Likely Benign | 0.2506 | 0.5311 | 0.21 | Neutral | 0.121 | Benign | 0.013 | Benign | 4.04 | Benign | 0.63 | Tolerated | 3.77 | 5 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||
| c.3160G>C | G1054R 2D AIThe SynGAP1 missense variant G1054R 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 G1054R, 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 | 0.983019 | Disordered | 0.878015 | Binding | 0.389 | 0.936 | 0.875 | -8.863 | Likely Pathogenic | 0.326 | Likely Benign | Likely Benign | 0.234 | Likely Benign | 0.1164 | 0.4342 | 0.29 | Neutral | 0.988 | Probably Damaging | 0.589 | Possibly Damaging | 4.05 | Benign | 0.42 | Tolerated | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.3160G>T | G1054C 2D AIThe SynGAP1 missense variant G1054C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.878015 | Binding | 0.389 | 0.936 | 0.875 | -9.548 | Likely Pathogenic | 0.118 | Likely Benign | Likely Benign | 0.297 | Likely Benign | 0.1413 | 0.4427 | -0.59 | Neutral | 0.999 | Probably Damaging | 0.907 | Possibly Damaging | 4.00 | Benign | 0.10 | Tolerated | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||
| c.3161G>A | G1054D 2D AISynGAP1 missense variant G1054D is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates the variant is most likely benign, which does not contradict the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.983019 | Disordered | 0.878015 | Binding | 0.389 | 0.936 | 0.875 | Uncertain | 1 | -10.385 | Likely Pathogenic | 0.351 | Ambiguous | Likely Benign | 0.279 | Likely Benign | 0.1824 | 0.2035 | -0.26 | Neutral | 0.818 | Possibly Damaging | 0.266 | Benign | 4.07 | Benign | 0.37 | Tolerated | 3.77 | 5 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||
| c.3161G>C | G1054A 2D AIThe SynGAP1 missense variant G1054A is catalogued in gnomAD (ID 6‑33443713‑G‑C) but has no ClinVar entry. Across a broad panel of in‑silico predictors, every tool reports a benign outcome: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity, so the pathogenic‑prediction group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant, so its status is unavailable. Based on the unanimous benign predictions and the lack of any ClinVar pathogenic classification, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.878015 | Binding | 0.389 | 0.936 | 0.875 | 6-33443713-G-C | -6.786 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.243 | Likely Benign | 0.3305 | 0.5144 | -0.05 | Neutral | 0.288 | Benign | 0.071 | Benign | 4.03 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||
| c.3161G>T | G1054V 2D AIThe SynGAP1 missense variant G1054V 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 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; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.878015 | Binding | 0.389 | 0.936 | 0.875 | -6.994 | Likely Benign | 0.110 | Likely Benign | Likely Benign | 0.171 | Likely Benign | 0.1578 | 0.3694 | -0.22 | Neutral | 0.818 | Possibly Damaging | 0.221 | Benign | 4.01 | Benign | 0.18 | Tolerated | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||
| c.3163G>A | G1055R 2D AIThe SynGAP1 missense variant G1055R is not reported 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, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion 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. | 0.982235 | Disordered | 0.872113 | Binding | 0.379 | 0.935 | 0.875 | -8.778 | Likely Pathogenic | 0.375 | Ambiguous | Likely Benign | 0.275 | Likely Benign | 0.1013 | 0.4733 | -0.09 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 3.31 | Benign | 0.08 | Tolerated | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||
| c.3163G>C | G1055R 2D AIThe SynGAP1 missense variant G1055R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. AlphaMissense‑Default is uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign outcome (2 benign vs. 1 pathogenic, 1 uncertain). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates 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. | 0.982235 | Disordered | 0.872113 | Binding | 0.379 | 0.935 | 0.875 | -8.778 | Likely Pathogenic | 0.375 | Ambiguous | Likely Benign | 0.275 | Likely Benign | 0.1013 | 0.4733 | -0.09 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 3.31 | Benign | 0.08 | Tolerated | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||
| c.3163G>T | G1055W 2D AIThe SynGAP1 missense variant G1055W is not reported 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 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 | 0.982235 | Disordered | 0.872113 | Binding | 0.379 | 0.935 | 0.875 | -11.436 | Likely Pathogenic | 0.317 | Likely Benign | Likely Benign | 0.367 | Likely Benign | 0.0899 | 0.4246 | -0.77 | Neutral | 0.997 | Probably Damaging | 0.946 | Probably Damaging | 3.28 | Benign | 0.01 | Affected | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||
| c.3164G>A | G1055E 2D AIThe SynGAP1 missense variant G1055E is catalogued in gnomAD (variant ID 6‑33443716‑G‑A) but has no ClinVar entry. In silico prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a benign effect. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.982235 | Disordered | 0.872113 | Binding | 0.379 | 0.935 | 0.875 | 6-33443716-G-A | 1 | 6.21e-7 | -10.951 | Likely Pathogenic | 0.290 | Likely Benign | Likely Benign | 0.320 | Likely Benign | 0.1525 | 0.4459 | -0.03 | Neutral | 0.901 | Possibly Damaging | 0.456 | Possibly Damaging | 3.30 | Benign | 0.10 | Tolerated | 3.77 | 5 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||
| c.3164G>C | G1055A 2D AIThe SynGAP1 missense variant G1055A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumDiv indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus also reports Likely Benign; Foldetta results are unavailable. Overall, the consensus of the available predictions points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.982235 | Disordered | 0.872113 | Binding | 0.379 | 0.935 | 0.875 | -6.835 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.244 | Likely Benign | 0.3350 | 0.5144 | 0.15 | Neutral | 0.649 | Possibly Damaging | 0.148 | Benign | 3.30 | Benign | 1.00 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3164G>T | G1055V 2D AIThe SynGAP1 missense variant G1055V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while ESM1b remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.982235 | Disordered | 0.872113 | Binding | 0.379 | 0.935 | 0.875 | -7.434 | In-Between | 0.114 | Likely Benign | Likely Benign | 0.399 | Likely Benign | 0.1399 | 0.3694 | 0.26 | Neutral | 0.818 | Possibly Damaging | 0.222 | Benign | 3.28 | Benign | 0.17 | Tolerated | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||
| c.3166G>A | G1056S 2D AIThe SynGAP1 missense variant G1056S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, 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. Overall, the majority of evidence points to a benign impact, 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 | 0.988291 | Disordered | 0.868632 | Binding | 0.402 | 0.935 | 0.875 | -5.252 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.339 | Likely Benign | 0.2497 | 0.5702 | -0.28 | Neutral | 0.451 | Benign | 0.149 | Benign | 1.87 | Pathogenic | 0.55 | Tolerated | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.3166G>C | G1056R 2D AIThe SynGAP1 missense variant G1056R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM, while AlphaMissense‑Default remains uncertain. High‑accuracy assessment shows AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) favors a pathogenic outcome, and Foldetta data are unavailable. Overall, the majority of conventional predictors indicate a benign impact, whereas the SGM Consensus suggests pathogenicity. Given the preponderance of benign predictions and the lack of ClinVar evidence, the variant is most likely benign, and this assessment does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988291 | Disordered | 0.868632 | Binding | 0.402 | 0.935 | 0.875 | -9.358 | Likely Pathogenic | 0.390 | Ambiguous | Likely Benign | 0.410 | Likely Benign | 0.1127 | 0.4533 | 0.12 | Neutral | 0.011 | Benign | 0.010 | Benign | 1.83 | Pathogenic | 0.13 | Tolerated | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||
| c.3166G>T | G1056C 2D AIThe SynGAP1 missense variant G1056C is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign impact. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988291 | Disordered | 0.868632 | Binding | 0.402 | 0.935 | 0.875 | -9.974 | Likely Pathogenic | 0.122 | Likely Benign | Likely Benign | 0.432 | Likely Benign | 0.1414 | 0.4439 | -0.70 | Neutral | 0.994 | Probably Damaging | 0.777 | Possibly Damaging | 1.83 | Pathogenic | 0.06 | Tolerated | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||
| c.3167G>A | G1056D 2D AIThe SynGAP1 missense variant G1056D is not reported 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs. 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence (six benign vs. three pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988291 | Disordered | 0.868632 | Binding | 0.402 | 0.935 | 0.875 | -10.352 | Likely Pathogenic | 0.328 | Likely Benign | Likely Benign | 0.380 | Likely Benign | 0.1912 | 0.2626 | 0.09 | Neutral | 0.666 | Possibly Damaging | 0.193 | Benign | 1.83 | Pathogenic | 0.92 | Tolerated | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||
| c.3167G>C | G1056A 2D AIThe SynGAP1 missense variant G1056A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign consensus (2 benign vs. 1 pathogenic, with one uncertain). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988291 | Disordered | 0.868632 | Binding | 0.402 | 0.935 | 0.875 | -7.458 | In-Between | 0.086 | Likely Benign | Likely Benign | 0.325 | Likely Benign | 0.3325 | 0.4957 | -0.25 | Neutral | 0.264 | Benign | 0.097 | Benign | 1.85 | Pathogenic | 0.49 | Tolerated | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.3167G>T | G1056V 2D AIThe SynGAP1 missense variant G1056V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence (7 benign vs 2 pathogenic) supports a benign classification. This consensus does not contradict ClinVar status, which has no entry for this variant. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988291 | Disordered | 0.868632 | Binding | 0.402 | 0.935 | 0.875 | -8.130 | Likely Pathogenic | 0.097 | Likely Benign | Likely Benign | 0.448 | Likely Benign | 0.1488 | 0.3507 | -0.24 | Neutral | 0.292 | Benign | 0.110 | Benign | 1.83 | Pathogenic | 0.08 | Tolerated | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||
| c.3169A>C | S1057R 2D AIThe SynGAP1 missense variant S1057R is catalogued in gnomAD (ID 6‑33443721‑A‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence 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 | 0.988291 | Disordered | 0.869507 | Binding | 0.413 | 0.927 | 0.875 | 6-33443721-A-C | -6.648 | Likely Benign | 0.379 | Ambiguous | Likely Benign | 0.221 | Likely Benign | 0.1584 | 0.3620 | -0.24 | Neutral | 0.677 | Possibly Damaging | 0.168 | Benign | 5.30 | Benign | 0.21 | Tolerated | 3.77 | 5 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||
| c.3169A>G | S1057G 2D AIThe SynGAP1 missense variant S1057G is reported in gnomAD (ID 6‑33443721‑A‑G) but has no ClinVar entry. All evaluated in‑silico predictors uniformly classify the change 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 current predictions, and this assessment does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988291 | Disordered | 0.869507 | Binding | 0.413 | 0.927 | 0.875 | 6-33443721-A-G | 1 | 7.20e-7 | -1.005 | Likely Benign | 0.049 | Likely Benign | Likely Benign | 0.211 | Likely Benign | 0.2654 | 0.4846 | -0.47 | Neutral | 0.421 | Benign | 0.111 | Benign | 5.76 | Benign | 0.52 | Tolerated | 3.77 | 5 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||
| c.3169A>T | S1057C 2D AIThe SynGAP1 missense variant S1057C is reported in gnomAD (ID 6‑33443721‑A‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Two tools, polyPhen‑2 HumDiv and polyPhen‑2 HumVar, predict a pathogenic impact, while ESM1b is 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 effect, 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 | 0.988291 | Disordered | 0.869507 | Binding | 0.413 | 0.927 | 0.875 | 6-33443721-A-T | -7.529 | In-Between | 0.100 | Likely Benign | Likely Benign | 0.258 | Likely Benign | 0.1856 | 0.6106 | -0.64 | Neutral | 0.977 | Probably Damaging | 0.683 | Possibly Damaging | 5.23 | Benign | 0.10 | Tolerated | 3.77 | 5 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||
| c.3170G>A | S1057N 2D AIThe SynGAP1 missense variant S1057N is listed in ClinVar with an “Uncertain” status 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 all return benign scores, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” 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 outputs) has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, and this is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988291 | Disordered | 0.869507 | Binding | 0.413 | 0.927 | 0.875 | Uncertain | 1 | -6.386 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.218 | Likely Benign | 0.2232 | 0.4605 | -0.41 | Neutral | 0.451 | Benign | 0.129 | Benign | 5.25 | Benign | 0.28 | Tolerated | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||
| c.3170G>C | S1057T 2D AIThe SynGAP1 missense variant S1057T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods indicates that the variant is most likely benign, and this assessment is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988291 | Disordered | 0.869507 | Binding | 0.413 | 0.927 | 0.875 | -6.375 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.241 | Likely Benign | 0.2289 | 0.5976 | -0.18 | Neutral | 0.625 | Possibly Damaging | 0.170 | Benign | 5.26 | Benign | 0.60 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3170G>T | S1057I 2D AIThe SynGAP1 missense variant S1057I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to the variant being most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988291 | Disordered | 0.869507 | Binding | 0.413 | 0.927 | 0.875 | -6.887 | Likely Benign | 0.186 | Likely Benign | Likely Benign | 0.259 | Likely Benign | 0.1802 | 0.4980 | -0.87 | Neutral | 0.925 | Possibly Damaging | 0.238 | Benign | 5.24 | Benign | 0.07 | Tolerated | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||
| c.3171C>A | S1057R 2D AIThe SynGAP1 missense variant S1057R 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. Overall, the preponderance 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 | 0.988291 | Disordered | 0.869507 | Binding | 0.413 | 0.927 | 0.875 | -6.648 | Likely Benign | 0.379 | Ambiguous | Likely Benign | 0.272 | Likely Benign | 0.1584 | 0.3620 | -0.24 | Neutral | 0.677 | Possibly Damaging | 0.168 | Benign | 5.30 | Benign | 0.21 | Tolerated | 3.77 | 5 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||
| c.3171C>G | S1057R 2D AIThe SynGAP1 missense variant S1057R is catalogued in gnomAD (ID 6‑33443723‑C‑G) but has no ClinVar submission. Functional prediction tools largely converge on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all report benign or tolerated. 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, classifies the variant as Likely Benign. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus confirms a benign likelihood; Foldetta data are unavailable, so no stability evidence is provided. Taken together, the preponderance of evidence indicates the variant is most likely benign, 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 | 0.988291 | Disordered | 0.869507 | Binding | 0.413 | 0.927 | 0.875 | 6-33443723-C-G | -6.648 | Likely Benign | 0.379 | Ambiguous | Likely Benign | 0.272 | Likely Benign | 0.1584 | 0.3620 | -0.24 | Neutral | 0.677 | Possibly Damaging | 0.168 | Benign | 5.30 | Benign | 0.21 | Tolerated | 3.77 | 5 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||
| c.3172G>A | G1058S 2D AIThe SynGAP1 missense variant G1058S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6-33443724-G-A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also benign. Foldetta results are unavailable. Overall, the majority of computational evidence indicates that the variant is most likely benign, 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 | 0.980739 | Disordered | 0.885724 | Binding | 0.407 | 0.929 | 0.875 | Conflicting | 3 | 6-33443724-G-A | 114 | 7.08e-5 | -5.178 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.108 | Likely Benign | 0.2488 | 0.5511 | 0.26 | Neutral | 0.001 | Benign | 0.001 | Benign | 5.38 | Benign | 0.04 | Affected | 3.77 | 5 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||
| c.3172G>C | G1058R 2D AIThe SynGAP1 missense variant G1058R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only two predictors—SIFT and ESM1b—suggest a pathogenic impact. 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 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 | 0.980739 | Disordered | 0.885724 | Binding | 0.407 | 0.929 | 0.875 | -8.967 | Likely Pathogenic | 0.339 | Likely Benign | Likely Benign | 0.138 | Likely Benign | 0.1145 | 0.4342 | 0.34 | Neutral | 0.174 | Benign | 0.140 | Benign | 5.29 | Benign | 0.00 | Affected | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.3172G>T | G1058C 2D AIThe SynGAP1 missense variant G1058C is reported in gnomAD (ID 6‑33443724‑G‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, SIFT, and ESM1b. 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 result is available, so it does not influence the assessment. Overall, the majority of computational evidence points to a benign effect, and this is not contradicted by any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.980739 | Disordered | 0.885724 | Binding | 0.407 | 0.929 | 0.875 | 6-33443724-G-T | 1 | 6.21e-7 | -9.384 | Likely Pathogenic | 0.132 | Likely Benign | Likely Benign | 0.264 | Likely Benign | 0.1456 | 0.4627 | -0.19 | Neutral | 0.600 | Possibly Damaging | 0.433 | Benign | 5.19 | Benign | 0.01 | Affected | 3.77 | 5 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||
| c.3173G>A | G1058D 2D AIThe SynGAP1 missense variant G1058D is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443725‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and ESM1b, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.980739 | Disordered | 0.885724 | Binding | 0.407 | 0.929 | 0.875 | 6-33443725-G-A | 1 | 6.21e-7 | -10.344 | Likely Pathogenic | 0.391 | Ambiguous | Likely Benign | 0.177 | Likely Benign | 0.1889 | 0.2435 | -0.33 | Neutral | 0.077 | Benign | 0.042 | Benign | 5.20 | Benign | 0.01 | Affected | 3.77 | 5 | -1 | 1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||
| c.3173G>C | G1058A 2D AIThe SynGAP1 missense variant G1058A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.980739 | Disordered | 0.885724 | Binding | 0.407 | 0.929 | 0.875 | -6.823 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.159 | Likely Benign | 0.3288 | 0.5144 | 0.21 | Neutral | 0.000 | Benign | 0.002 | Benign | 5.29 | Benign | 0.55 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3173G>T | G1058V 2D AIThe SynGAP1 missense variant G1058V is reported in gnomAD (variant ID 6‑33443725‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while 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. 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 | 0.980739 | Disordered | 0.885724 | Binding | 0.407 | 0.929 | 0.875 | 6-33443725-G-T | 1 | 6.21e-7 | -6.877 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.152 | Likely Benign | 0.1561 | 0.3694 | -0.12 | Neutral | 0.000 | Benign | 0.001 | Benign | 5.22 | Benign | 0.01 | Affected | 3.77 | 5 | -3 | -1 | 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). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and ESM1b, while AlphaMissense‑Default remains uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to a benign prediction (2 benign vs. 1 pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus also benign; Foldetta’s protein‑folding stability analysis is unavailable for this variant. Overall, the collective evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | Uncertain | 1 | 6-33443727-G-A | 68 | 4.23e-5 | -8.452 | Likely Pathogenic | 0.376 | Ambiguous | Likely Benign | 0.333 | Likely Benign | 0.1052 | 0.4342 | -0.55 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.53 | Benign | 0.00 | Affected | 4.32 | 2 | -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 | 0.1052 | 0.4342 | -0.55 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.53 | Benign | 0.00 | Affected | 4.32 | 2 | -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 | 0.0925 | 0.4046 | -1.18 | Neutral | 0.983 | Probably Damaging | 0.813 | Possibly Damaging | 2.53 | Benign | 0.00 | Affected | -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 | 0.1464 | 0.4069 | -0.71 | Neutral | 0.126 | Benign | 0.066 | Benign | 2.53 | Benign | 0.00 | Affected | 4.32 | 2 | -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 | 0.3295 | 0.4944 | -0.17 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.56 | Benign | 0.00 | Affected | 4.32 | 2 | 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 | 0.1462 | 0.3494 | -0.82 | Neutral | 0.259 | Benign | 0.066 | Benign | 2.54 | Benign | 0.00 | Affected | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||
| 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 | 0.2468 | 0.5311 | -0.08 | Neutral | 0.271 | Benign | 0.054 | Benign | 2.69 | Benign | 0.49 | Tolerated | 4.32 | 2 | 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 | 0.1038 | 0.4342 | -0.29 | Neutral | 0.971 | Probably Damaging | 0.580 | Possibly Damaging | 2.63 | Benign | 0.17 | Tolerated | -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 | 0.1340 | 0.4227 | -0.60 | Neutral | 0.999 | Probably Damaging | 0.917 | Probably Damaging | 2.63 | Benign | 0.12 | Tolerated | -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 | 0.1703 | 0.2035 | -0.58 | Neutral | 0.905 | Possibly Damaging | 0.538 | Possibly Damaging | 2.63 | Benign | 0.20 | Tolerated | 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 | 0.3335 | 0.4944 | 0.30 | Neutral | 0.664 | Possibly Damaging | 0.283 | Benign | 2.69 | Benign | 0.98 | Tolerated | 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 | 0.1453 | 0.3494 | -0.73 | Neutral | 0.986 | Probably Damaging | 0.728 | Possibly Damaging | 2.63 | Benign | 0.33 | Tolerated | 4.32 | 2 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||
| 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 | 0.2404 | 0.5300 | -0.68 | Neutral | 0.004 | Benign | 0.004 | Benign | 4.00 | Benign | 0.00 | Affected | 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 | 0.1037 | 0.4332 | -0.17 | Neutral | 0.411 | Benign | 0.132 | Benign | 3.99 | Benign | 0.00 | Affected | -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 | 0.1283 | 0.4227 | -1.46 | Neutral | 0.938 | Possibly Damaging | 0.665 | Possibly Damaging | 3.97 | Benign | 0.00 | Affected | 4.32 | 2 | -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 | 0.1671 | 0.2024 | -1.32 | Neutral | 0.224 | Benign | 0.120 | Benign | 4.01 | Benign | 0.00 | Affected | 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 | 0.3289 | 0.5133 | -0.34 | Neutral | 0.004 | Benign | 0.002 | Benign | 4.01 | Benign | 0.00 | Affected | 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 | 0.1431 | 0.3684 | -1.41 | Neutral | 0.224 | Benign | 0.066 | Benign | 3.98 | Benign | 0.00 | Affected | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1013 | 0.4342 | -0.34 | Neutral | 0.797 | Possibly Damaging | 0.139 | Benign | 4.10 | Benign | 0.01 | Affected | 4.32 | 2 | -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 | 0.1013 | 0.4342 | -0.34 | Neutral | 0.797 | Possibly Damaging | 0.139 | Benign | 4.10 | Benign | 0.01 | Affected | 4.32 | 2 | -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 | 0.0908 | 0.4246 | -1.38 | Neutral | 0.993 | Probably Damaging | 0.890 | Possibly Damaging | 4.09 | Benign | 0.00 | Affected | -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 | 0.1490 | 0.4069 | -1.02 | Neutral | 0.126 | Benign | 0.041 | Benign | 4.10 | Benign | 0.01 | Affected | 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 | 0.3305 | 0.5144 | 0.20 | Neutral | 0.059 | Benign | 0.028 | Benign | 4.20 | Benign | 0.51 | Tolerated | 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 | 0.1441 | 0.3694 | -0.78 | Neutral | 0.259 | Benign | 0.066 | Benign | 4.12 | Benign | 0.01 | Affected | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||
| 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 | 0.2491 | 0.5702 | 0.20 | Neutral | 0.004 | Benign | 0.003 | Benign | 4.33 | Benign | 0.09 | Tolerated | 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 | 0.1037 | 0.5133 | 0.55 | Neutral | 0.411 | Benign | 0.114 | Benign | 4.28 | Benign | 0.09 | Tolerated | -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 | 0.1440 | 0.4639 | -1.07 | Neutral | 0.938 | Possibly Damaging | 0.477 | Possibly Damaging | 4.19 | Benign | 0.01 | Affected | -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 | 0.1878 | 0.3026 | -0.30 | Neutral | 0.411 | Benign | 0.058 | Benign | 4.24 | Benign | 0.08 | Tolerated | 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 | 0.3348 | 0.4957 | 0.33 | Neutral | 0.000 | Benign | 0.002 | Benign | 4.30 | Benign | 0.12 | Tolerated | 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 | 0.1434 | 0.3707 | -0.82 | Neutral | 0.004 | Benign | 0.002 | Benign | 4.29 | Benign | 0.03 | Affected | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||
| 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 | 0.2758 | 0.4192 | -0.32 | Neutral | 0.224 | Benign | 0.120 | Benign | 4.23 | Benign | 0.24 | Tolerated | 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 | 0.2259 | 0.2843 | -0.48 | Neutral | 0.203 | Benign | 0.077 | Benign | 4.22 | Benign | 0.32 | Tolerated | 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 | 0.2819 | 0.4766 | 0.93 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.23 | Benign | 0.20 | Tolerated | 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 | 0.2257 | 0.3654 | -0.28 | Neutral | 0.586 | Possibly Damaging | 0.159 | Benign | 4.19 | Benign | 0.16 | Tolerated | 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 | 0.1817 | 0.5485 | -1.16 | Neutral | 0.224 | Benign | 0.091 | Benign | 4.20 | Benign | 0.13 | Tolerated | -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 | 0.2467 | 0.4243 | -0.66 | Neutral | 0.938 | Possibly Damaging | 0.596 | Possibly Damaging | 4.15 | Benign | 0.05 | Affected | 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 | 0.2467 | 0.4243 | -0.66 | Neutral | 0.938 | Possibly Damaging | 0.596 | Possibly Damaging | 4.15 | Benign | 0.05 | Affected | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1577 | 0.6788 | -1.23 | Neutral | 0.770 | Possibly Damaging | 0.481 | Possibly Damaging | 2.04 | Pathogenic | 0.00 | Affected | 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 | 0.3140 | 0.5790 | -1.85 | Neutral | 0.580 | Possibly Damaging | 0.184 | Benign | 2.19 | Pathogenic | 0.00 | Affected | 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 | 0.3172 | 0.6021 | -2.07 | Neutral | 0.770 | Possibly Damaging | 0.255 | Benign | 2.06 | Pathogenic | 0.00 | Affected | 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 | 0.1487 | 0.5478 | -2.44 | Neutral | 0.102 | Benign | 0.057 | Benign | 2.00 | Pathogenic | 0.00 | Affected | 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 | 0.1439 | 0.4369 | -2.46 | Neutral | 0.102 | Benign | 0.052 | Benign | 2.00 | Pathogenic | 0.00 | Affected | 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 | 0.2286 | 0.6922 | -2.94 | Deleterious | 0.950 | Possibly Damaging | 0.419 | Benign | 2.01 | Pathogenic | 0.00 | Affected | 4.32 | 2 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
| c.3196C>A | P1066T 2D AIThe SynGAP1 missense variant P1066T 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 further support a benign classification: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of computational evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.967676 | Disordered | 0.968838 | Binding | 0.403 | 0.913 | 0.875 | -5.973 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.167 | Likely Benign | 0.1652 | 0.7240 | -2.61 | Deleterious | 0.996 | Probably Damaging | 0.928 | Probably Damaging | 2.66 | Benign | 0.00 | Affected | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||
| c.3196C>G | P1066A 2D AIThe SynGAP1 missense variant P1066A 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 | 0.967676 | Disordered | 0.968838 | Binding | 0.403 | 0.913 | 0.875 | -4.856 | Likely Benign | 0.050 | Likely Benign | Likely Benign | 0.149 | Likely Benign | 0.3228 | 0.6042 | -2.35 | Neutral | 0.972 | Probably Damaging | 0.802 | Possibly Damaging | 2.78 | Benign | 0.00 | Affected | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| c.3196C>T | P1066S 2D AIThe SynGAP1 missense variant P1066S is listed in ClinVar as Pathogenic (ClinVar ID 1343237.0) and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, which contradicts the ClinVar pathogenic classification. Thus, based on current predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.967676 | Disordered | 0.968838 | Binding | 0.403 | 0.913 | 0.875 | Likely Pathogenic | 1 | -4.746 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.145 | Likely Benign | 0.3304 | 0.6353 | -2.47 | Neutral | 0.972 | Probably Damaging | 0.850 | Possibly Damaging | 2.74 | Benign | 0.00 | Affected | 4.32 | 2 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||
| c.3197C>A | P1066H 2D AIThe SynGAP1 missense variant P1066H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. 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, 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 | 0.967676 | Disordered | 0.968838 | Binding | 0.403 | 0.913 | 0.875 | -6.034 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.146 | Likely Benign | 0.1984 | 0.5861 | -2.90 | Deleterious | 1.000 | Probably Damaging | 0.975 | Probably Damaging | 2.61 | Benign | 0.00 | Affected | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||
| c.3197C>G | P1066R 2D AIThe SynGAP1 missense variant P1066R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. 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 | 0.967676 | Disordered | 0.968838 | Binding | 0.403 | 0.913 | 0.875 | -5.154 | Likely Benign | 0.292 | Likely Benign | Likely Benign | 0.176 | Likely Benign | 0.1523 | 0.4742 | -2.89 | Deleterious | 0.992 | Probably Damaging | 0.873 | Possibly Damaging | 2.63 | Benign | 0.00 | Affected | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.3197C>T | P1066L 2D AIThe SynGAP1 missense variant P1066L is listed in ClinVar as a benign variant (ClinVar ID 951518.0) and is present in gnomAD (ID 6‑33443749‑C‑T). Prediction tools that agree on a benign effect include REVEL, 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 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 unavailable. Overall, the majority of evidence points to a benign impact, 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 | 0.967676 | Disordered | 0.968838 | Binding | 0.403 | 0.913 | 0.875 | Likely Benign | 1 | 6-33443749-C-T | 14 | 8.71e-6 | -5.478 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.173 | Likely Benign | 0.2269 | 0.6780 | -3.68 | Deleterious | 0.996 | Probably Damaging | 0.903 | Possibly Damaging | 2.72 | Benign | 0.00 | Affected | 4.32 | 2 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||
| c.3199C>A | P1067T 2D AIThe SynGAP1 missense variant P1067T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 HumDiv and SIFT predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.966441 | Disordered | 0.975099 | Binding | 0.459 | 0.907 | 0.875 | -4.898 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.062 | Likely Benign | 0.1449 | 0.6132 | -1.94 | Neutral | 0.827 | Possibly Damaging | 0.375 | Benign | 2.79 | Benign | 0.04 | Affected | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||
| c.3199C>G | P1067A 2D AIThe SynGAP1 missense variant P1067A 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, representing the sole discordant prediction. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: 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 preponderance of evidence supports a benign classification for P1067A, 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 | 0.966441 | Disordered | 0.975099 | Binding | 0.459 | 0.907 | 0.875 | -4.639 | Likely Benign | 0.052 | Likely Benign | Likely Benign | 0.073 | Likely Benign | 0.3097 | 0.5322 | -2.05 | Neutral | 0.664 | Possibly Damaging | 0.283 | Benign | 2.87 | Benign | 0.07 | Tolerated | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| c.3199C>T | P1067S 2D AIThe SynGAP1 missense variant P1067S 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. 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 | 0.966441 | Disordered | 0.975099 | Binding | 0.459 | 0.907 | 0.875 | -4.673 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.079 | Likely Benign | 0.3086 | 0.5753 | -1.43 | Neutral | 0.271 | Benign | 0.054 | Benign | 2.91 | Benign | 0.48 | Tolerated | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||
| c.3200C>A | P1067Q 2D AIThe SynGAP1 missense variant P1067Q 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 benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports 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 unavailable. Overall, the preponderance of evidence points to a benign effect for P1067Q, 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 | 0.966441 | Disordered | 0.975099 | Binding | 0.459 | 0.907 | 0.875 | -4.767 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.136 | Likely Benign | 0.1369 | 0.5415 | -2.39 | Neutral | 0.463 | Possibly Damaging | 0.087 | Benign | 2.84 | Benign | 0.01 | Affected | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||
| c.3200C>G | P1067R 2D AIThe SynGAP1 missense variant P1067R is not 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 further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta’s stability analysis is unavailable. Taken together, the majority of reliable predictors and the high‑accuracy tools indicate a benign impact. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.966441 | Disordered | 0.975099 | Binding | 0.459 | 0.907 | 0.875 | -4.878 | Likely Benign | 0.376 | Ambiguous | Likely Benign | 0.167 | Likely Benign | 0.1300 | 0.3651 | -2.74 | Deleterious | 0.971 | Probably Damaging | 0.580 | Possibly Damaging | 2.78 | Benign | 0.01 | Affected | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||
| c.3200C>T | P1067L 2D AIThe SynGAP1 missense variant P1067L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of predictions and the consensus analysis indicate 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 | 0.966441 | Disordered | 0.975099 | Binding | 0.459 | 0.907 | 0.875 | -4.461 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.157 | Likely Benign | 0.2047 | 0.6198 | -3.01 | Deleterious | 0.951 | Possibly Damaging | 0.619 | Possibly Damaging | 2.76 | Benign | 0.01 | Affected | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||
| c.3202T>A | L1068M 2D AIThe SynGAP1 missense variant L1068M is 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 impact. 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 | 0.947281 | Disordered | 0.981041 | Binding | 0.362 | 0.907 | 0.875 | -5.739 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.043 | Likely Benign | 0.0930 | 0.4582 | -0.22 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 2.49 | Pathogenic | 0.00 | Affected | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||
| c.3202T>G | L1068V 2D AIThe SynGAP1 missense variant L1068V is not reported 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 | 0.947281 | Disordered | 0.981041 | Binding | 0.362 | 0.907 | 0.875 | -5.325 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.051 | Likely Benign | 0.1619 | 0.4404 | -0.58 | Neutral | 0.451 | Benign | 0.110 | Benign | 2.54 | Benign | 0.00 | Affected | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3203T>C | L1068S 2D  AIThe SynGAP1 missense variant L1068S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, while only SIFT predicts it as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments 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 status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.947281 | Disordered | 0.981041 | Binding | 0.362 | 0.907 | 0.875 | -6.297 | Likely Benign | 0.211 | Likely Benign | Likely Benign | 0.175 | Likely Benign | 0.2810 | 0.1853 | -0.57 | Neutral | 0.032 | Benign | 0.017 | Benign | 2.59 | Benign | 0.00 | Affected | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||||||||
| c.3203T>G | L1068W 2D  AIThe SynGAP1 missense variant L1068W 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 AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all predict a pathogenic outcome; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized remains benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) resolves as pathogenic, and Foldetta’s protein‑folding stability analysis is unavailable. Overall, the majority of evidence points toward a pathogenic impact for L1068W. 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. | 0.947281 | Disordered | 0.981041 | Binding | 0.362 | 0.907 | 0.875 | -8.574 | Likely Pathogenic | 0.342 | Ambiguous | Likely Benign | 0.151 | Likely Benign | 0.0742 | 0.3763 | -1.96 | Neutral | 0.994 | Probably Damaging | 0.884 | Possibly Damaging | 2.46 | Pathogenic | 0.00 | Affected | -2 | -2 | -4.7 | 73.05 | ||||||||||||||||||||||||||||||||||||
| c.3204G>C | L1068F 2D AIThe SynGAP1 missense variant L1068F is 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) favor a benign classification. Thus, the variant is most likely benign based on current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.947281 | Disordered | 0.981041 | Binding | 0.362 | 0.907 | 0.875 | -6.338 | Likely Benign | 0.182 | Likely Benign | Likely Benign | 0.107 | Likely Benign | 0.0754 | 0.4202 | -1.38 | Neutral | 0.934 | Possibly Damaging | 0.537 | Possibly Damaging | 2.49 | Pathogenic | 0.00 | Affected | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||
| c.3204G>T | L1068F 2D AIThe SynGAP1 missense variant L1068F is 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) favor a benign classification. Thus, the variant is most likely benign based on current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.947281 | Disordered | 0.981041 | Binding | 0.362 | 0.907 | 0.875 | -6.338 | Likely Benign | 0.182 | Likely Benign | Likely Benign | 0.106 | Likely Benign | 0.0754 | 0.4202 | -1.38 | Neutral | 0.934 | Possibly Damaging | 0.537 | Possibly Damaging | 2.49 | Pathogenic | 0.00 | Affected | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||
| c.3205C>A | Q1069K 2D AIThe SynGAP1 missense variant Q1069K is not reported 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 predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the majority of computational evidence points to a benign effect, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.943310 | Disordered | 0.981477 | Binding | 0.333 | 0.906 | 0.875 | -5.080 | Likely Benign | 0.542 | Ambiguous | Likely Benign | 0.099 | Likely Benign | 0.1904 | 0.5071 | -0.88 | Neutral | 0.625 | Possibly Damaging | 0.266 | Benign | 2.77 | Benign | 0.28 | Tolerated | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||
| c.3205C>G | Q1069E 2D AIThe SynGAP1 missense variant Q1069E 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 | 0.943310 | Disordered | 0.981477 | Binding | 0.333 | 0.906 | 0.875 | -5.165 | Likely Benign | 0.322 | Likely Benign | Likely Benign | 0.107 | Likely Benign | 0.1460 | 0.3127 | -0.68 | Neutral | 0.451 | Benign | 0.266 | Benign | 2.76 | Benign | 0.33 | Tolerated | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||
| c.3206A>C | Q1069P 2D AIThe SynGAP1 missense variant Q1069P 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 the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign consensus. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, 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 | 0.943310 | Disordered | 0.981477 | Binding | 0.333 | 0.906 | 0.875 | -3.458 | Likely Benign | 0.056 | Likely Benign | Likely Benign | 0.211 | Likely Benign | 0.2179 | 0.5944 | 0.75 | Neutral | 0.977 | Probably Damaging | 0.722 | Possibly Damaging | 2.73 | Benign | 1.00 | Tolerated | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||
| c.3206A>G | Q1069R 2D AIThe SynGAP1 missense variant Q1069R is not reported in ClinVar (ClinVar ID = None) and has no entries in gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable. Overall, the preponderance of evidence points to 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 | 0.943310 | Disordered | 0.981477 | Binding | 0.333 | 0.906 | 0.875 | -3.257 | Likely Benign | 0.467 | Ambiguous | Likely Benign | 0.094 | Likely Benign | 0.1557 | 0.3114 | -1.17 | Neutral | 0.666 | Possibly Damaging | 0.355 | Benign | 2.73 | Benign | 0.21 | Tolerated | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||
| c.3206A>T | Q1069L 2D AIThe SynGAP1 missense variant Q1069L 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 | 0.943310 | Disordered | 0.981477 | Binding | 0.333 | 0.906 | 0.875 | -4.278 | Likely Benign | 0.141 | Likely Benign | Likely Benign | 0.104 | Likely Benign | 0.0936 | 0.6624 | -0.96 | Neutral | 0.003 | Benign | 0.008 | Benign | 2.83 | Benign | 0.10 | Tolerated | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||
| c.3207G>C | Q1069H 2D AIThe SynGAP1 missense variant Q1069H is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.943310 | Disordered | 0.981477 | Binding | 0.333 | 0.906 | 0.875 | -4.723 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.085 | Likely Benign | 0.1560 | 0.4678 | -1.31 | Neutral | 0.006 | Benign | 0.008 | Benign | 2.69 | Benign | 0.06 | Tolerated | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.3207G>T | Q1069H 2D AIThe SynGAP1 missense variant Q1069H is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.943310 | Disordered | 0.981477 | Binding | 0.333 | 0.906 | 0.875 | -4.723 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.085 | Likely Benign | 0.1560 | 0.4678 | -1.31 | Neutral | 0.006 | Benign | 0.008 | Benign | 2.69 | Benign | 0.06 | Tolerated | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.3208A>G | R1070G 2D AIThe SynGAP1 missense variant R1070G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Consensus from standard in silico predictors shows five tools (REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized) classifying it as benign, while four (PROVEAN, polyPhen‑2 HumDiv, SIFT, AlphaMissense‑Default) predict pathogenicity. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 vs 2), and Foldetta data are unavailable. Overall, the balance of evidence leans toward a benign effect. This conclusion does not conflict with ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.930790 | Disordered | 0.982693 | Binding | 0.297 | 0.906 | 0.875 | -4.731 | Likely Benign | 0.568 | Likely Pathogenic | Likely Benign | 0.149 | Likely Benign | 0.3150 | 0.4070 | -2.88 | Deleterious | 0.789 | Possibly Damaging | 0.258 | Benign | 3.75 | Benign | 0.01 | Affected | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||
| c.3208A>T | R1070W 2D AIThe SynGAP1 missense variant R1070W is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized labeling the variant as benign, whereas the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates it is likely pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this residue. Overall, the majority of tools and the SGM‑Consensus support a pathogenic effect, so the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.930790 | Disordered | 0.982693 | Binding | 0.297 | 0.906 | 0.875 | -8.063 | Likely Pathogenic | 0.743 | Likely Pathogenic | Likely Benign | 0.139 | Likely Benign | 0.1195 | 0.4293 | -3.42 | Deleterious | 0.999 | Probably Damaging | 0.956 | Probably Damaging | 3.72 | Benign | 0.00 | Affected | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.3209G>A | R1070K 2D AIThe SynGAP1 missense variant R1070K is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. 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, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” High‑accuracy tools reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta results are unavailable. Based on the unanimous benign predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.930790 | Disordered | 0.982693 | Binding | 0.297 | 0.906 | 0.875 | Conflicting | 2 | -5.093 | Likely Benign | 0.326 | Likely Benign | Likely Benign | 0.104 | Likely Benign | 0.4997 | 0.4867 | -1.42 | Neutral | 0.049 | Benign | 0.048 | Benign | 3.86 | Benign | 0.09 | Tolerated | 3.77 | 5 | 3 | 2 | 0.6 | -28.01 | |||||||||||||||||||||||||||||||
| c.3209G>C | R1070T 2D AIThe SynGAP1 missense variant R1070T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are not available. Overall, the balance of evidence leans toward a benign impact, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.930790 | Disordered | 0.982693 | Binding | 0.297 | 0.906 | 0.875 | -5.093 | Likely Benign | 0.860 | Likely Pathogenic | Ambiguous | 0.144 | Likely Benign | 0.1634 | 0.4727 | -2.35 | Neutral | 0.948 | Possibly Damaging | 0.507 | Possibly Damaging | 3.78 | Benign | 0.01 | Affected | 3.77 | 5 | -1 | -1 | 3.8 | -55.08 | |||||||||||||||||||||||||||||||||
| c.3209G>T | R1070M 2D AIThe SynGAP1 missense variant R1070M 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, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the balance of evidence, including the consensus benign call and the absence of pathogenic predictions from the most reliable tools, suggests the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.930790 | Disordered | 0.982693 | Binding | 0.297 | 0.906 | 0.875 | -6.455 | Likely Benign | 0.917 | Likely Pathogenic | Ambiguous | 0.183 | Likely Benign | 0.1661 | 0.4324 | -2.27 | Neutral | 0.995 | Probably Damaging | 0.907 | Possibly Damaging | 3.74 | Benign | 0.00 | Affected | 0 | -1 | 6.4 | -24.99 | |||||||||||||||||||||||||||||||||||
| c.3209_3210delinsCA | R1070T 2D AIThe SynGAP1 missense variant R1070T is listed in ClinVar (ID 2759838.0) with an “Uncertain” clinical significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (which aggregates these three benign calls with the pathogenic AlphaMissense‑Default to yield a Likely Benign verdict). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized returns an uncertain result. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and no Foldetta stability data is available. Overall, the balance of evidence leans toward a benign impact, which is consistent with the ClinVar “Uncertain” status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.930790 | Disordered | 0.982693 | Binding | 0.297 | 0.906 | 0.875 | Uncertain | 1 | -5.093 | Likely Benign | 0.860 | Likely Pathogenic | Ambiguous | 0.1634 | 0.4727 | -2.35 | Neutral | 0.948 | Possibly Damaging | 0.507 | Possibly Damaging | 3.78 | Benign | 0.01 | Affected | 3.77 | 5 | -1 | -1 | 3.8 | -55.08 | |||||||||||||||||||||||||||||||||
| c.3210G>C | R1070S 2D AIThe SynGAP1 missense variant R1070S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while Foldetta results are unavailable. Overall, the majority of evidence points to 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 | 0.930790 | Disordered | 0.982693 | Binding | 0.297 | 0.906 | 0.875 | -4.311 | Likely Benign | 0.913 | Likely Pathogenic | Ambiguous | 0.091 | Likely Benign | 0.2640 | 0.4042 | -2.07 | Neutral | 0.789 | Possibly Damaging | 0.258 | Benign | 3.85 | Benign | 0.01 | Affected | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||
| c.3210G>T | R1070S 2D AIThe SynGAP1 missense variant R1070S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as 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 | 0.930790 | Disordered | 0.982693 | Binding | 0.297 | 0.906 | 0.875 | -4.311 | Likely Benign | 0.913 | Likely Pathogenic | Ambiguous | 0.091 | Likely Benign | 0.2640 | 0.4042 | -2.07 | Neutral | 0.789 | Possibly Damaging | 0.258 | Benign | 3.85 | Benign | 0.01 | Affected | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||
| c.3211G>A | G1071S 2D AIThe SynGAP1 missense variant G1071S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign impact for G1071S, 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 | 0.919029 | Disordered | 0.983740 | Binding | 0.313 | 0.905 | 0.875 | -1.139 | Likely Benign | 0.168 | Likely Benign | Likely Benign | 0.093 | Likely Benign | 0.2468 | 0.5451 | -1.06 | Neutral | 0.692 | Possibly Damaging | 0.222 | Benign | 4.10 | Benign | 0.28 | Tolerated | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.3211G>C | G1071R 2D AIThe SynGAP1 missense variant G1071R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus unavailable; Foldetta results are not provided and are therefore unavailable. Overall, more tools predict pathogenicity (5) than benignity (3), and no ClinVar entry contradicts this assessment. **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. | 0.919029 | Disordered | 0.983740 | Binding | 0.313 | 0.905 | 0.875 | -3.052 | Likely Benign | 0.886 | Likely Pathogenic | Ambiguous | 0.135 | Likely Benign | 0.0980 | 0.4482 | -2.61 | Deleterious | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 4.06 | Benign | 0.00 | Affected | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||
| c.3211G>T | G1071C 2D AIThe SynGAP1 missense variant G1071C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence—including the consensus and high‑accuracy predictions—supports a benign classification, 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 | 0.919029 | Disordered | 0.983740 | Binding | 0.313 | 0.905 | 0.875 | -5.364 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.182 | Likely Benign | 0.1323 | 0.4227 | -2.16 | Neutral | 0.997 | Probably Damaging | 0.889 | Possibly Damaging | 4.01 | Benign | 0.00 | Affected | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||
| c.3212G>A | G1071D 2D AIThe SynGAP1 missense variant G1071D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the majority of evidence points toward a benign impact, with no conflict with ClinVar status (which has no entry). Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.983740 | Binding | 0.313 | 0.905 | 0.875 | -4.704 | Likely Benign | 0.866 | Likely Pathogenic | Ambiguous | 0.101 | Likely Benign | 0.1760 | 0.2175 | -1.92 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 4.05 | Benign | 0.01 | Affected | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||
| c.3212G>C | G1071A 2D AIThe SynGAP1 missense variant G1071A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign effect, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.983740 | Binding | 0.313 | 0.905 | 0.875 | -1.825 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.070 | Likely Benign | 0.3376 | 0.5084 | -1.34 | Neutral | 0.025 | Benign | 0.022 | Benign | 4.12 | Benign | 0.05 | Affected | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3212G>T | G1071V 2D AIThe SynGAP1 missense variant G1071V is catalogued in gnomAD (ID 6‑33443764‑G‑T) but has no ClinVar entry. In silico prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or likely 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 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, supports a benign interpretation. This prediction 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 | 0.919029 | Disordered | 0.983740 | Binding | 0.313 | 0.905 | 0.875 | 6-33443764-G-T | 3 | 1.87e-6 | -2.901 | Likely Benign | 0.300 | Likely Benign | Likely Benign | 0.110 | Likely Benign | 0.1408 | 0.3634 | -2.42 | Neutral | 0.057 | Benign | 0.022 | Benign | 4.14 | Benign | 0.01 | Affected | 3.77 | 5 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||
| c.3214A>C | K1072Q 2D AIThe SynGAP1 missense variant K1072Q is not reported 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 because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.984675 | Binding | 0.307 | 0.907 | 0.750 | -1.631 | Likely Benign | 0.589 | Likely Pathogenic | Likely Benign | 0.081 | Likely Benign | 0.4465 | 0.1804 | -0.63 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 3.95 | Benign | 0.12 | Tolerated | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||
| c.3214A>G | K1072E 2D AIThe SynGAP1 missense variant K1072E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions are returned by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments indicate that AlphaMissense‑Optimized classifies the variant as pathogenic, whereas the SGM‑Consensus (derived from the same set of predictors) labels it as likely benign. No Foldetta stability analysis is available for this residue. Overall, the majority of tools lean toward a benign effect, but the presence of pathogenic calls from several high‑confidence predictors suggests uncertainty. The variant is most likely benign based on the preponderance of evidence, 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 | 0.922952 | Disordered | 0.984675 | Binding | 0.307 | 0.907 | 0.750 | -3.889 | Likely Benign | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.105 | Likely Benign | 0.3636 | 0.1874 | -0.90 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 3.96 | Benign | 0.08 | Tolerated | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||||
| c.3215A>C | K1072T 2D AIThe SynGAP1 missense variant K1072T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and the SGM‑Consensus result is benign; Foldetta predictions are unavailable. Overall, the balance of evidence leans toward a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.984675 | Binding | 0.307 | 0.907 | 0.750 | -2.557 | Likely Benign | 0.834 | Likely Pathogenic | Ambiguous | 0.082 | Likely Benign | 0.1967 | 0.4307 | -1.31 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 3.92 | Benign | 0.06 | Tolerated | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||
| c.3215A>G | K1072R 2D AIThe SynGAP1 missense variant K1072R is reported in gnomAD (ID 6‑33443767‑A‑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. In contrast, polyPhen‑2 (HumDiv and HumVar) predict it to be pathogenic. When predictions are grouped by consensus, the benign group contains seven tools, whereas the pathogenic group contains two. High‑accuracy assessments reinforce the benign view: AlphaMissense‑Optimized reports a benign outcome, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. No Foldetta stability data are available, so folding‑stability evidence is unavailable. Overall, the majority of evidence points to a benign impact, and this is not in conflict with ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.984675 | Binding | 0.307 | 0.907 | 0.750 | 6-33443767-A-G | 1 | 6.23e-7 | -2.458 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.116 | Likely Benign | 0.4655 | 0.2061 | -0.15 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 4.16 | Benign | 0.88 | Tolerated | 3.77 | 5 | 2 | 3 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||
| c.3215A>T | K1072M 2D AIThe SynGAP1 K1072M missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points toward a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign based on current predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.984675 | Binding | 0.307 | 0.907 | 0.750 | -2.821 | Likely Benign | 0.928 | Likely Pathogenic | Ambiguous | 0.144 | Likely Benign | 0.1266 | 0.4877 | -1.37 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.88 | Benign | 0.02 | Affected | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||
| c.3216G>C | K1072N 2D AIThe SynGAP1 missense variant K1072N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are not available. Overall, the balance of evidence leans toward a benign impact, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.984675 | Binding | 0.307 | 0.907 | 0.750 | -2.215 | Likely Benign | 0.953 | Likely Pathogenic | Ambiguous | 0.078 | Likely Benign | 0.3449 | 0.2391 | -1.18 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 3.92 | Benign | 0.05 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||
| c.3216G>T | K1072N 2D AIThe SynGAP1 missense variant K1072N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are not available. Overall, the balance of evidence leans toward a benign impact, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.984675 | Binding | 0.307 | 0.907 | 0.750 | -2.215 | Likely Benign | 0.953 | Likely Pathogenic | Ambiguous | 0.078 | Likely Benign | 0.3449 | 0.2391 | -1.18 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 3.92 | Benign | 0.05 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||
| c.3217T>A | S1073T 2D AIThe SynGAP1 missense variant S1073T is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.916840 | Disordered | 0.985818 | Binding | 0.313 | 0.905 | 0.750 | -5.203 | Likely Benign | 0.169 | Likely Benign | Likely Benign | 0.161 | Likely Benign | 0.1696 | 0.6509 | -0.26 | Neutral | 0.025 | Benign | 0.026 | Benign | 4.06 | Benign | 0.55 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3217T>C | S1073P 2D AIThe SynGAP1 missense variant S1073P is reported in gnomAD (variant ID 6‑33443769‑T‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact for S1073P, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.916840 | Disordered | 0.985818 | Binding | 0.313 | 0.905 | 0.750 | 6-33443769-T-C | 1 | 6.23e-7 | -4.520 | Likely Benign | 0.338 | Likely Benign | Likely Benign | 0.082 | Likely Benign | 0.2243 | 0.5900 | -0.76 | Neutral | 0.006 | Benign | 0.008 | Benign | 3.85 | Benign | 0.01 | Affected | 3.77 | 5 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||
| c.3217T>G | S1073A 2D AIThe SynGAP1 missense variant S1073A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, while only SIFT predicts it as pathogenic. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) confirms a benign status. Foldetta’s protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and high‑accuracy tools suggests that the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.916840 | Disordered | 0.985818 | Binding | 0.313 | 0.905 | 0.750 | -5.333 | Likely Benign | 0.220 | Likely Benign | Likely Benign | 0.104 | Likely Benign | 0.4571 | 0.5883 | -0.96 | Neutral | 0.447 | Benign | 0.103 | Benign | 3.95 | Benign | 0.02 | Affected | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||
| c.3218C>A | S1073Y 2D AIThe SynGAP1 missense change S1073Y 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, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, 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 | 0.916840 | Disordered | 0.985818 | Binding | 0.313 | 0.905 | 0.750 | -6.768 | Likely Benign | 0.752 | Likely Pathogenic | Likely Benign | 0.165 | Likely Benign | 0.0977 | 0.5684 | -2.43 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 3.81 | Benign | 0.00 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||
| c.3218C>G | S1073C 2D AISynGAP1 missense variant S1073C is recorded in gnomAD (ID 6‑33443770‑C‑G) but has no ClinVar submission. Functional prediction tools show mixed results: benign calls come from REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The AlphaMissense‑Default score is uncertain. A consensus from the SGM framework (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because the votes are split. High‑accuracy methods give a benign prediction from AlphaMissense‑Optimized; the SGM Consensus remains ambiguous, and Foldetta stability analysis is unavailable. Consequently, the evidence does not strongly favor either outcome. The variant is most likely of uncertain significance, with no contradiction to ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.916840 | Disordered | 0.985818 | Binding | 0.313 | 0.905 | 0.750 | 6-33443770-C-G | 1 | 6.23e-7 | -8.862 | Likely Pathogenic | 0.461 | Ambiguous | Likely Benign | 0.137 | Likely Benign | 0.1343 | 0.6088 | -1.52 | Neutral | 0.997 | Probably Damaging | 0.840 | Possibly Damaging | 3.81 | Benign | 0.00 | Affected | 3.77 | 5 | -1 | 0 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||
| c.3218C>T | S1073F 2D AIThe SynGAP1 missense variant S1073F 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 FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (five pathogenic vs. three benign) lean toward a pathogenic impact. Thus, the variant is most likely pathogenic based on current computational evidence, 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. | 0.916840 | Disordered | 0.985818 | Binding | 0.313 | 0.905 | 0.750 | -6.783 | Likely Benign | 0.836 | Likely Pathogenic | Ambiguous | 0.161 | Likely Benign | 0.0952 | 0.5957 | -2.58 | Deleterious | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 3.81 | Benign | 0.00 | Affected | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||
| c.3220C>A | Q1074K 2D AIThe SynGAP1 missense variant Q1074K is not reported 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, the SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion is consistent with the lack of any ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.930790 | Disordered | 0.987006 | Binding | 0.339 | 0.897 | 0.750 | -6.162 | Likely Benign | 0.712 | Likely Pathogenic | Likely Benign | 0.110 | Likely Benign | 0.1865 | 0.4600 | -0.88 | Neutral | 0.011 | Benign | 0.006 | Benign | 2.75 | Benign | 0.36 | Tolerated | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||
| c.3220C>G | Q1074E 2D AIThe SynGAP1 missense variant Q1074E 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 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 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 | 0.930790 | Disordered | 0.987006 | Binding | 0.339 | 0.897 | 0.750 | -2.815 | Likely Benign | 0.419 | Ambiguous | Likely Benign | 0.096 | Likely Benign | 0.1386 | 0.2856 | -0.79 | Neutral | 0.264 | Benign | 0.103 | Benign | 2.79 | Benign | 0.24 | Tolerated | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||
| c.3221A>C | Q1074P 2D AIThe SynGAP1 missense variant Q1074P is listed in gnomAD (ID 6‑33443773‑A‑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 report benign or tolerated. Only polyPhen‑2 HumDiv flags it as pathogenic, creating a single outlier. 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 results are unavailable. Overall, the preponderance of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.930790 | Disordered | 0.987006 | Binding | 0.339 | 0.897 | 0.750 | 6-33443773-A-C | 1 | 6.23e-7 | -4.259 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.188 | Likely Benign | 0.2046 | 0.5784 | 0.52 | Neutral | 0.925 | Possibly Damaging | 0.432 | Benign | 2.66 | Benign | 0.13 | Tolerated | 3.77 | 5 | -1 | 0 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||
| c.3221A>G | Q1074R 2D AIThe SynGAP1 missense variant Q1074R is listed in gnomAD (ID 6‑33443773‑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, PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by 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 | 0.930790 | Disordered | 0.987006 | Binding | 0.339 | 0.897 | 0.750 | 6-33443773-A-G | -5.710 | Likely Benign | 0.594 | Likely Pathogenic | Likely Benign | 0.124 | Likely Benign | 0.1523 | 0.2643 | -0.54 | Neutral | 0.292 | Benign | 0.157 | Benign | 2.70 | Benign | 0.28 | Tolerated | 3.77 | 5 | 1 | 1 | -1.0 | 28.06 | ||||||||||||||||||||||||||||||||
| c.3221A>T | Q1074L 2D AIThe SynGAP1 missense variant Q1074L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion 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 | 0.987006 | Binding | 0.339 | 0.897 | 0.750 | -3.561 | Likely Benign | 0.259 | Likely Benign | Likely Benign | 0.118 | Likely Benign | 0.0840 | 0.6293 | -1.29 | Neutral | 0.625 | Possibly Damaging | 0.266 | Benign | 2.68 | Benign | 1.00 | Tolerated | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||
| c.3222G>C | Q1074H 2D AIThe SynGAP1 missense variant Q1074H is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools uniformly favor a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity, and the only uncertain call comes from AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as “Likely Benign.” High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.930790 | Disordered | 0.987006 | Binding | 0.339 | 0.897 | 0.750 | -5.051 | Likely Benign | 0.381 | Ambiguous | Likely Benign | 0.053 | Likely Benign | 0.1436 | 0.4407 | -0.12 | Neutral | 0.006 | Benign | 0.008 | Benign | 2.67 | Benign | 0.07 | Tolerated | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.3222G>T | Q1074H 2D AIThe SynGAP1 missense variant Q1074H is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools uniformly favor a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity, and the only uncertain call comes from AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as “Likely Benign.” High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.930790 | Disordered | 0.987006 | Binding | 0.339 | 0.897 | 0.750 | -5.051 | Likely Benign | 0.381 | Ambiguous | Likely Benign | 0.053 | Likely Benign | 0.1436 | 0.4407 | -0.12 | Neutral | 0.006 | Benign | 0.008 | Benign | 2.67 | Benign | 0.07 | Tolerated | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.3223C>A | Q1075K 2D AIThe SynGAP1 missense variant Q1075K (ClinVar ID 2762879.0) is listed as “Uncertain” in ClinVar and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign” because three of the four contributing tools predict benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) as benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.988305 | Binding | 0.354 | 0.894 | 0.750 | Uncertain | 1 | -5.135 | Likely Benign | 0.728 | Likely Pathogenic | Likely Benign | 0.134 | Likely Benign | 0.1898 | 0.4411 | -0.67 | Neutral | 0.963 | Probably Damaging | 0.959 | Probably Damaging | 2.75 | Benign | 1.00 | Tolerated | 3.77 | 5 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||
| c.3223C>G | Q1075E 2D AIThe SynGAP1 missense variant Q1075E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. AlphaMissense‑Default remains 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 outcome: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is Likely Benign, and Foldetta data is missing. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.988305 | Binding | 0.354 | 0.894 | 0.750 | -2.275 | Likely Benign | 0.401 | Ambiguous | Likely Benign | 0.065 | Likely Benign | 0.1459 | 0.2463 | -0.70 | Neutral | 0.963 | Probably Damaging | 0.959 | Probably Damaging | 2.75 | Benign | 0.25 | Tolerated | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||
| c.3224A>C | Q1075P 2D AIThe SynGAP1 missense variant Q1075P 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 corroborate this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.988305 | Binding | 0.354 | 0.894 | 0.750 | -1.854 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.175 | Likely Benign | 0.2288 | 0.5741 | 0.78 | Neutral | 0.996 | Probably Damaging | 0.988 | Probably Damaging | 2.68 | Benign | 0.28 | Tolerated | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||
| c.3224A>G | Q1075R 2D AIThe SynGAP1 missense variant Q1075R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise 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 effect, and this conclusion does not contradict any ClinVar status, as none is assigned to the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.988305 | Binding | 0.354 | 0.894 | 0.750 | -5.039 | Likely Benign | 0.697 | Likely Pathogenic | Likely Benign | 0.142 | Likely Benign | 0.1504 | 0.2650 | -0.37 | Neutral | 0.985 | Probably Damaging | 0.973 | Probably Damaging | 2.72 | Benign | 0.93 | Tolerated | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||
| c.3224A>T | Q1075L 2D AIThe SynGAP1 missense variant Q1075L 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 confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence supports a benign impact for Q1075L, and this conclusion is consistent with the absence of a ClinVar assertion. The variant is most likely benign based on predictions, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.988305 | Binding | 0.354 | 0.894 | 0.750 | -3.976 | Likely Benign | 0.209 | Likely Benign | Likely Benign | 0.128 | Likely Benign | 0.0888 | 0.6454 | -2.10 | Neutral | 0.985 | Probably Damaging | 0.973 | Probably Damaging | 2.72 | Benign | 0.15 | Tolerated | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||
| c.3225G>C | Q1075H 2D AIThe SynGAP1 missense variant Q1075H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM‑Consensus also indicates likely benign, while Foldetta data is missing. Overall, the majority of reliable predictors classify the variant as benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.988305 | Binding | 0.354 | 0.894 | 0.750 | -4.616 | Likely Benign | 0.486 | Ambiguous | Likely Benign | 0.072 | Likely Benign | 0.1457 | 0.4214 | -1.06 | Neutral | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.68 | Benign | 0.13 | Tolerated | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.3225G>T | Q1075H 2D AIThe SynGAP1 missense variant Q1075H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM‑Consensus also indicates likely benign, while Foldetta data is missing. Overall, the majority of reliable predictors classify the variant as benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.988305 | Binding | 0.354 | 0.894 | 0.750 | -4.616 | Likely Benign | 0.486 | Ambiguous | Likely Benign | 0.072 | Likely Benign | 0.1457 | 0.4214 | -1.06 | Neutral | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.68 | Benign | 0.13 | Tolerated | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.3226T>A | L1076M 2D AIThe SynGAP1 missense variant L1076M is 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 | 0.922952 | Disordered | 0.989617 | Binding | 0.301 | 0.892 | 0.750 | -5.047 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.087 | Likely Benign | 0.0886 | 0.4147 | 0.02 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.42 | Pathogenic | 0.04 | Affected | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||
| c.3226T>G | L1076V 2D AIThe SynGAP1 missense variant L1076V 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, 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. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this 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 | 0.922952 | Disordered | 0.989617 | Binding | 0.301 | 0.892 | 0.750 | -3.615 | Likely Benign | 0.344 | Ambiguous | Likely Benign | 0.097 | Likely Benign | 0.1632 | 0.3781 | -0.56 | Neutral | 0.995 | Probably Damaging | 0.982 | Probably Damaging | 2.53 | Benign | 0.11 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3227T>C | L1076S 2D AIThe SynGAP1 missense variant L1076S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, whereas polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default all predict a pathogenic outcome. High‑accuracy assessments are less decisive: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs. two pathogenic votes); and Foldetta results are unavailable. Consequently, the evidence is evenly split between benign and pathogenic predictions. The variant is therefore most likely of uncertain significance, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.922952 | Disordered | 0.989617 | Binding | 0.301 | 0.892 | 0.750 | -2.975 | Likely Benign | 0.913 | Likely Pathogenic | Ambiguous | 0.225 | Likely Benign | 0.3045 | 0.1178 | 0.55 | Neutral | 0.999 | Probably Damaging | 0.983 | Probably Damaging | 2.43 | Pathogenic | 0.75 | Tolerated | -3 | -2 | -4.6 | -26.08 | ||||||||||||||||||||||||||||||||||||
| c.3227T>G | L1076W 2D AIThe SynGAP1 missense variant L1076W is not 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 evaluated predictors (five pathogenic vs. three benign) lean toward a pathogenic interpretation. This prediction is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.922952 | Disordered | 0.989617 | Binding | 0.301 | 0.892 | 0.750 | -6.377 | Likely Benign | 0.822 | Likely Pathogenic | Ambiguous | 0.183 | Likely Benign | 0.0749 | 0.3740 | -1.40 | Neutral | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.38 | Pathogenic | 0.02 | Affected | -2 | -2 | -4.7 | 73.05 | ||||||||||||||||||||||||||||||||||||
| c.3228G>C | L1076F 2D AIThe SynGAP1 missense variant L1076F is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that classify the variant as benign include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (5 pathogenic vs. 4 benign) lean toward pathogenicity, and this is consistent with the lack of ClinVar annotation. Thus, the variant is most likely pathogenic, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.922952 | Disordered | 0.989617 | Binding | 0.301 | 0.892 | 0.750 | -4.606 | Likely Benign | 0.675 | Likely Pathogenic | Likely Benign | 0.092 | Likely Benign | 0.0759 | 0.3767 | -0.92 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.42 | Pathogenic | 0.03 | Affected | 2 | 0 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||||||
| c.3228G>T | L1076F 2D AIThe SynGAP1 missense variant L1076F is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that classify the variant as benign include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (5 pathogenic vs. 4 benign) lean toward pathogenicity, and this is consistent with the lack of ClinVar annotation. Thus, the variant is most likely pathogenic, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.922952 | Disordered | 0.989617 | Binding | 0.301 | 0.892 | 0.750 | -4.606 | Likely Benign | 0.675 | Likely Pathogenic | Likely Benign | 0.092 | Likely Benign | 0.0759 | 0.3767 | -0.92 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.42 | Pathogenic | 0.03 | Affected | 2 | 0 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||||||
| c.3229A>C | T1077P 2D AIThe SynGAP1 missense variant T1077P is reported in ClinVar as “Not submitted” and is not present in gnomAD. Functional 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 no Foldetta stability assessment is available. High‑accuracy evidence shows AlphaMissense‑Optimized classifying the variant as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicating a likely benign outcome, and Foldetta results are unavailable. Overall, the majority of predictions and the high‑accuracy consensus point to a benign impact. This conclusion is not contradicted by ClinVar status, which has no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.988141 | Binding | 0.329 | 0.892 | 0.750 | -2.436 | Likely Benign | 0.345 | Ambiguous | Likely Benign | 0.164 | Likely Benign | 0.1876 | 0.4788 | -0.91 | Neutral | 0.970 | Probably Damaging | 0.787 | Possibly Damaging | 4.16 | Benign | 0.04 | Affected | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||
| c.3229A>G | T1077A 2D AIThe SynGAP1 missense variant T1077A is catalogued in gnomAD (ID 6‑33443781‑A‑G) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized returns a benign prediction, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.988141 | Binding | 0.329 | 0.892 | 0.750 | 6-33443781-A-G | -3.303 | Likely Benign | 0.280 | Likely Benign | Likely Benign | 0.153 | Likely Benign | 0.3373 | 0.4393 | -0.60 | Neutral | 0.288 | Benign | 0.194 | Benign | 4.25 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0 | 1 | 2.5 | -30.03 | ||||||||||||||||||||||||||||||||
| c.3229A>T | T1077S 2D AIThe SynGAP1 missense variant T1077S 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 | 0.903857 | Disordered | 0.988141 | Binding | 0.329 | 0.892 | 0.750 | -2.929 | Likely Benign | 0.201 | Likely Benign | Likely Benign | 0.114 | Likely Benign | 0.2788 | 0.4635 | -0.45 | Neutral | 0.068 | Benign | 0.025 | Benign | 4.32 | Benign | 0.06 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3230C>A | T1077K 2D  AIThe SynGAP1 missense variant T1077K is not reported 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—including the SGM‑Consensus—suggests a benign impact, and this conclusion does not contradict the absence of a ClinVar entry. Thus, based on current predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.988141 | Binding | 0.329 | 0.892 | 0.750 | -4.196 | Likely Benign | 0.928 | Likely Pathogenic | Ambiguous | 0.110 | Likely Benign | 0.1176 | 0.3968 | -1.44 | Neutral | 0.818 | Possibly Damaging | 0.460 | Possibly Damaging | 4.21 | Benign | 0.03 | Affected | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||
| c.3230C>G | T1077R 2D  AIThe SynGAP1 missense variant T1077R is not reported in ClinVar and is absent from 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, and PROVEAN), which collectively classify the variant as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and no Foldetta stability assessment is available. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.988141 | Binding | 0.329 | 0.892 | 0.750 | -4.109 | Likely Benign | 0.890 | Likely Pathogenic | Ambiguous | 0.121 | Likely Benign | 0.1028 | 0.3491 | -1.01 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 4.18 | Benign | 0.03 | Affected | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||||||||
| c.3230C>T | T1077I 2D AIThe SynGAP1 missense variant T1077I is listed in gnomAD (ID 6‑33443782‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions (REVEL, PROVEAN, SIFT, ESM1b, FATHMM) and pathogenic predictions (PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, AlphaMissense‑Default). The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to a likely benign verdict (3 benign vs. 1 pathogenic). High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized returns an uncertain result, while Foldetta (combining FoldX‑MD and Rosetta outputs) is not available for this residue. Taken together, the majority of evidence points toward a benign effect. This conclusion is consistent with the absence of a ClinVar pathogenic classification, and there is no contradiction with existing database annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.988141 | Binding | 0.329 | 0.892 | 0.750 | 6-33443782-C-T | 1 | 6.25e-7 | -4.710 | Likely Benign | 0.919 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | 0.1135 | 0.5870 | -1.11 | Neutral | 0.970 | Probably Damaging | 0.787 | Possibly Damaging | 4.19 | Benign | 0.33 | Tolerated | 3.77 | 5 | -1 | 0 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||
| c.3232G>A | V1078I 2D AIThe SynGAP1 missense variant V1078I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as likely benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and consensus methods suggests that V1078I is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.986989 | Binding | 0.294 | 0.898 | 0.750 | -3.652 | Likely Benign | 0.200 | Likely Benign | Likely Benign | 0.120 | Likely Benign | 0.0771 | 0.4693 | -0.16 | Neutral | 0.625 | Possibly Damaging | 0.266 | Benign | 3.98 | Benign | 0.07 | Tolerated | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3232G>C | V1078L 2D AIThe SynGAP1 missense variant V1078L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign classification. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is likely benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the collective evidence strongly suggests that V1078L is most likely benign, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.986989 | Binding | 0.294 | 0.898 | 0.750 | -2.547 | Likely Benign | 0.523 | Ambiguous | Likely Benign | 0.091 | Likely Benign | 0.0889 | 0.5349 | -0.16 | Neutral | 0.451 | Benign | 0.209 | Benign | 4.13 | Benign | 0.56 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3232G>T | V1078F 2D AIThe SynGAP1 missense variant V1078F 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, SIFT, and AlphaMissense‑Default. 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 effect for V1078F, 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 | 0.882776 | Disordered | 0.986989 | Binding | 0.294 | 0.898 | 0.750 | -3.768 | Likely Benign | 0.570 | Likely Pathogenic | Likely Benign | 0.142 | Likely Benign | 0.0677 | 0.4561 | -0.97 | Neutral | 0.977 | Probably Damaging | 0.722 | Possibly Damaging | 3.87 | Benign | 0.02 | Affected | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||||||||
| c.3233T>A | V1078D 2D AIThe SynGAP1 missense variant V1078D is listed in ClinVar (ID 2993122.0) 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, and FATHMM. Tools that predict a pathogenic effect are AlphaMissense‑Default, AlphaMissense‑Optimized, 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 pathogenic, SGM‑Consensus as likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the majority of predictions lean toward a benign impact, and this is consistent with the ClinVar “Uncertain” designation; there is no contradiction with the existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.986989 | Binding | 0.294 | 0.898 | 0.750 | Uncertain | 1 | -5.155 | Likely Benign | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.158 | Likely Benign | 0.1570 | 0.1173 | -1.45 | Neutral | 0.003 | Benign | 0.008 | Benign | 3.84 | Benign | 0.00 | Affected | 3.77 | 5 | -3 | -2 | -7.7 | 15.96 | |||||||||||||||||||||||||||||||
| c.3233T>C | V1078A 2D AIThe SynGAP1 missense variant V1078A 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 outcome: 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 predictions indicate that V1078A is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.986989 | Binding | 0.294 | 0.898 | 0.750 | -2.794 | Likely Benign | 0.690 | Likely Pathogenic | Likely Benign | 0.089 | Likely Benign | 0.2679 | 0.2546 | -0.27 | Neutral | 0.011 | Benign | 0.006 | Benign | 3.94 | Benign | 0.02 | Affected | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||
| c.3233T>G | V1078G 2D AIThe SynGAP1 missense variant V1078G is not 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. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign (3 benign vs 1 pathogenic). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence indicates a benign impact. This conclusion is not contradicted by ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.882776 | Disordered | 0.986989 | Binding | 0.294 | 0.898 | 0.750 | -3.270 | Likely Benign | 0.699 | Likely Pathogenic | Likely Benign | 0.168 | Likely Benign | 0.2041 | 0.2693 | -0.54 | Neutral | 0.157 | Benign | 0.292 | Benign | 3.85 | Benign | 0.00 | Affected | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||||||||
| c.3235A>C | S1079R 2D AIThe SynGAP1 missense variant S1079R 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, and FATHMM. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. AlphaMissense‑Optimized returns an uncertain result. 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 (a protein‑folding stability method combining FoldX‑MD and Rosetta) 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 reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.983887 | Binding | 0.307 | 0.900 | 0.750 | -4.579 | Likely Benign | 0.955 | Likely Pathogenic | Ambiguous | 0.163 | Likely Benign | 0.0811 | 0.4028 | -1.81 | Neutral | 0.177 | Benign | 0.075 | Benign | 3.86 | Benign | 0.00 | Affected | 3.77 | 5 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||
| c.3235A>G | S1079G 2D AIThe SynGAP1 missense variant S1079G is reported in gnomAD (variant ID 6‑33443787‑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 status. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods points to a benign effect. This conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.983887 | Binding | 0.307 | 0.900 | 0.750 | 6-33443787-A-G | 6 | 3.76e-6 | -3.552 | Likely Benign | 0.177 | Likely Benign | Likely Benign | 0.065 | Likely Benign | 0.2151 | 0.4623 | -1.50 | Neutral | 0.036 | Benign | 0.018 | Benign | 3.87 | Benign | 0.00 | Affected | 3.77 | 5 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||
| c.3235A>T | S1079C 2D AIThe SynGAP1 missense variant S1079C is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and 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, and Foldetta data are unavailable. Overall, the balance of evidence slightly favors a pathogenic interpretation, with four tools supporting pathogenicity versus three supporting benignity. 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. | 0.919029 | Disordered | 0.983887 | Binding | 0.307 | 0.900 | 0.750 | -7.333 | In-Between | 0.370 | Ambiguous | Likely Benign | 0.138 | Likely Benign | 0.0949 | 0.5536 | -2.61 | Deleterious | 0.898 | Possibly Damaging | 0.477 | Possibly Damaging | 3.81 | Benign | 0.00 | Affected | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||
| c.3236G>A | S1079N 2D AIThe SynGAP1 missense variant S1079N 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), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority of the high‑accuracy tools) 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 predictions 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 | 0.919029 | Disordered | 0.983887 | Binding | 0.307 | 0.900 | 0.750 | -4.989 | Likely Benign | 0.505 | Ambiguous | Likely Benign | 0.026 | Likely Benign | 0.1225 | 0.4657 | -0.97 | Neutral | 0.001 | Benign | 0.001 | Benign | 3.93 | Benign | 0.00 | Affected | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||
| c.3236G>C | S1079T 2D AIThe SynGAP1 missense variant S1079T is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence strongly suggests the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for S1079T. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.983887 | Binding | 0.307 | 0.900 | 0.750 | -3.225 | Likely Benign | 0.163 | Likely Benign | Likely Benign | 0.023 | Likely Benign | 0.1283 | 0.5920 | -1.28 | Neutral | 0.001 | Benign | 0.003 | Benign | 3.91 | Benign | 0.00 | Affected | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3236G>T | S1079I 2D AIThe SynGAP1 missense variant S1079I 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 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 (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 evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.919029 | Disordered | 0.983887 | Binding | 0.307 | 0.900 | 0.750 | -4.732 | Likely Benign | 0.688 | Likely Pathogenic | Likely Benign | 0.093 | Likely Benign | 0.0921 | 0.4775 | -2.86 | Deleterious | 0.078 | Benign | 0.025 | Benign | 3.83 | Benign | 0.00 | Affected | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||
| c.3237C>A | S1079R 2D AIThe SynGAP1 missense variant S1079R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (gnomAD ID 6‑33443789‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Those that predict a pathogenic effect are SIFT and AlphaMissense‑Default. AlphaMissense‑Optimized is inconclusive. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments are limited: AlphaMissense‑Optimized remains uncertain, SGM‑Consensus is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.983887 | Binding | 0.307 | 0.900 | 0.750 | Uncertain | 1 | 6-33443789-C-A | 4 | 2.51e-6 | -4.579 | Likely Benign | 0.955 | Likely Pathogenic | Ambiguous | 0.123 | Likely Benign | 0.0811 | 0.4028 | -1.81 | Neutral | 0.177 | Benign | 0.075 | Benign | 3.86 | Benign | 0.00 | Affected | 3.77 | 5 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||
| c.3237C>G | S1079R 2D AIThe SynGAP1 missense variant S1079R is listed in ClinVar (ID 1047537.0) 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, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and no Foldetta (FoldX‑MD/Rosetta stability) result is available. High‑accuracy assessments therefore show a benign consensus (SGM‑Consensus) with one uncertain AlphaMissense‑Optimized prediction and no destabilizing Foldetta evidence. Overall, the majority of predictions support 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 | 0.919029 | Disordered | 0.983887 | Binding | 0.307 | 0.900 | 0.750 | Benign | 1 | -4.579 | Likely Benign | 0.955 | Likely Pathogenic | Ambiguous | 0.124 | Likely Benign | 0.0811 | 0.4028 | -1.81 | Neutral | 0.177 | Benign | 0.075 | Benign | 3.86 | Benign | 0.00 | Affected | 3.77 | 5 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||
| c.3238G>A | A1080T 2D AIThe SynGAP1 missense variant A1080T (ClinVar ID 1473274.0) is listed as “Uncertain” in ClinVar and is present in gnomAD (ID 6‑33443790‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized 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. Overall, the computational evidence strongly suggests the variant is most likely benign, which 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 | 0.912647 | Disordered | 0.981457 | Binding | 0.303 | 0.900 | 0.750 | Conflicting | 2 | 6-33443790-G-A | 17 | 1.06e-5 | -3.928 | Likely Benign | 0.133 | Likely Benign | Likely Benign | 0.144 | Likely Benign | 0.1564 | 0.7103 | -0.19 | Neutral | 0.253 | Benign | 0.042 | Benign | 4.10 | Benign | 0.60 | Tolerated | 3.77 | 5 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||
| c.3238G>C | A1080P 2D AIThe SynGAP1 missense variant A1080P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for A1080P, 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 | 0.912647 | Disordered | 0.981457 | Binding | 0.303 | 0.900 | 0.750 | -2.429 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.170 | Likely Benign | 0.1884 | 0.5324 | -1.15 | Neutral | 0.996 | Probably Damaging | 0.833 | Possibly Damaging | 3.96 | Benign | 0.02 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||
| c.3238G>T | A1080S 2D AIThe SynGAP1 missense variant A1080S is listed in ClinVar (ID 2703014.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443790‑G‑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 SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign effect, and this conclusion does not contradict the ClinVar designation, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.981457 | Binding | 0.303 | 0.900 | 0.750 | Uncertain | 1 | 6-33443790-G-T | 1 | 6.26e-7 | -3.277 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.103 | Likely Benign | 0.2498 | 0.5915 | 0.01 | Neutral | 0.702 | Possibly Damaging | 0.346 | Benign | 4.16 | Benign | 0.08 | Tolerated | 3.77 | 5 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||
| c.3239C>A | A1080E 2D  AIThe SynGAP1 missense variant A1080E is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33443791‑C‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM. Tools that predict a pathogenic outcome are 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. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. High‑accuracy evidence therefore points to a benign or uncertain impact: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus is benign, and Foldetta data are missing. Overall, the balance of predictions leans toward 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 | 0.912647 | Disordered | 0.981457 | Binding | 0.303 | 0.900 | 0.750 | 6-33443791-C-A | -3.672 | Likely Benign | 0.855 | Likely Pathogenic | Ambiguous | 0.090 | Likely Benign | 0.1394 | 0.2437 | -1.50 | Neutral | 0.901 | Possibly Damaging | 0.540 | Possibly Damaging | 4.00 | Benign | 0.01 | Affected | 3.77 | 5 | -1 | 0 | -5.3 | 58.04 | ||||||||||||||||||||||||||||||||
| c.3239C>G | A1080G 2D AIThe SynGAP1 missense variant A1080G 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 Likely Benign. Foldetta results are unavailable. Overall, the consensus of the majority of prediction algorithms and the high‑accuracy tools points to a benign effect for A1080G, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.981457 | Binding | 0.303 | 0.900 | 0.750 | -3.515 | Likely Benign | 0.213 | Likely Benign | Likely Benign | 0.089 | Likely Benign | 0.2153 | 0.4958 | -0.80 | Neutral | 0.901 | Possibly Damaging | 0.355 | Benign | 4.00 | Benign | 0.04 | Affected | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3239C>T | A1080V 2D AIThe SynGAP1 missense variant A1080V is listed in gnomAD (ID 6‑33443791‑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 outcome 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; no Foldetta stability data are available. Overall, the majority of evidence points to a benign effect, 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 | 0.912647 | Disordered | 0.981457 | Binding | 0.303 | 0.900 | 0.750 | 6-33443791-C-T | -4.087 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.124 | Likely Benign | 0.1298 | 0.6056 | -1.06 | Neutral | 0.481 | Possibly Damaging | 0.144 | Benign | 3.99 | Benign | 0.04 | Affected | 3.77 | 5 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||
| c.3241G>A | A1081T 2D AIThe SynGAP1 missense variant A1081T 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 “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 classification, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.979759 | Binding | 0.288 | 0.895 | 0.750 | -3.887 | Likely Benign | 0.129 | Likely Benign | Likely Benign | 0.078 | Likely Benign | 0.1567 | 0.6112 | -1.07 | Neutral | 0.440 | Benign | 0.184 | Benign | 4.01 | Benign | 0.15 | Tolerated | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.3241G>C | A1081P 2D AIThe SynGAP1 missense variant A1081P 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 | 0.874069 | Disordered | 0.979759 | Binding | 0.288 | 0.895 | 0.750 | -2.967 | Likely Benign | 0.178 | Likely Benign | Likely Benign | 0.051 | Likely Benign | 0.1878 | 0.4540 | -1.07 | Neutral | 0.005 | Benign | 0.010 | Benign | 4.00 | Benign | 0.14 | Tolerated | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||
| c.3241G>T | A1081S 2D AIThe SynGAP1 missense variant A1081S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Consequently, the variant is most likely benign, 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 | 0.874069 | Disordered | 0.979759 | Binding | 0.288 | 0.895 | 0.750 | -3.536 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.078 | Likely Benign | 0.2268 | 0.4915 | -0.29 | Neutral | 0.021 | Benign | 0.031 | Benign | 4.02 | Benign | 0.23 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||
| c.3242C>A | A1081D 2D AIThe SynGAP1 missense variant A1081D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized result is Uncertain, and the Foldetta protein‑folding stability assessment is unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is 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 | 0.874069 | Disordered | 0.979759 | Binding | 0.288 | 0.895 | 0.750 | -4.603 | Likely Benign | 0.892 | Likely Pathogenic | Ambiguous | 0.095 | Likely Benign | 0.2069 | 0.2600 | -1.84 | Neutral | 0.611 | Possibly Damaging | 0.404 | Benign | 3.97 | Benign | 0.04 | Affected | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||
| c.3242C>G | A1081G 2D AIThe missense variant A1081G in SynGAP1 has no entry in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as likely benign. Foldetta results are unavailable. Overall, the computational evidence strongly supports a benign classification, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.979759 | Binding | 0.288 | 0.895 | 0.750 | -3.174 | Likely Benign | 0.191 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.1751 | 0.4348 | -1.43 | Neutral | 0.393 | Benign | 0.184 | Benign | 3.99 | Benign | 0.23 | Tolerated | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3242C>T | A1081V 2D AIThe SynGAP1 missense variant A1081V is reported in gnomAD (ID 6‑33443794‑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, creating a single discordant signal. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments 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 A1081V 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 | 0.874069 | Disordered | 0.979759 | Binding | 0.288 | 0.895 | 0.750 | 6-33443794-C-T | -3.973 | Likely Benign | 0.172 | Likely Benign | Likely Benign | 0.036 | Likely Benign | 0.1353 | 0.4884 | -1.32 | Neutral | 0.611 | Possibly Damaging | 0.399 | Benign | 4.04 | Benign | 0.37 | Tolerated | 3.77 | 5 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||
| c.3244C>A | Q1082K 2D AIThe SynGAP1 missense variant Q1082K 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 score benign, and AlphaMissense‑Optimized also predicts benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. No tools predict pathogenicity, and AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is Likely Benign, while Foldetta results are unavailable. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.819762 | Disordered | 0.979325 | Binding | 0.347 | 0.896 | 0.875 | -4.488 | Likely Benign | 0.460 | Ambiguous | Likely Benign | 0.087 | Likely Benign | 0.2008 | 0.4972 | -1.13 | Neutral | 0.224 | Benign | 0.058 | Benign | 4.19 | Benign | 0.12 | Tolerated | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||
| c.3244C>G | Q1082E 2D AIThe SynGAP1 missense variant Q1082E is reported in gnomAD (ID 6‑33443796‑C‑G) and has no ClinVar entry. All evaluated in‑silico predictors classify it as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Based on the unanimous benign predictions and lack of ClinVar pathogenic annotation, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.819762 | Disordered | 0.979325 | Binding | 0.347 | 0.896 | 0.875 | 6-33443796-C-G | -3.437 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.090 | Likely Benign | 0.1485 | 0.3227 | -0.87 | Neutral | 0.112 | Benign | 0.026 | Benign | 4.19 | Benign | 0.07 | Tolerated | 3.77 | 5 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||
| c.3245A>C | Q1082P 2D AIThe SynGAP1 missense variant Q1082P is not reported 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 | 0.819762 | Disordered | 0.979325 | Binding | 0.347 | 0.896 | 0.875 | -2.141 | Likely Benign | 0.064 | Likely Benign | Likely Benign | 0.287 | Likely Benign | 0.2121 | 0.6144 | -0.71 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.16 | Benign | 0.05 | Affected | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||
| c.3245A>G | Q1082R 2D AIThe SynGAP1 missense variant Q1082R 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, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.819762 | Disordered | 0.979325 | Binding | 0.347 | 0.896 | 0.875 | -3.584 | Likely Benign | 0.418 | Ambiguous | Likely Benign | 0.076 | Likely Benign | 0.1590 | 0.3014 | -0.96 | Neutral | 0.224 | Benign | 0.058 | Benign | 4.14 | Benign | 0.10 | Tolerated | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||
| c.3245A>T | Q1082L 2D AIThe SynGAP1 missense variant Q1082L 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 | 0.819762 | Disordered | 0.979325 | Binding | 0.347 | 0.896 | 0.875 | -3.284 | Likely Benign | 0.171 | Likely Benign | Likely Benign | 0.097 | Likely Benign | 0.0979 | 0.6824 | -1.30 | Neutral | 0.224 | Benign | 0.058 | Benign | 4.12 | Benign | 1.00 | Tolerated | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||
| c.3246G>C | Q1082H 2D AIThe SynGAP1 missense variant Q1082H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.819762 | Disordered | 0.979325 | Binding | 0.347 | 0.896 | 0.875 | -4.307 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.092 | Likely Benign | 0.1580 | 0.4779 | -1.27 | Neutral | 0.002 | Benign | 0.002 | Benign | 4.11 | Benign | 0.03 | Affected | 3.77 | 5 | 0 | 3 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||
| c.3246G>T | Q1082H 2D AIThe SynGAP1 missense variant Q1082H is listed in gnomAD (ID 6‑33443798‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated outcomes, while only SIFT predicts a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.819762 | Disordered | 0.979325 | Binding | 0.347 | 0.896 | 0.875 | 6-33443798-G-T | -4.307 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.092 | Likely Benign | 0.1580 | 0.4779 | -1.27 | Neutral | 0.002 | Benign | 0.002 | Benign | 4.11 | Benign | 0.03 | Affected | 3.77 | 5 | 0 | 3 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||
| c.3247A>C | K1083Q 2D AIThe SynGAP1 missense variant K1083Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 HumDiv and HumVar. AlphaMissense‑Default is 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 outcome: 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 from both general and high‑accuracy tools points to a benign impact for K1083Q, 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 | 0.978906 | Binding | 0.302 | 0.893 | 1.000 | -2.214 | Likely Benign | 0.390 | Ambiguous | Likely Benign | 0.099 | Likely Benign | 0.4821 | 0.1647 | -0.50 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 4.06 | Benign | 0.37 | Tolerated | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||
| c.3247A>G | K1083E 2D AIThe SynGAP1 missense variant K1083E is not reported 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 (combining FoldX‑MD and Rosetta outputs) is not available for this variant. 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 | 0.837511 | Disordered | 0.978906 | Binding | 0.302 | 0.893 | 1.000 | -3.538 | Likely Benign | 0.864 | Likely Pathogenic | Ambiguous | 0.133 | Likely Benign | 0.4135 | 0.1717 | -0.78 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 4.09 | Benign | 0.27 | Tolerated | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||||
| c.3248A>C | K1083T 2D AIThe SynGAP1 missense variant K1083T is reported in gnomAD (ID 6‑33443800‑A‑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 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, 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 is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.978906 | Binding | 0.302 | 0.893 | 1.000 | 6-33443800-A-C | 2 | 1.26e-6 | -2.870 | Likely Benign | 0.690 | Likely Pathogenic | Likely Benign | 0.233 | Likely Benign | 0.2192 | 0.4150 | -0.76 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 4.05 | Benign | 0.31 | Tolerated | 3.77 | 5 | -1 | 0 | 3.2 | -27.07 | ||||||||||||||||||||||||||||||
| c.3248A>G | K1083R 2D AIThe SynGAP1 missense variant K1083R is not reported 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 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 | 0.837511 | Disordered | 0.978906 | Binding | 0.302 | 0.893 | 1.000 | -2.212 | Likely Benign | 0.132 | Likely Benign | Likely Benign | 0.119 | Likely Benign | 0.5053 | 0.1903 | Weaken | -0.53 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 4.06 | Benign | 0.84 | Tolerated | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||||||
| c.3248A>T | K1083I 2D  AIThe SynGAP1 missense variant K1083I is not reported 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 the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.978906 | Binding | 0.302 | 0.893 | 1.000 | -3.207 | Likely Benign | 0.836 | Likely Pathogenic | Ambiguous | 0.239 | Likely Benign | 0.1394 | 0.3978 | -1.65 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 4.02 | Benign | 0.30 | Tolerated | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||||||||||||
| c.3249A>C | K1083N 2D AIThe SynGAP1 missense variant K1083N is not reported 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 | 0.837511 | Disordered | 0.978906 | Binding | 0.302 | 0.893 | 1.000 | -4.088 | Likely Benign | 0.873 | Likely Pathogenic | Ambiguous | 0.053 | Likely Benign | 0.3939 | 0.2234 | -0.83 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 4.04 | Benign | 0.21 | Tolerated | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||
| c.3249A>T | K1083N 2D AIThe SynGAP1 missense variant K1083N is not reported 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 | 0.837511 | Disordered | 0.978906 | Binding | 0.302 | 0.893 | 1.000 | -4.088 | Likely Benign | 0.873 | Likely Pathogenic | Ambiguous | 0.053 | Likely Benign | 0.3939 | 0.2234 | -0.83 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 4.04 | Benign | 0.21 | Tolerated | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||
| c.3250C>A | P1084T 2D AIThe SynGAP1 missense variant P1084T is reported in ClinVar as “Not submitted” and is present in gnomAD (ID 6‑33443802‑C‑A). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it as pathogenic, but this is the sole discordant call. 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 results are not available. Overall, the preponderance of evidence indicates the variant is most likely benign, 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 | 0.979020 | Binding | 0.348 | 0.889 | 1.000 | 6-33443802-C-A | -4.665 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.127 | Likely Benign | 0.1546 | 0.6793 | -2.14 | Neutral | 0.025 | Benign | 0.012 | Benign | 4.11 | Benign | 0.01 | Affected | 3.77 | 5 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||
| c.3250C>G | P1084A 2D AIThe SynGAP1 missense variant P1084A is listed in ClinVar (ID 2827308.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which itself is “Likely Benign”). In contrast, PROVEAN and polyPhen‑2 HumDiv predict a pathogenic impact. 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 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 | 0.842060 | Disordered | 0.979020 | Binding | 0.348 | 0.889 | 1.000 | Uncertain | 1 | -3.928 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.114 | Likely Benign | 0.3164 | 0.5784 | -2.54 | Deleterious | 0.649 | Possibly Damaging | 0.157 | Benign | 4.05 | Benign | 0.35 | Tolerated | 3.77 | 5 | -1 | 1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||
| c.3250C>T | P1084S 2D AIThe SynGAP1 missense variant P1084S is reported in gnomAD (variant ID 6‑33443802‑C‑T) 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 benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic 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 is benign, and the SGM‑Consensus 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, 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 | 0.842060 | Disordered | 0.979020 | Binding | 0.348 | 0.889 | 1.000 | 6-33443802-C-T | 1 | 6.31e-7 | -3.987 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.086 | Likely Benign | 0.3102 | 0.6215 | -2.24 | Neutral | 0.481 | Possibly Damaging | 0.157 | Benign | 4.03 | Benign | 0.03 | Affected | 3.77 | 5 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||
| c.3251C>A | P1084H 2D AIThe SynGAP1 missense variant P1084H is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443803‑C‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which reports “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 unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the ClinVar designation of uncertainty rather than a definitive pathogenic claim. Thus, the variant is most likely benign, and its prediction profile does not contradict the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.979020 | Binding | 0.348 | 0.889 | 1.000 | Uncertain | 1 | 6-33443803-C-A | 1 | 6.31e-7 | -4.125 | Likely Benign | 0.323 | Likely Benign | Likely Benign | 0.134 | Likely Benign | 0.1751 | 0.5523 | -3.16 | Deleterious | 0.997 | Probably Damaging | 0.840 | Possibly Damaging | 3.96 | Benign | 0.00 | Affected | 3.77 | 5 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||||
| c.3251C>G | P1084R 2D AIThe SynGAP1 missense variant P1084R is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443803‑C‑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, 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 favors a benign outcome (2 benign vs 1 pathogenic vote). Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for P1084R, and this conclusion does not contradict the ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.842060 | Disordered | 0.979020 | Binding | 0.348 | 0.889 | 1.000 | 6-33443803-C-G | 4 | 2.52e-6 | -4.171 | Likely Benign | 0.562 | Ambiguous | Likely Benign | 0.153 | Likely Benign | 0.1370 | 0.4153 | -2.87 | Deleterious | 0.970 | Probably Damaging | 0.637 | Possibly Damaging | 3.99 | Benign | 0.01 | Affected | 3.77 | 5 | -2 | 0 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||
| c.3251C>T | P1084L 2D AIThe SynGAP1 missense variant P1084L is reported in gnomAD (ID 6‑33443803‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar; 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 unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.979020 | Binding | 0.348 | 0.889 | 1.000 | 6-33443803-C-T | 1 | 6.31e-7 | -4.547 | Likely Benign | 0.175 | Likely Benign | Likely Benign | 0.124 | Likely Benign | 0.2218 | 0.6470 | -3.33 | Deleterious | 0.649 | Possibly Damaging | 0.157 | Benign | 4.00 | Benign | 0.01 | Affected | 3.77 | 5 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||
| c.3253C>G | R1085G 2D AIThe SynGAP1 missense variant R1085G is reported in gnomAD (ID 6‑33443805‑C‑G) but has no ClinVar entry. 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) that aggregates 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 classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.978838 | Binding | 0.270 | 0.888 | 1.000 | 6-33443805-C-G | -4.225 | Likely Benign | 0.846 | Likely Pathogenic | Ambiguous | 0.179 | Likely Benign | 0.3310 | 0.3693 | -2.79 | Deleterious | 0.997 | Probably Damaging | 0.993 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | 3.77 | 5 | -2 | -3 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||
| c.3253C>T | R1085W 2D AISynGAP1 missense variant R1085W is listed in ClinVar as Uncertain and is present in gnomAD (ID 6‑33443805‑C‑T). Prediction tools that classify the variant as benign include REVEL, ESM1b, and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is Uncertain, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta stability assessment are unavailable. Overall, the majority of available predictions (five pathogenic vs. three benign) indicate a pathogenic effect. Thus, the variant is most likely pathogenic, which contradicts the ClinVar designation of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.978838 | Binding | 0.270 | 0.888 | 1.000 | Uncertain | 1 | 6-33443805-C-T | 2 | 1.26e-6 | -6.339 | Likely Benign | 0.821 | Likely Pathogenic | Ambiguous | 0.202 | Likely Benign | 0.1238 | 0.3700 | -3.15 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.70 | Benign | 0.00 | Affected | 3.77 | 5 | -3 | 2 | 3.6 | 30.03 | |||||||||||||||||||||||||||||
| c.3254G>A | R1085Q 2D AIThe SynGAP1 missense variant R1085Q (ClinVar ID 1729448.0) is listed as ClinVar status Uncertain and is present in gnomAD (6‑33443806‑G‑A). Functional prediction tools show a split opinion: benign predictions come from REVEL, PROVEAN, ESM1b, and FATHMM, whereas pathogenic predictions are reported by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also favors benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points 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 | 0.852992 | Disordered | 0.978838 | Binding | 0.270 | 0.888 | 1.000 | Uncertain | 1 | 6-33443806-G-A | 5 | 3.16e-6 | -3.843 | Likely Benign | 0.589 | Likely Pathogenic | Likely Benign | 0.224 | Likely Benign | 0.2962 | 0.2751 | -1.43 | Neutral | 0.998 | Probably Damaging | 0.988 | Probably Damaging | 2.73 | Benign | 0.02 | Affected | 3.77 | 5 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||
| c.3254G>C | R1085P 2D AIThe SynGAP1 missense variant R1085P is not 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 agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, 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 (2 vs 2). Foldetta results are unavailable. Overall, the majority of standard predictors (five pathogenic vs. four benign) lean toward a pathogenic interpretation, but the high‑accuracy AlphaMissense‑Optimized prediction and the inconclusive SGM Consensus temper this view. 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. | 0.852992 | Disordered | 0.978838 | Binding | 0.270 | 0.888 | 1.000 | -2.527 | Likely Benign | 0.759 | Likely Pathogenic | Likely Benign | 0.260 | Likely Benign | 0.1988 | 0.4524 | -2.55 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.71 | Benign | 0.01 | Affected | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||
| c.3254G>T | R1085L 2D AIThe SynGAP1 missense variant R1085L is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for R1085L, 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 | 0.852992 | Disordered | 0.978838 | Binding | 0.270 | 0.888 | 1.000 | -3.674 | Likely Benign | 0.734 | Likely Pathogenic | Likely Benign | 0.243 | Likely Benign | 0.1909 | 0.4568 | -2.38 | Neutral | 0.997 | Probably Damaging | 0.993 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||
| c.3256C>A | P1086T 2D AIThe SynGAP1 missense variant P1086T is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443808‑C‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic impact. The variant is most likely pathogenic based on the available computational evidence, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.849326 | Disordered | 0.977190 | Binding | 0.393 | 0.885 | 1.000 | 6-33443808-C-A | -4.181 | Likely Benign | 0.568 | Likely Pathogenic | Likely Benign | 0.229 | Likely Benign | 0.1343 | 0.5848 | -2.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.75 | Benign | 0.00 | Affected | 3.77 | 5 | -1 | 0 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||
| c.3256C>G | P1086A 2D AIThe SynGAP1 missense variant P1086A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors benign, and Foldetta data are unavailable. Taken together, the balance of evidence points to a benign effect for P1086A. This conclusion does not conflict with the ClinVar status, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.849326 | Disordered | 0.977190 | Binding | 0.393 | 0.885 | 1.000 | -4.317 | Likely Benign | 0.372 | Ambiguous | Likely Benign | 0.206 | Likely Benign | 0.3084 | 0.4463 | -2.98 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.78 | Benign | 0.00 | Affected | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||
| c.3256C>T | P1086S 2D AIThe SynGAP1 missense variant P1086S is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443808‑C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.849326 | Disordered | 0.977190 | Binding | 0.393 | 0.885 | 1.000 | 6-33443808-C-T | -3.165 | Likely Benign | 0.604 | Likely Pathogenic | Likely Benign | 0.212 | Likely Benign | 0.3067 | 0.4894 | -3.04 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.78 | Benign | 0.00 | Affected | 3.77 | 5 | -1 | 1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||
| c.3257C>A | P1086Q 2D AIThe SynGAP1 missense variant P1086Q is not reported in ClinVar (ClinVar status: None) but is present in gnomAD (ID 6‑33443809‑C‑A). 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 (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 predictions (five pathogenic vs. four benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.849326 | Disordered | 0.977190 | Binding | 0.393 | 0.885 | 1.000 | 6-33443809-C-A | -4.668 | Likely Benign | 0.652 | Likely Pathogenic | Likely Benign | 0.185 | Likely Benign | 0.1285 | 0.4784 | -2.92 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.77 | Benign | 0.00 | Affected | 3.77 | 5 | -1 | 0 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||
| c.3257C>G | P1086R 2D AIThe SynGAP1 missense variant P1086R is not 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, 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, more tools (five) predict pathogenicity than benign (three), and the high‑accuracy consensus is inconclusive. Therefore, the variant is most likely pathogenic based on the current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.849326 | Disordered | 0.977190 | Binding | 0.393 | 0.885 | 1.000 | -5.190 | Likely Benign | 0.848 | Likely Pathogenic | Ambiguous | 0.205 | Likely Benign | 0.1319 | 0.3551 | -3.42 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.86 | Benign | 0.00 | Affected | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||
| c.3257C>T | P1086L 2D AIThe SynGAP1 missense variant P1086L is not reported in ClinVar (ClinVar status: not present) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which simply indicates the variant has not yet been reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.849326 | Disordered | 0.977190 | Binding | 0.393 | 0.885 | 1.000 | -4.694 | Likely Benign | 0.607 | Likely Pathogenic | Likely Benign | 0.166 | Likely Benign | 0.2055 | 0.6326 | -3.57 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.73 | Benign | 0.00 | Affected | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||
| c.3259T>A | S1087T 2D AIThe SynGAP1 missense variant S1087T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to the variant being most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | -4.455 | Likely Benign | 0.128 | Likely Benign | Likely Benign | 0.044 | Likely Benign | 0.1333 | 0.6503 | -1.01 | Neutral | 0.790 | Possibly Damaging | 0.266 | Benign | 2.66 | Benign | 0.25 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3259T>C | S1087P 2D AIThe SynGAP1 missense variant S1087P is reported in gnomAD (ID 6‑33443811‑T‑C) and has no ClinVar entry. All available in silico predictors classify it as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Based on the unanimous benign predictions and lack of ClinVar pathogenic annotation, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | 6-33443811-T-C | 1 | 6.34e-7 | -2.946 | Likely Benign | 0.133 | Likely Benign | Likely Benign | 0.135 | Likely Benign | 0.1803 | 0.5700 | -1.92 | Neutral | 0.006 | Benign | 0.008 | Benign | 2.56 | Benign | 0.12 | Tolerated | 3.77 | 5 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||
| c.3259T>G | S1087A 2D AIThe SynGAP1 missense variant S1087A is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Based on the consensus of all available predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | -3.649 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.057 | Likely Benign | 0.4464 | 0.5405 | -1.03 | Neutral | 0.447 | Benign | 0.139 | Benign | 2.64 | Benign | 0.34 | Tolerated | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||
| c.3260C>A | S1087Y 2D AIThe SynGAP1 missense variant S1087Y is catalogued in gnomAD (ID 6‑33443812‑C‑A) and has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as benign, and no Foldetta stability result is available. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | 6-33443812-C-A | -4.194 | Likely Benign | 0.587 | Likely Pathogenic | Likely Benign | 0.107 | Likely Benign | 0.0671 | 0.5845 | -2.41 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.56 | Benign | 0.02 | Affected | 3.77 | 5 | -2 | -3 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||
| c.3260C>G | S1087C 2D AIThe SynGAP1 missense variant S1087C is catalogued in gnomAD (ID 6‑33443812‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact, while ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, 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 | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | 6-33443812-C-G | 1 | 6.34e-7 | -7.369 | In-Between | 0.194 | Likely Benign | Likely Benign | 0.083 | Likely Benign | 0.0979 | 0.6118 | -2.22 | Neutral | 0.997 | Probably Damaging | 0.840 | Possibly Damaging | 2.55 | Benign | 0.05 | Affected | 3.77 | 5 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||
| c.3260C>T | S1087F 2D AISynGAP1 missense variant S1087F is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of reliable predictors and the two high‑accuracy tools suggest a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | Uncertain | 1 | -3.843 | Likely Benign | 0.497 | Ambiguous | Likely Benign | 0.105 | Likely Benign | 0.0645 | 0.6029 | -2.75 | Deleterious | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.56 | Benign | 0.03 | Affected | 3.77 | 5 | -2 | -3 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||
| c.3262A>C | S1088R 2D AIThe SynGAP1 missense variant S1088R is not reported in ClinVar and has no gnomAD entry. 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves as Likely Benign, reflecting the majority of benign calls. High‑accuracy assessments further support this: AlphaMissense‑Optimized labels the variant as Pathogenic, but the SGM‑Consensus (majority vote) remains Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence leans toward a benign effect; this conclusion does not conflict with ClinVar, which contains no entry for S1088R. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | -4.588 | Likely Benign | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.209 | Likely Benign | 0.1190 | 0.4502 | -1.96 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | 3.77 | 5 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||
| c.3262A>G | S1088G 2D AIThe SynGAP1 missense variant S1088G is listed in ClinVar (ID 2742833.0) with an “Uncertain” clinical significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as Likely Benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this is consistent with the ClinVar “Uncertain” status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | Uncertain | 1 | -5.034 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.163 | Likely Benign | 0.2541 | 0.5170 | -1.83 | Neutral | 0.979 | Probably Damaging | 0.973 | Probably Damaging | 2.63 | Benign | 0.03 | Affected | 3.77 | 5 | 0 | 1 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||
| c.3262A>T | S1088C 2D AIThe SynGAP1 missense variant S1088C is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and SIFT. 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 contains two benign and two uncertain calls, and Foldetta data 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. | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | -7.532 | In-Between | 0.547 | Ambiguous | Likely Benign | 0.212 | Likely Benign | 0.1571 | 0.6166 | -2.33 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.59 | Benign | 0.01 | Affected | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||
| c.3263G>A | S1088N 2D AIThe SynGAP1 missense variant S1088N has no ClinVar record and is not listed 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. The high‑accuracy AlphaMissense‑Optimized score is uncertain, while the SGM‑Consensus (derived from the four high‑accuracy tools) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence leans toward a benign impact, and this assessment does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | -5.227 | Likely Benign | 0.791 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | 0.1940 | 0.5197 | -1.25 | Neutral | 0.991 | Probably Damaging | 0.982 | Probably Damaging | 2.69 | Benign | 0.02 | Affected | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||
| c.3263G>C | S1088T 2D AIThe SynGAP1 missense variant S1088T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | -4.569 | Likely Benign | 0.295 | Likely Benign | Likely Benign | 0.175 | Likely Benign | 0.2048 | 0.6514 | -1.32 | Neutral | 0.979 | Probably Damaging | 0.973 | Probably Damaging | 2.71 | Benign | 0.04 | Affected | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3263G>T | S1088I 2D AIThe SynGAP1 missense variant S1088I is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33443815‑G‑T). 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 is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. AlphaMissense‑Optimized is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the balance of evidence, the variant is most likely benign; this assessment does not contradict ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | 6-33443815-G-T | -4.893 | Likely Benign | 0.891 | Likely Pathogenic | Ambiguous | 0.288 | Likely Benign | 0.1322 | 0.5712 | -2.05 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.62 | Benign | 0.01 | Affected | 3.77 | 5 | -2 | -1 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||
| c.3264C>A | S1088R 2D AIThe SynGAP1 missense variant S1088R is not reported in ClinVar and is present in gnomAD (ID 6‑33443816‑C‑A). Prediction tools that classify the variant as benign include REVEL, PROVEAN, ESM1b, and FATHMM, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized predict it to be pathogenic. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains benign; Foldetta results are unavailable. Overall, the balance of evidence—five pathogenic versus four benign predictions—suggests the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for S1088R. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | 6-33443816-C-A | -4.588 | Likely Benign | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.181 | Likely Benign | 0.1190 | 0.4502 | -1.96 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | 3.77 | 5 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||
| c.3264C>G | S1088R 2D AIThe SynGAP1 missense variant S1088R has no ClinVar record and is not listed in 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, whereas the SGM‑Consensus remains Benign; Foldetta results are unavailable. Overall, the balance of evidence slightly favors a pathogenic interpretation, with 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 | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | -4.588 | Likely Benign | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.181 | Likely Benign | 0.1190 | 0.4502 | -1.96 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | 3.77 | 5 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||
| c.3265G>A | G1089R 2D AIThe SynGAP1 missense variant G1089R is catalogued in gnomAD (ID 6‑33443817‑G‑A) but has no ClinVar entry. Functional prediction tools split in a 6‑to‑3 ratio: benign calls come from REVEL, polyPhen‑2 HumVar, and ESM1b, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. AlphaMissense‑Optimized yields an Uncertain result, and no Foldetta stability assessment is available. Overall, the majority of high‑confidence predictors lean toward pathogenicity, and this assessment does not conflict with ClinVar status, which is currently unreported. Thus, the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.891961 | Disordered | 0.976771 | Binding | 0.366 | 0.890 | 1.000 | 6-33443817-G-A | 1 | 6.35e-7 | -4.757 | Likely Benign | 0.897 | Likely Pathogenic | Ambiguous | 0.222 | Likely Benign | 0.0934 | 0.4415 | -3.13 | Deleterious | 0.896 | Possibly Damaging | 0.325 | Benign | 2.42 | Pathogenic | 0.01 | Affected | 3.77 | 5 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.3265G>C | G1089R 2D AIThe SynGAP1 missense variant G1089R is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 HumVar, and ESM1b, while pathogenic calls are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, FATHMM, and AlphaMissense‑Default. Grouping by consensus, seven tools predict pathogenicity and three predict benign, giving a net pathogenic signal. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized is uncertain, but the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic. Foldetta stability analysis is unavailable. Overall, the evidence points to the variant being most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.891961 | Disordered | 0.976771 | Binding | 0.366 | 0.890 | 1.000 | -4.757 | Likely Benign | 0.897 | Likely Pathogenic | Ambiguous | 0.228 | Likely Benign | 0.0934 | 0.4415 | -3.13 | Deleterious | 0.896 | Possibly Damaging | 0.325 | Benign | 2.42 | Pathogenic | 0.01 | Affected | 3.77 | 5 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||
| c.3265G>T | G1089W 2D AIThe SynGAP1 missense variant G1089W is not reported in ClinVar and has no allele in gnomAD. Functional prediction tools show a split: benign calls come from REVEL and ESM1b, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the consensus 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 Foldetta stability data. Overall, the majority of evidence points to a deleterious effect, so the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.891961 | Disordered | 0.976771 | Binding | 0.366 | 0.890 | 1.000 | -6.561 | Likely Benign | 0.863 | Likely Pathogenic | Ambiguous | 0.236 | Likely Benign | 0.0840 | 0.4610 | -3.45 | Deleterious | 1.000 | Probably Damaging | 0.988 | Probably Damaging | 2.37 | Pathogenic | 0.00 | Affected | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||
| c.3266G>A | G1089E 2D AIThe SynGAP1 missense variant G1089E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas a majority (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 of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a 2‑vs‑2 split, and Foldetta results are unavailable. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.891961 | Disordered | 0.976771 | Binding | 0.366 | 0.890 | 1.000 | -3.233 | Likely Benign | 0.926 | Likely Pathogenic | Ambiguous | 0.170 | Likely Benign | 0.1460 | 0.4387 | -2.85 | Deleterious | 0.992 | Probably Damaging | 0.834 | Possibly Damaging | 2.59 | Benign | 0.01 | Affected | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||
| c.3266G>C | G1089A 2D AIThe SynGAP1 missense variant G1089A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation—there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.976771 | Binding | 0.366 | 0.890 | 1.000 | -2.864 | Likely Benign | 0.224 | Likely Benign | Likely Benign | 0.142 | Likely Benign | 0.3475 | 0.5331 | -1.73 | Neutral | 0.186 | Benign | 0.055 | Benign | 2.45 | Pathogenic | 0.02 | Affected | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3266G>T | G1089V 2D AIThe SynGAP1 missense variant G1089V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact for G1089V. 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. | 0.891961 | Disordered | 0.976771 | Binding | 0.366 | 0.890 | 1.000 | -4.809 | Likely Benign | 0.527 | Ambiguous | Likely Benign | 0.182 | Likely Benign | 0.1326 | 0.4413 | -2.81 | Deleterious | 0.984 | Probably Damaging | 0.722 | Possibly Damaging | 2.40 | Pathogenic | 0.00 | Affected | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||
| c.3268A>C | N1090H 2D AIThe SynGAP1 missense variant N1090H 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 remains 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 | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | -3.744 | Likely Benign | 0.447 | Ambiguous | Likely Benign | 0.094 | Likely Benign | 0.1604 | 0.7550 | -1.42 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.67 | Benign | 0.10 | Tolerated | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||
| c.3268A>G | N1090D 2D AIThe SynGAP1 missense variant N1090D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and no Foldetta stability data is available. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | -3.354 | Likely Benign | 0.827 | Likely Pathogenic | Ambiguous | 0.066 | Likely Benign | 0.1994 | 0.4375 | -1.39 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.70 | Benign | 0.47 | Tolerated | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||
| c.3268A>T | N1090Y 2D AIThe SynGAP1 missense variant N1090Y is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, 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 the variant, 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 | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | -4.744 | Likely Benign | 0.651 | Likely Pathogenic | Likely Benign | 0.139 | Likely Benign | 0.0661 | 0.5998 | -2.26 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.66 | Benign | 0.05 | Affected | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||||||||
| c.3269A>C | N1090T 2D AIThe SynGAP1 missense variant N1090T is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of high‑accuracy predictors (AlphaMissense‑Optimized and the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also support a benign classification. In contrast, polyPhen‑2 (both HumDiv and HumVar tracks) predict a pathogenic impact, but these are the only tools in disagreement. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. Overall, the preponderance of evidence points to a benign effect for the variant, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | -3.478 | Likely Benign | 0.542 | Ambiguous | Likely Benign | 0.129 | Likely Benign | 0.1451 | 0.7930 | -0.78 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.77 | Benign | 0.58 | Tolerated | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||||||
| c.3269A>G | N1090S 2D AIThe SynGAP1 missense variant N1090S 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 | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | -2.451 | Likely Benign | 0.228 | Likely Benign | Likely Benign | 0.135 | Likely Benign | 0.3980 | 0.7620 | -0.49 | Neutral | 0.997 | Probably Damaging | 0.983 | Probably Damaging | 2.97 | Benign | 0.38 | Tolerated | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||||||
| c.3269A>T | N1090I 2D AIThe SynGAP1 missense variant N1090I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports 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. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the balance of evidence from both general and high‑accuracy predictors points to a benign classification, and this conclusion does not contradict the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | -4.356 | Likely Benign | 0.765 | Likely Pathogenic | Likely Benign | 0.173 | Likely Benign | 0.0781 | 0.6279 | -2.14 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.67 | Benign | 0.02 | Affected | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||||||||
| c.3270T>A | N1090K 2D AIThe SynGAP1 missense variant N1090K is reported in ClinVar as “None” and is present in gnomAD (ID 6‑33443822‑T‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains likely benign; a Foldetta stability analysis is unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) and the consensus result lean toward a benign interpretation. This conclusion does not contradict ClinVar, which currently has no pathogenic classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | 6-33443822-T-A | 2 | 1.28e-6 | -3.423 | Likely Benign | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.053 | Likely Benign | 0.2147 | 0.6121 | -1.52 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.73 | Benign | 0.18 | Tolerated | 3.77 | 5 | 0 | 1 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.3270T>G | N1090K 2D AIThe SynGAP1 missense variant N1090K has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. The overall balance of evidence leans toward a benign interpretation, and this is consistent with the lack of a ClinVar classification. Thus, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | -3.423 | Likely Benign | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.053 | Likely Benign | 0.2147 | 0.6121 | -1.52 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.73 | Benign | 0.18 | Tolerated | 3.77 | 5 | 0 | 1 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||
| c.3271C>A | L1091I 2D AIThe SynGAP1 missense variant L1091I is reported in gnomAD (ID 6‑33443823‑C‑A) but has no ClinVar entry. Across the available in‑silico predictors, every tool classified the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all returned benign scores. No tool predicted pathogenicity, so the pathogenic‑prediction group is empty. High‑accuracy assessments reinforce this benign 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 for this variant. Overall, the computational evidence strongly supports a benign effect, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.924947 | Disordered | 0.984454 | Binding | 0.376 | 0.889 | 1.000 | 6-33443823-C-A | -4.304 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.057 | Likely Benign | 0.1073 | 0.3911 | -0.66 | Neutral | 0.186 | Benign | 0.055 | Benign | 2.55 | Benign | 0.13 | Tolerated | 3.77 | 5 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||||
| c.3271C>G | L1091V 2D AIThe SynGAP1 missense variant L1091V 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 also reports 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, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.924947 | Disordered | 0.984454 | Binding | 0.376 | 0.889 | 1.000 | -4.587 | Likely Benign | 0.328 | Likely Benign | Likely Benign | 0.048 | Likely Benign | 0.1560 | 0.3561 | -0.62 | Neutral | 0.779 | Possibly Damaging | 0.211 | Benign | 2.57 | Benign | 0.08 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3272T>A | L1091Q 2D AIThe SynGAP1 missense variant L1091Q is not 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. High‑accuracy assessments are less definitive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs 2 benign), and Foldetta results are unavailable. Overall, the majority of available predictions (five pathogenic vs three benign) lean toward a pathogenic impact. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar status because the variant has not yet been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.924947 | Disordered | 0.984454 | Binding | 0.376 | 0.889 | 1.000 | -4.381 | Likely Benign | 0.854 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | 0.1192 | 0.1514 | -1.32 | Neutral | 0.997 | Probably Damaging | 0.939 | Probably Damaging | 2.47 | Pathogenic | 0.02 | Affected | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||||
| c.3272T>C | L1091P 2D AIThe SynGAP1 missense variant L1091P is listed in gnomAD (ID 6‑33443824‑T‑C) but has no ClinVar entry. 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, and AlphaMissense‑Default. AlphaMissense‑Optimized returns an uncertain result, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, leaving it inconclusive. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of tools (five pathogenic vs three benign) predict a deleterious effect, and the high‑accuracy AlphaMissense‑Optimized score is uncertain. Consequently, the variant is most likely pathogenic based on current predictions, 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. | 0.924947 | Disordered | 0.984454 | Binding | 0.376 | 0.889 | 1.000 | 6-33443824-T-C | -4.139 | Likely Benign | 0.871 | Likely Pathogenic | Ambiguous | 0.180 | Likely Benign | 0.3199 | 0.1918 | -1.25 | Neutral | 0.997 | Probably Damaging | 0.939 | Probably Damaging | 2.45 | Pathogenic | 0.04 | Affected | 3.77 | 5 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||
| c.3272T>G | L1091R 2D AIThe SynGAP1 missense variant L1091R is not 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, has no available result for this variant. Overall, the majority of consensus tools (five pathogenic vs. three benign) suggest a pathogenic impact. 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. | 0.924947 | Disordered | 0.984454 | Binding | 0.376 | 0.889 | 1.000 | -3.662 | Likely Benign | 0.896 | Likely Pathogenic | Ambiguous | 0.191 | Likely Benign | 0.1274 | 0.1357 | -1.51 | Neutral | 0.997 | Probably Damaging | 0.939 | Probably Damaging | 2.47 | Pathogenic | 0.02 | Affected | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||
| c.3274T>A | L1092M 2D AIThe SynGAP1 missense variant L1092M is not reported in ClinVar and has no entries in gnomAD, indicating it has not been catalogued in these databases. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the substitution as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports 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 predictions from AlphaMissense‑Optimized and the SGM‑Consensus both support a benign outcome, whereas the absence of a Foldetta result precludes a stability‑based conclusion. Overall, the majority of evidence points to a benign effect for the variant, 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 | 0.924947 | Disordered | 0.985431 | Binding | 0.385 | 0.890 | 1.000 | -5.348 | Likely Benign | 0.383 | Ambiguous | Likely Benign | 0.083 | Likely Benign | 0.0919 | 0.4479 | -0.15 | Neutral | 0.986 | Probably Damaging | 0.875 | Possibly Damaging | 2.66 | Benign | 0.21 | Tolerated | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||
| c.3274T>G | L1092V 2D AIThe SynGAP1 missense variant L1092V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. 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 | 0.924947 | Disordered | 0.985431 | Binding | 0.385 | 0.890 | 1.000 | -4.906 | Likely Benign | 0.451 | Ambiguous | Likely Benign | 0.034 | Likely Benign | 0.1658 | 0.3912 | -0.36 | Neutral | 0.051 | Benign | 0.037 | Benign | 2.79 | Benign | 0.37 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3275T>C | L1092S 2D AIThe SynGAP1 missense variant L1092S is not reported 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 this variant. 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 | 0.924947 | Disordered | 0.985431 | Binding | 0.385 | 0.890 | 1.000 | -3.649 | Likely Benign | 0.900 | Likely Pathogenic | Ambiguous | 0.121 | Likely Benign | 0.3086 | 0.1119 | -0.42 | Neutral | 0.986 | Probably Damaging | 0.823 | Possibly Damaging | 2.68 | Benign | 0.25 | Tolerated | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||||||||
| c.3275T>G | L1092W 2D AIThe SynGAP1 missense variant L1092W 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 FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. Two tools give uncertain results: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta is unavailable. Overall, the majority of conventional tools predict pathogenicity, but the high‑accuracy consensus leans toward a benign interpretation. Thus, the variant is most likely benign based on the most reliable predictions, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.924947 | Disordered | 0.985431 | Binding | 0.385 | 0.890 | 1.000 | -7.014 | In-Between | 0.804 | Likely Pathogenic | Ambiguous | 0.120 | Likely Benign | 0.0787 | 0.4033 | -2.00 | Neutral | 0.999 | Probably Damaging | 0.968 | Probably Damaging | 2.58 | Benign | 0.03 | Affected | -2 | -2 | -4.7 | 73.05 | ||||||||||||||||||||||||||||||||||||
| c.3276G>C | L1092F 2D AIThe SynGAP1 missense variant L1092F is reported in gnomAD (6‑33443828‑G‑C) but has no ClinVar entry. 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, 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 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 | 0.924947 | Disordered | 0.985431 | Binding | 0.385 | 0.890 | 1.000 | 6-33443828-G-C | 1 | 6.40e-7 | -5.010 | Likely Benign | 0.623 | Likely Pathogenic | Likely Benign | 0.067 | Likely Benign | 0.0772 | 0.4060 | -1.40 | Neutral | 0.986 | Probably Damaging | 0.823 | Possibly Damaging | 2.63 | Benign | 0.18 | Tolerated | 3.77 | 5 | 0 | 2 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||
| c.3276G>T | L1092F 2D AIThe SynGAP1 missense variant L1092F is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools show a split: benign calls from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also leans benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the lack of ClinVar annotation and gnomAD absence. Therefore, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.924947 | Disordered | 0.985431 | Binding | 0.385 | 0.890 | 1.000 | -5.010 | Likely Benign | 0.623 | Likely Pathogenic | Likely Benign | 0.067 | Likely Benign | 0.0772 | 0.4060 | -1.40 | Neutral | 0.986 | Probably Damaging | 0.823 | Possibly Damaging | 2.63 | Benign | 0.18 | Tolerated | 3.77 | 5 | 0 | 2 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||
| c.3277C>A | Q1093K 2D AIThe SynGAP1 missense variant Q1093K is reported in gnomAD (variant ID 6‑33443829‑C‑A) but has no ClinVar entry. Functional prediction tools uniformly favor 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 benign. No tool predicts pathogenicity; AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions 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 | 0.919029 | Disordered | 0.983312 | Binding | 0.351 | 0.886 | 1.000 | 6-33443829-C-A | -3.919 | Likely Benign | 0.558 | Ambiguous | Likely Benign | 0.061 | Likely Benign | 0.1926 | 0.5861 | -0.92 | Neutral | 0.224 | Benign | 0.091 | Benign | 2.78 | Benign | 0.06 | Tolerated | 3.77 | 5 | 1 | 1 | -0.4 | 0.04 | ||||||||||||||||||||||||||||||||
| c.3277C>G | Q1093E 2D AIThe SynGAP1 missense change Q1093E is not reported in ClinVar and is absent from gnomAD. In silico assessment shows unanimous benign predictions: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. No tool predicts pathogenicity. High‑accuracy consensus methods reinforce this view: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” The protein‑folding stability predictor Foldetta was not available for this variant. Overall, the evidence strongly supports a benign effect, and this conclusion is consistent with the lack of ClinVar annotation. Thus, the variant is most likely benign and does not contradict existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.983312 | Binding | 0.351 | 0.886 | 1.000 | -3.104 | Likely Benign | 0.265 | Likely Benign | Likely Benign | 0.047 | Likely Benign | 0.1514 | 0.3717 | -0.59 | Neutral | 0.112 | Benign | 0.041 | Benign | 2.78 | Benign | 0.07 | Tolerated | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||
| c.3278A>C | Q1093P 2D AIThe SynGAP1 missense variant Q1093P is not reported in ClinVar and is absent from gnomAD. Consensus from most in silico predictors classifies it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic effect. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized scores benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely benign, while Foldetta stability analysis is unavailable. Overall, the evidence points to a benign effect for Q1093P, 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 | 0.919029 | Disordered | 0.983312 | Binding | 0.351 | 0.886 | 1.000 | -2.613 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.137 | Likely Benign | 0.2059 | 0.5956 | -0.96 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.69 | Benign | 0.05 | Affected | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||
| c.3278A>G | Q1093R 2D AIThe SynGAP1 missense variant Q1093R is reported in gnomAD (ID 6‑33443830‑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, and AlphaMissense‑Optimized all classify the change as benign, while the only pathogenic prediction 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, and the SGM‑Consensus also indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion 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 | 0.919029 | Disordered | 0.983312 | Binding | 0.351 | 0.886 | 1.000 | 6-33443830-A-G | 1 | 6.40e-7 | -3.681 | Likely Benign | 0.483 | Ambiguous | Likely Benign | 0.065 | Likely Benign | 0.1537 | 0.3904 | -1.06 | Neutral | 0.224 | Benign | 0.091 | Benign | 2.73 | Benign | 0.04 | Affected | 3.77 | 5 | 1 | 1 | -1.0 | 28.06 | ||||||||||||||||||||||||||||||
| c.3278A>T | Q1093L 2D AIThe SynGAP1 missense variant Q1093L is not reported 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 | 0.919029 | Disordered | 0.983312 | Binding | 0.351 | 0.886 | 1.000 | -3.242 | Likely Benign | 0.165 | Likely Benign | Likely Benign | 0.055 | Likely Benign | 0.0899 | 0.6837 | -1.10 | Neutral | 0.224 | Benign | 0.091 | Benign | 2.72 | Benign | 0.03 | Affected | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||
| c.3279G>C | Q1093H 2D AIThe SynGAP1 missense variant Q1093H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.983312 | Binding | 0.351 | 0.886 | 1.000 | -4.003 | Likely Benign | 0.337 | Likely Benign | Likely Benign | 0.060 | Likely Benign | 0.1600 | 0.5269 | -1.14 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.69 | Benign | 0.02 | Affected | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.3279G>T | Q1093H 2D AIThe SynGAP1 missense variant Q1093H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.983312 | Binding | 0.351 | 0.886 | 1.000 | -4.003 | Likely Benign | 0.337 | Likely Benign | Likely Benign | 0.060 | Likely Benign | 0.1600 | 0.5269 | -1.14 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.69 | Benign | 0.02 | Affected | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.3280T>A | S1094T 2D AIThe SynGAP1 missense variant S1094T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.938133 | Disordered | 0.981352 | Binding | 0.358 | 0.877 | 1.000 | -4.009 | Likely Benign | 0.194 | Likely Benign | Likely Benign | 0.077 | Likely Benign | 0.1874 | 0.6902 | -0.57 | Neutral | 0.790 | Possibly Damaging | 0.433 | Benign | 2.59 | Benign | 0.16 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3280T>C | S1094P 2D AIThe SynGAP1 missense variant S1094P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S1094P, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.938133 | Disordered | 0.981352 | Binding | 0.358 | 0.877 | 1.000 | -2.430 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.124 | Likely Benign | 0.2322 | 0.6099 | -1.31 | Neutral | 0.990 | Probably Damaging | 0.798 | Possibly Damaging | 2.46 | Pathogenic | 0.13 | Tolerated | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.3280T>G | S1094A 2D AIThe SynGAP1 missense variant S1094A 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, so the pathogenic‑prediction group is empty. 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 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 | 0.938133 | Disordered | 0.981352 | Binding | 0.358 | 0.877 | 1.000 | -3.595 | Likely Benign | 0.188 | Likely Benign | Likely Benign | 0.117 | Likely Benign | 0.4692 | 0.5403 | -0.78 | Neutral | 0.447 | Benign | 0.252 | Benign | 2.66 | Benign | 1.00 | Tolerated | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||
| c.3281C>A | S1094Y 2D AIThe SynGAP1 missense variant S1094Y is not reported in ClinVar (status: none) but is present in gnomAD (ID 6‑33443833‑C‑A). 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 (two benign, two pathogenic). Foldetta, a protein‑folding‑stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy predictions therefore show a benign call from AlphaMissense‑Optimized, an inconclusive SGM Consensus, and no Foldetta data. Overall, the balance of evidence leans toward a pathogenic interpretation (five pathogenic versus four benign calls), and this does not contradict the ClinVar status, which currently has no assertion for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.938133 | Disordered | 0.981352 | Binding | 0.358 | 0.877 | 1.000 | 6-33443833-C-A | -5.609 | Likely Benign | 0.631 | Likely Pathogenic | Likely Benign | 0.155 | Likely Benign | 0.1007 | 0.5877 | -2.07 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.45 | Pathogenic | 0.02 | Affected | 3.77 | 5 | -2 | -3 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||
| c.3281C>G | S1094C 2D AIThe SynGAP1 missense variant S1094C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Two tools—AlphaMissense‑Default and ESM1b—return uncertain results. High‑accuracy assessments are limited: AlphaMissense‑Optimized indicates a benign effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields no clear consensus and is treated as unavailable; Foldetta data are not provided, so its stability prediction is also unavailable. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.938133 | Disordered | 0.981352 | Binding | 0.358 | 0.877 | 1.000 | -7.143 | In-Between | 0.425 | Ambiguous | Likely Benign | 0.131 | Likely Benign | 0.1403 | 0.6309 | -1.81 | Neutral | 0.997 | Probably Damaging | 0.946 | Probably Damaging | 2.45 | Pathogenic | 0.05 | Affected | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||
| c.3281C>T | S1094F 2D AIThe SynGAP1 missense variant S1094F is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, 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 would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the majority of conventional predictors lean toward pathogenicity, but the single high‑accuracy tool predicts benign and the consensus is unresolved. Thus, the variant is most likely pathogenic based on the 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. | 0.938133 | Disordered | 0.981352 | Binding | 0.358 | 0.877 | 1.000 | -5.655 | Likely Benign | 0.666 | Likely Pathogenic | Likely Benign | 0.150 | Likely Benign | 0.0925 | 0.5851 | -2.17 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.45 | Pathogenic | 0.02 | Affected | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||
| c.3283C>A | P1095T 2D AIThe SynGAP1 missense variant P1095T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumDiv indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the consensus of the available predictions points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.979251 | Binding | 0.387 | 0.870 | 1.000 | -4.706 | Likely Benign | 0.195 | Likely Benign | Likely Benign | 0.108 | Likely Benign | 0.1685 | 0.6677 | -1.42 | Neutral | 0.872 | Possibly Damaging | 0.399 | Benign | 2.77 | Benign | 0.13 | Tolerated | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||
| c.3283C>G | P1095A 2D AIThe SynGAP1 missense variant P1095A 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 not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.979251 | Binding | 0.387 | 0.870 | 1.000 | -4.555 | Likely Benign | 0.129 | Likely Benign | Likely Benign | 0.060 | Likely Benign | 0.3122 | 0.5703 | -0.80 | Neutral | 0.580 | Possibly Damaging | 0.242 | Benign | 2.79 | Benign | 0.18 | Tolerated | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| c.3283C>T | P1095S 2D AIThe SynGAP1 missense variant P1095S is reported in gnomAD (ID 6‑33443835‑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 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, was not available for this variant. Based on the unanimous benign predictions and the absence of any pathogenic signal, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.979251 | Binding | 0.387 | 0.870 | 1.000 | 6-33443835-C-T | 7 | 4.51e-6 | -3.819 | Likely Benign | 0.182 | Likely Benign | Likely Benign | 0.128 | Likely Benign | 0.3150 | 0.5963 | -0.64 | Neutral | 0.207 | Benign | 0.072 | Benign | 2.80 | Benign | 1.00 | Tolerated | 3.77 | 5 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||
| c.3284C>A | P1095Q 2D AIThe SynGAP1 missense variant P1095Q 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, 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 also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.979251 | Binding | 0.387 | 0.870 | 1.000 | -4.171 | Likely Benign | 0.295 | Likely Benign | Likely Benign | 0.110 | Likely Benign | 0.1573 | 0.5519 | -1.64 | Neutral | 0.922 | Possibly Damaging | 0.441 | Benign | 2.85 | Benign | 0.45 | Tolerated | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||
| c.3284C>G | P1095R 2D AIThe SynGAP1 missense variant P1095R is reported in ClinVar as “Not submitted” and is not present in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, all of which classify the change as benign or tolerant. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. AlphaMissense‑Default remains uncertain, and no Foldetta stability assessment is available. High‑accuracy consensus methods reinforce the benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” and Foldetta data are missing. Overall, the majority of reliable predictors and consensus analyses indicate that P1095R is most likely benign, 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 | 0.922952 | Disordered | 0.979251 | Binding | 0.387 | 0.870 | 1.000 | -5.180 | Likely Benign | 0.553 | Ambiguous | Likely Benign | 0.091 | Likely Benign | 0.1513 | 0.4576 | -1.93 | Neutral | 0.922 | Possibly Damaging | 0.528 | Possibly Damaging | 2.77 | Benign | 0.04 | Affected | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.3284C>T | P1095L 2D AIThe SynGAP1 missense variant P1095L is catalogued in gnomAD (ID 6‑33443836‑C‑T) but has no ClinVar record. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, and Foldetta data 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. | 0.922952 | Disordered | 0.979251 | Binding | 0.387 | 0.870 | 1.000 | 6-33443836-C-T | 1 | 6.44e-7 | -4.697 | Likely Benign | 0.363 | Ambiguous | Likely Benign | 0.126 | Likely Benign | 0.2199 | 0.6347 | -2.78 | Deleterious | 0.960 | Probably Damaging | 0.604 | Possibly Damaging | 2.74 | Benign | 0.03 | Affected | 3.77 | 5 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||
| c.3286G>A | E1096K 2D AIThe SynGAP1 missense variant E1096K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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, 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 | 0.926919 | Disordered | 0.976475 | Binding | 0.308 | 0.858 | 1.000 | -4.148 | Likely Benign | 0.845 | Likely Pathogenic | Ambiguous | 0.097 | Likely Benign | 0.2440 | 0.7533 | -1.44 | Neutral | 0.872 | Possibly Damaging | 0.478 | Possibly Damaging | 2.75 | Benign | 0.15 | Tolerated | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||
| c.3286G>C | E1096Q 2D AIThe SynGAP1 missense variant E1096Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (both HumDiv and HumVar) predict a pathogenic outcome. AlphaMissense‑Default remains uncertain, and 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 from multiple prediction algorithms and high‑accuracy tools suggests that E1096Q 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 | 0.926919 | Disordered | 0.976475 | Binding | 0.308 | 0.858 | 1.000 | -3.134 | Likely Benign | 0.462 | Ambiguous | Likely Benign | 0.142 | Likely Benign | 0.1527 | 0.7459 | -1.08 | Neutral | 0.954 | Possibly Damaging | 0.654 | Possibly Damaging | 2.73 | Benign | 0.29 | Tolerated | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||
| c.3287A>C | E1096A 2D AIThe SynGAP1 missense variant E1096A is listed in ClinVar (ID 2579889.0) with an uncertain significance annotation and is not reported in gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only polyPhen‑2 HumDiv assigns a pathogenic label, while AlphaMissense‑Default remains uncertain. 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, has no available result for this variant. Overall, the aggregate evidence points to a benign effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.926919 | Disordered | 0.976475 | Binding | 0.308 | 0.858 | 1.000 | Uncertain | 1 | -4.504 | Likely Benign | 0.510 | Ambiguous | Likely Benign | 0.164 | Likely Benign | 0.3805 | 0.7569 | -1.37 | Neutral | 0.626 | Possibly Damaging | 0.184 | Benign | 2.77 | Benign | 0.16 | Tolerated | 3.77 | 5 | -1 | 0 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||
| c.3287A>G | E1096G 2D AIThe SynGAP1 missense variant E1096G is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors shows a split: polyPhen‑2 HumDiv and HumVar classify it as pathogenic, whereas REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized predict a benign effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome, and AlphaMissense‑Optimized itself 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 high‑accuracy tools (AlphaMissense‑Optimized and SGM‑Consensus) indicate a benign impact, and no evidence contradicts this assessment with ClinVar data, which is currently lacking. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.926919 | Disordered | 0.976475 | Binding | 0.308 | 0.858 | 1.000 | -2.749 | Likely Benign | 0.536 | Ambiguous | Likely Benign | 0.118 | Likely Benign | 0.2789 | 0.6220 | -2.14 | Neutral | 0.872 | Possibly Damaging | 0.478 | Possibly Damaging | 2.70 | Benign | 0.06 | Tolerated | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||
| c.3287A>T | E1096V 2D AIThe SynGAP1 missense variant E1096V is not reported in ClinVar and is absent from gnomAD. 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 further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign. No Foldetta stability result is available. Overall, the majority of evidence indicates 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 | 0.926919 | Disordered | 0.976475 | Binding | 0.308 | 0.858 | 1.000 | -3.588 | Likely Benign | 0.650 | Likely Pathogenic | Likely Benign | 0.138 | Likely Benign | 0.1082 | 0.7596 | -1.06 | Neutral | 0.043 | Benign | 0.017 | Benign | 2.81 | Benign | 0.03 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||
| c.3288G>C | E1096D 2D AIThe SynGAP1 missense variant E1096D 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 | 0.926919 | Disordered | 0.976475 | Binding | 0.308 | 0.858 | 1.000 | -3.818 | Likely Benign | 0.192 | Likely Benign | Likely Benign | 0.116 | Likely Benign | 0.2034 | 0.4994 | -0.40 | Neutral | 0.115 | Benign | 0.052 | Benign | 2.71 | Benign | 0.38 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3288G>T | E1096D 2D AIThe SynGAP1 missense variant E1096D 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 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 | 0.926919 | Disordered | 0.976475 | Binding | 0.308 | 0.858 | 1.000 | -3.818 | Likely Benign | 0.192 | Likely Benign | Likely Benign | 0.116 | Likely Benign | 0.2034 | 0.4994 | -0.40 | Neutral | 0.115 | Benign | 0.052 | Benign | 2.71 | Benign | 0.38 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3289C>A | P1097T 2D AIThe SynGAP1 missense variant P1097T 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, 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 absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.974957 | Binding | 0.384 | 0.858 | 1.000 | -5.000 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.110 | Likely Benign | 0.1751 | 0.6567 | -1.38 | Neutral | 0.009 | Benign | 0.013 | Benign | 2.61 | Benign | 0.21 | Tolerated | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||
| c.3289C>G | P1097A 2D AIThe SynGAP1 missense variant P1097A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts pathogenicity. The high‑accuracy consensus (SGM‑Consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the unanimous benign predictions and the lack of any pathogenic 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 | 0.919029 | Disordered | 0.974957 | Binding | 0.384 | 0.858 | 1.000 | -4.315 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.059 | Likely Benign | 0.3199 | 0.5381 | -1.77 | Neutral | 0.245 | Benign | 0.140 | Benign | 2.71 | Benign | 0.26 | Tolerated | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| c.3289C>T | P1097S 2D AIThe SynGAP1 missense variant P1097S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.974957 | Binding | 0.384 | 0.858 | 1.000 | -3.748 | Likely Benign | 0.116 | Likely Benign | Likely Benign | 0.053 | Likely Benign | 0.3332 | 0.5691 | -1.04 | Neutral | 0.025 | Benign | 0.023 | Benign | 2.62 | Benign | 0.70 | Tolerated | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||
| c.3290C>A | P1097Q 2D AIThe SynGAP1 missense variant P1097Q is reported in gnomAD (ID 6‑33443842‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. 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 effect, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.974957 | Binding | 0.384 | 0.858 | 1.000 | 6-33443842-C-A | -4.765 | Likely Benign | 0.198 | Likely Benign | Likely Benign | 0.092 | Likely Benign | 0.1613 | 0.5136 | -1.10 | Neutral | 0.918 | Possibly Damaging | 0.604 | Possibly Damaging | 2.58 | Benign | 0.12 | Tolerated | 3.77 | 5 | -1 | 0 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||
| c.3290C>G | P1097R 2D AIThe SynGAP1 missense variant P1097R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and 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. Based on the preponderance of benign predictions and the lack of pathogenic evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.974957 | Binding | 0.384 | 0.858 | 1.000 | -4.938 | Likely Benign | 0.422 | Ambiguous | Likely Benign | 0.079 | Likely Benign | 0.1517 | 0.4027 | -1.75 | Neutral | 0.918 | Possibly Damaging | 0.525 | Possibly Damaging | 2.58 | Benign | 0.07 | Tolerated | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.3290C>T | P1097L 2D AIThe SynGAP1 missense variant P1097L is listed in ClinVar as Benign (ClinVar ID 2060978.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, 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 SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as benign; Foldetta results are unavailable. Overall, the majority of evidence supports a benign impact, and this conclusion is consistent with the ClinVar designation. 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 | 0.919029 | Disordered | 0.974957 | Binding | 0.384 | 0.858 | 1.000 | Benign | 1 | -4.410 | Likely Benign | 0.145 | Likely Benign | Likely Benign | 0.131 | Likely Benign | 0.2349 | 0.6356 | -2.07 | Neutral | 0.611 | Possibly Damaging | 0.198 | Benign | 2.64 | Benign | 0.05 | Affected | 3.77 | 5 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||
| c.3292A>C | S1098R 2D AIThe SynGAP1 missense variant S1098R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign, reflecting the majority of benign predictions. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, and the SGM‑Consensus (majority vote) also indicates Benign. Foldetta results are not available, so no stability evidence is considered. Overall, the majority of computational evidence supports a benign impact for S1098R, 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 | 0.919029 | Disordered | 0.973030 | Binding | 0.337 | 0.855 | 1.000 | -4.583 | Likely Benign | 0.775 | Likely Pathogenic | Likely Benign | 0.127 | Likely Benign | 0.1053 | 0.4012 | -1.00 | Neutral | 0.586 | Possibly Damaging | 0.223 | Benign | 2.72 | Benign | 0.16 | Tolerated | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||
| c.3292A>G | S1098G 2D AIThe SynGAP1 missense variant S1098G 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 collective predictions strongly support a benign impact, and this conclusion is consistent with the lack of a ClinVar pathogenic classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.973030 | Binding | 0.337 | 0.855 | 1.000 | -3.494 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.066 | Likely Benign | 0.2634 | 0.5206 | -0.39 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.72 | Benign | 0.57 | Tolerated | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.3292A>T | S1098C 2D AIThe SynGAP1 missense variant S1098C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) 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, 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 | 0.919029 | Disordered | 0.973030 | Binding | 0.337 | 0.855 | 1.000 | -6.553 | Likely Benign | 0.106 | Likely Benign | Likely Benign | 0.094 | Likely Benign | 0.1249 | 0.6233 | -1.46 | Neutral | 0.938 | Possibly Damaging | 0.665 | Possibly Damaging | 2.65 | Benign | 0.12 | Tolerated | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.3293G>A | S1098N 2D AIThe SynGAP1 missense variant S1098N is listed in ClinVar (ID 864704.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33443845‑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 | 0.919029 | Disordered | 0.973030 | Binding | 0.337 | 0.855 | 1.000 | Conflicting | 2 | 6-33443845-G-A | 6 | 3.89e-6 | -5.120 | Likely Benign | 0.156 | Likely Benign | Likely Benign | 0.063 | Likely Benign | 0.1665 | 0.5145 | -0.58 | Neutral | 0.369 | Benign | 0.120 | Benign | 2.76 | Benign | 0.36 | Tolerated | 3.77 | 5 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||
| c.3293G>C | S1098T 2D AIThe SynGAP1 missense variant S1098T is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.973030 | Binding | 0.337 | 0.855 | 1.000 | -4.144 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.051 | Likely Benign | 0.1706 | 0.6653 | -0.18 | Neutral | 0.224 | Benign | 0.120 | Benign | 2.76 | Benign | 0.88 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3293G>T | S1098I 2D AIThe SynGAP1 missense variant S1098I is catalogued in gnomAD (ID 6‑33443845‑G‑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 reports a pathogenic outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta results are 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 | 0.919029 | Disordered | 0.973030 | Binding | 0.337 | 0.855 | 1.000 | 6-33443845-G-T | -4.497 | Likely Benign | 0.182 | Likely Benign | Likely Benign | 0.139 | Likely Benign | 0.1219 | 0.5601 | -0.92 | Neutral | 0.259 | Benign | 0.066 | Benign | 2.67 | Benign | 0.15 | Tolerated | 3.77 | 5 | -2 | -1 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||
| c.3294T>A | S1098R 2D AIThe SynGAP1 missense variant S1098R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments therefore support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is benign, and the protein‑folding stability method Foldetta is not available 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 reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.973030 | Binding | 0.337 | 0.855 | 1.000 | -4.583 | Likely Benign | 0.775 | Likely Pathogenic | Likely Benign | 0.133 | Likely Benign | 0.1053 | 0.4012 | -1.00 | Neutral | 0.586 | Possibly Damaging | 0.223 | Benign | 2.72 | Benign | 0.16 | Tolerated | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||
| c.3294T>G | S1098R 2D AIThe SynGAP1 missense variant S1098R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments therefore support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is benign, and the protein‑folding stability method Foldetta is not available 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 reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.973030 | Binding | 0.337 | 0.855 | 1.000 | -4.583 | Likely Benign | 0.775 | Likely Pathogenic | Likely Benign | 0.134 | Likely Benign | 0.1053 | 0.4012 | -1.00 | Neutral | 0.586 | Possibly Damaging | 0.223 | Benign | 2.72 | Benign | 0.16 | Tolerated | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||
| c.3295T>A | Y1099N 2D AIThe SynGAP1 missense variant Y1099N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumDiv indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the consensus of the available predictions points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.974267 | Binding | 0.400 | 0.862 | 1.000 | -4.329 | Likely Benign | 0.269 | Likely Benign | Likely Benign | 0.143 | Likely Benign | 0.2121 | 0.0935 | -1.01 | Neutral | 0.818 | Possibly Damaging | 0.360 | Benign | 2.83 | Benign | 0.16 | Tolerated | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||||||||
| c.3295T>C | Y1099H 2D AIThe SynGAP1 missense variant Y1099H is reported in gnomAD (variant ID 6-33443847‑T‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict 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 reinforce this: AlphaMissense‑Optimized is 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 preponderance of evidence points to a benign impact, 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 | 0.885302 | Disordered | 0.974267 | Binding | 0.400 | 0.862 | 1.000 | 6-33443847-T-C | 1 | 6.49e-7 | -3.620 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.123 | Likely Benign | 0.2453 | 0.0735 | -0.50 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.76 | Benign | 0.18 | Tolerated | 3.77 | 5 | 2 | 0 | -1.9 | -26.03 | ||||||||||||||||||||||||||||||
| c.3295T>G | Y1099D 2D AIThe SynGAP1 missense variant Y1099D is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all score the change as tolerated or benign, while only polyPhen‑2 HumDiv flags it as pathogenic. 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, SGM‑Consensus is Likely Benign, and Foldetta results are unavailable. Taken together, the majority of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar assertion, 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 | 0.885302 | Disordered | 0.974267 | Binding | 0.400 | 0.862 | 1.000 | -4.193 | Likely Benign | 0.429 | Ambiguous | Likely Benign | 0.130 | Likely Benign | 0.3819 | 0.0935 | -1.08 | Neutral | 0.818 | Possibly Damaging | 0.435 | Benign | 2.79 | Benign | 0.13 | Tolerated | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||||||||
| c.3296A>C | Y1099S 2D AIThe SynGAP1 missense variant Y1099S 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 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 | 0.885302 | Disordered | 0.974267 | Binding | 0.400 | 0.862 | 1.000 | -1.775 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.156 | Likely Benign | 0.4564 | 0.2298 | -0.23 | Neutral | 0.149 | Benign | 0.026 | Benign | 2.90 | Benign | 0.62 | Tolerated | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||
| c.3296A>G | Y1099C 2D AIThe SynGAP1 missense variant Y1099C is reported in gnomAD (variant ID 6‑33443848‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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, 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 | 0.885302 | Disordered | 0.974267 | Binding | 0.400 | 0.862 | 1.000 | 6-33443848-A-G | 3 | 1.95e-6 | -5.670 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.122 | Likely Benign | 0.3008 | 0.2382 | -1.13 | Neutral | 0.997 | Probably Damaging | 0.840 | Possibly Damaging | 2.73 | Benign | 0.14 | Tolerated | 3.77 | 5 | -2 | 0 | 3.8 | -60.04 | ||||||||||||||||||||||||||||||
| c.3296A>T | Y1099F 2D AIThe SynGAP1 missense variant Y1099F 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 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 | 0.885302 | Disordered | 0.974267 | Binding | 0.400 | 0.862 | 1.000 | -3.651 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.082 | Likely Benign | 0.2453 | 0.2780 | -0.85 | Neutral | 0.006 | Benign | 0.008 | Benign | 2.75 | Benign | 0.27 | Tolerated | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||||||||
| c.3298G>A | G1100S 2D AIThe SynGAP1 missense variant G1100S is not reported 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; no Foldetta stability result is available. Overall, the majority of evidence points to a benign impact for G1100S, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.972009 | Binding | 0.360 | 0.865 | 0.875 | -2.898 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.114 | Likely Benign | 0.2501 | 0.5699 | -0.65 | Neutral | 0.943 | Possibly Damaging | 0.595 | Possibly Damaging | 2.10 | Pathogenic | 0.28 | Tolerated | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.3298G>C | G1100R 2D AIThe SynGAP1 missense variant G1100R is not 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 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 available predictions lean toward pathogenicity, and this does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.882776 | Disordered | 0.972009 | Binding | 0.360 | 0.865 | 0.875 | -2.923 | Likely Benign | 0.603 | Likely Pathogenic | Likely Benign | 0.176 | Likely Benign | 0.0986 | 0.5217 | -2.05 | Neutral | 0.992 | Probably Damaging | 0.906 | Possibly Damaging | 1.92 | Pathogenic | 0.00 | Affected | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||
| c.3298G>T | G1100C 2D AIThe SynGAP1 missense variant G1100C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments reinforce the benign trend: 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 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 | 0.882776 | Disordered | 0.972009 | Binding | 0.360 | 0.865 | 0.875 | -6.488 | Likely Benign | 0.150 | Likely Benign | Likely Benign | 0.174 | Likely Benign | 0.1354 | 0.4768 | -2.25 | Neutral | 0.999 | Probably Damaging | 0.950 | Probably Damaging | 1.91 | Pathogenic | 0.00 | Affected | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||
| c.3299G>A | G1100D 2D AIThe SynGAP1 missense variant G1100D is not 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 classifying the variant as benign, while the SGM Consensus (a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, 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. | 0.882776 | Disordered | 0.972009 | Binding | 0.360 | 0.865 | 0.875 | -5.235 | Likely Benign | 0.577 | Likely Pathogenic | Likely Benign | 0.141 | Likely Benign | 0.1924 | 0.3043 | -1.67 | Neutral | 0.049 | Benign | 0.030 | Benign | 1.93 | Pathogenic | 0.01 | Affected | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||
| c.3299G>C | G1100A 2D AIThe SynGAP1 missense variant G1100A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign based on current computational evidence, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.972009 | Binding | 0.360 | 0.865 | 0.875 | -2.862 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.146 | Likely Benign | 0.3442 | 0.5154 | -0.95 | Neutral | 0.943 | Possibly Damaging | 0.667 | Possibly Damaging | 2.01 | Pathogenic | 0.05 | Affected | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.3299G>T | G1100V 2D AIThe SynGAP1 missense variant G1100V is reported in gnomAD (variant ID 6‑33443851‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign); pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. 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 balance of evidence favors a benign classification for G1100V, 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 | 0.882776 | Disordered | 0.972009 | Binding | 0.360 | 0.865 | 0.875 | 6-33443851-G-T | 1 | 6.51e-7 | -2.362 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 0.198 | Likely Benign | 0.1297 | 0.4036 | -2.43 | Neutral | 0.992 | Probably Damaging | 0.906 | Possibly Damaging | 1.93 | Pathogenic | 0.01 | Affected | 3.77 | 5 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||
| c.3301C>A | P1101T 2D AIThe SynGAP1 missense variant P1101T is not reported 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 | 0.874069 | Disordered | 0.968967 | Binding | 0.457 | 0.861 | 0.875 | -4.161 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.126 | Likely Benign | 0.1729 | 0.5860 | -1.60 | Neutral | 0.115 | Benign | 0.031 | Benign | 4.22 | Benign | 0.04 | Affected | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||
| c.3301C>G | P1101A 2D AIThe SynGAP1 missense variant P1101A 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. 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 | 0.874069 | Disordered | 0.968967 | Binding | 0.457 | 0.861 | 0.875 | -3.825 | Likely Benign | 0.057 | Likely Benign | Likely Benign | 0.095 | Likely Benign | 0.3154 | 0.5218 | -1.34 | Neutral | 0.010 | Benign | 0.010 | Benign | 4.26 | Benign | 0.08 | Tolerated | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| c.3301C>T | P1101S 2D AIThe SynGAP1 missense variant P1101S is reported in gnomAD (variant ID 6‑33443853‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags it as pathogenic, creating a single discordant call. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. 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 | 0.874069 | Disordered | 0.968967 | Binding | 0.457 | 0.861 | 0.875 | 6-33443853-C-T | 1 | 6.52e-7 | -3.845 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.075 | Likely Benign | 0.3265 | 0.5400 | -1.31 | Neutral | 0.626 | Possibly Damaging | 0.255 | Benign | 4.25 | Benign | 0.07 | Tolerated | 3.77 | 5 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||
| c.3302C>A | P1101H 2D AIThe SynGAP1 missense variant P1101H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign effect for P1101H, 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 | 0.874069 | Disordered | 0.968967 | Binding | 0.457 | 0.861 | 0.875 | -5.370 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.167 | Likely Benign | 0.2046 | 0.4597 | -1.87 | Neutral | 0.996 | Probably Damaging | 0.864 | Possibly Damaging | 4.18 | Benign | 0.02 | Affected | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||
| c.3302C>G | P1101R 2D AIThe SynGAP1 missense variant P1101R 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 majority of evidence points to a benign effect, 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 | 0.874069 | Disordered | 0.968967 | Binding | 0.457 | 0.861 | 0.875 | -4.772 | Likely Benign | 0.227 | Likely Benign | Likely Benign | 0.103 | Likely Benign | 0.1497 | 0.4644 | -1.28 | Neutral | 0.960 | Probably Damaging | 0.761 | Possibly Damaging | 4.27 | Benign | 0.36 | Tolerated | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.3302C>T | P1101L 2D AIThe SynGAP1 missense variant P1101L 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 benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments 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 for P1101L, 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 | 0.874069 | Disordered | 0.968967 | Binding | 0.457 | 0.861 | 0.875 | -4.335 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.109 | Likely Benign | 0.2310 | 0.6050 | -2.19 | Neutral | 0.770 | Possibly Damaging | 0.255 | Benign | 4.27 | Benign | 0.04 | Affected | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||
| c.3304G>A | A1102T 2D AIThe SynGAP1 missense variant A1102T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443856‑G‑A). 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, 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 effect, and this does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.915074 | Disordered | 0.962659 | Binding | 0.388 | 0.859 | 0.875 | Uncertain | 1 | 6-33443856-G-A | 11 | 7.17e-6 | -3.540 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.044 | Likely Benign | 0.1755 | 0.7699 | -0.30 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.32 | Pathogenic | 0.95 | Tolerated | 3.77 | 5 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||
| c.3304G>C | A1102P 2D AIThe SynGAP1 missense variant A1102P is listed in ClinVar (ID 2789225.0) 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), 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; 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 | 0.915074 | Disordered | 0.962659 | Binding | 0.388 | 0.859 | 0.875 | Uncertain | 1 | -5.120 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.118 | Likely Benign | 0.1978 | 0.5919 | -0.97 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.26 | Pathogenic | 0.13 | Tolerated | 3.77 | 5 | -1 | 1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||
| c.3304G>T | A1102S 2D AIThe SynGAP1 missense variant A1102S 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 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 | 0.915074 | Disordered | 0.962659 | Binding | 0.388 | 0.859 | 0.875 | -2.900 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.041 | Likely Benign | 0.2666 | 0.6501 | 0.05 | Neutral | 0.019 | Benign | 0.032 | Benign | 2.57 | Benign | 0.59 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||
| c.3305C>A | A1102D 2D AIThe SynGAP1 missense variant A1102D is not 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, and AlphaMissense‑Optimized. Only FATHMM 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 from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.915074 | Disordered | 0.962659 | Binding | 0.388 | 0.859 | 0.875 | -4.647 | Likely Benign | 0.388 | Ambiguous | Likely Benign | 0.081 | Likely Benign | 0.2045 | 0.2984 | -1.38 | Neutral | 0.033 | Benign | 0.028 | Benign | 2.27 | Pathogenic | 0.12 | Tolerated | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||
| c.3305C>G | A1102G 2D AIThe SynGAP1 A1102G 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM 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 that integrates 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 because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.915074 | Disordered | 0.962659 | Binding | 0.388 | 0.859 | 0.875 | -3.070 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.060 | Likely Benign | 0.1947 | 0.4958 | 0.39 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.30 | Pathogenic | 0.14 | Tolerated | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3305C>T | A1102V 2D AIThe SynGAP1 missense variant A1102V is listed in ClinVar (ID 2846719.0) as Benign and is present in gnomAD (variant ID 6‑33443857‑C‑T). 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 aligns with the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.915074 | Disordered | 0.962659 | Binding | 0.388 | 0.859 | 0.875 | Benign | 1 | 6-33443857-C-T | -2.440 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.081 | Likely Benign | 0.1333 | 0.6264 | -1.27 | Neutral | 0.017 | Benign | 0.028 | Benign | 2.29 | Pathogenic | 0.12 | Tolerated | 3.77 | 5 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||
| 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 | 0.3025 | 0.4224 | -1.94 | Neutral | 0.511 | Possibly Damaging | 0.187 | Benign | 2.48 | Pathogenic | 0.28 | Tolerated | 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 | 0.3429 | 0.4077 | -2.65 | Deleterious | 0.911 | Possibly Damaging | 0.308 | Benign | 2.44 | Pathogenic | 0.03 | Affected | -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 | 0.3376 | 0.4121 | -3.01 | Deleterious | 0.996 | Probably Damaging | 0.787 | Possibly Damaging | 2.41 | Pathogenic | 0.01 | Affected | 3.77 | 5 | -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 | 0.2977 | 0.2380 | -1.97 | Neutral | 0.996 | Probably Damaging | 0.733 | Possibly Damaging | 2.49 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 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 | 0.2288 | 0.5109 | -2.48 | Neutral | 0.969 | Probably Damaging | 0.659 | Possibly Damaging | 2.43 | Pathogenic | 0.02 | Affected | 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 | 0.2098 | 0.5181 | -2.35 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.44 | Pathogenic | 0.02 | Affected | 3.77 | 5 | -3 | -2 | 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 | 0.1549 | 0.6700 | -0.14 | Neutral | 0.770 | Possibly Damaging | 0.481 | Possibly Damaging | 2.76 | Benign | 0.09 | Tolerated | 3.77 | 5 | -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 | 0.3289 | 0.5315 | -0.54 | Neutral | 0.409 | Benign | 0.184 | Benign | 2.74 | Benign | 0.22 | Tolerated | 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 | 0.3271 | 0.5746 | -0.30 | Neutral | 0.770 | Possibly Damaging | 0.404 | Benign | 2.77 | Benign | 0.10 | Tolerated | 3.77 | 5 | -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 | 0.1498 | 0.5063 | -0.64 | Neutral | 0.986 | Probably Damaging | 0.825 | Possibly Damaging | 2.68 | Benign | 0.06 | Tolerated | 3.77 | 5 | -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 | 0.1387 | 0.3703 | -0.64 | Neutral | 0.986 | Probably Damaging | 0.761 | Possibly Damaging | 2.68 | Benign | 0.06 | Tolerated | 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 | 0.2264 | 0.6795 | -0.33 | Neutral | 0.626 | Possibly Damaging | 0.168 | Benign | 2.81 | Benign | 1.00 | Tolerated | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||
| 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 | 0.3293 | 0.4269 | -3.48 | Deleterious | 0.677 | Possibly Damaging | 0.168 | Benign | 2.45 | Pathogenic | 0.09 | Tolerated | -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 | 0.1154 | 0.4117 | -4.34 | Deleterious | 0.999 | Probably Damaging | 0.696 | Possibly Damaging | 2.42 | Pathogenic | 0.02 | Affected | 3.77 | 5 | -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 | 0.2942 | 0.3174 | -1.21 | Neutral | 0.958 | Probably Damaging | 0.194 | Benign | 2.50 | Benign | 0.16 | Tolerated | 3.77 | 5 | 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 | 0.2031 | 0.5101 | -3.22 | Deleterious | 0.007 | Benign | 0.006 | Benign | 2.44 | Pathogenic | 0.08 | Tolerated | 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 | 0.1734 | 0.5373 | -3.51 | Deleterious | 0.677 | Possibly Damaging | 0.168 | Benign | 2.46 | Pathogenic | 0.19 | Tolerated | 3.77 | 5 | -2 | -3 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||
| 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 | 0.1827 | 0.4800 | -2.49 | Neutral | 0.963 | Probably Damaging | 0.959 | Probably Damaging | 1.82 | Pathogenic | 0.16 | Tolerated | 3.77 | 5 | 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 | 0.1381 | 0.2663 | -1.60 | Neutral | 0.963 | Probably Damaging | 0.959 | Probably Damaging | 1.80 | Pathogenic | 0.15 | Tolerated | 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 | 0.2029 | 0.5781 | -3.14 | Deleterious | 0.996 | Probably Damaging | 0.988 | Probably Damaging | 1.75 | Pathogenic | 0.31 | Tolerated | 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 | 0.1412 | 0.2850 | -2.20 | Neutral | 0.985 | Probably Damaging | 0.973 | Probably Damaging | 1.80 | Pathogenic | 0.09 | Tolerated | 1 | 1 | -1.0 | 28.06 | ||||||||||||||||||||||||||||||||||||
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