Table of SynGAP1 Isoform α2 (UniProt Q96PV0-1) Missense Variants.
| c.dna | Variant | SGM Consensus | Domain and Structure information: based on WT protein | Annotated databases | Deep learning-based pathogenicity predictions | Folding stability-based pathogenicity predictions | Sequence/structure-based pathogenicity predictions | Phase Separation | Evolutionary/physical properties | Molecular Dynamics-based analysis | DOI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Domain | IUPred2 | ANCHOR2 | AlphaFold | MobiDB | PhosphoSitePlus | ClinVar | gnomAD | ESM1b | AlphaMissense | FoldX | Rosetta | Foldetta | PremPS | REVEL | PROVEAN | PolyPhen-2 HumDiv | PolyPhen-2 HumVar | FATHMM | SIFT | PSMutPred | PAM | Physical | SASA | Normalized B-factor backbone | Normalized B-factor sidechain | SynGAP Structural Annotation | |||||||||||||||||||||||||||||||||||||||||||||
| Score | Prediction | Score | Prediction | pLDDT | disorder | disorder | LTP | HTP | KL | PTM | Clinical Status | Review | Subm. | ID | Allele count | Allele freq. | LLR score | Prediction | Pathogenicity | Class | Optimized | Average ΔΔG | Prediction | StdDev | ΔΔG | Prediction | ΔΔG | Prediction | ΔΔG | Prediction | Score | Prediction | Score | Prediction | pph2_prob | Prediction | pph2_prob | Prediction | Nervous System Score | Prediction | Prediction | Status | Conservation | Sequences | IP RF | SP RF | Prediction | PAM250 | PAM120 | Hydropathy Δ | MW Δ | Average | Δ | Δ | StdDev | Δ | StdDev | Secondary | Tertiary bonds | Inside out | GAP-Ras interface | At membrane | No effect | MD Alert | Verdict | Description | |||||
| c.287G>A | G96D 2D  AIThe SynGAP1 missense variant G96D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. The variant is most likely benign, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.657645 | Disordered | 0.599491 | Binding | 0.335 | 0.871 | 0.625 | -3.699 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.099 | Likely Benign | -0.95 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.18 | Benign | 0.00 | Affected | 0.2283 | 0.3150 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2903G>A | G968D 2D AIThe SynGAP1 missense variant G968D is catalogued in gnomAD (ID 6‑33443455‑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 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 results are not available for this variant. Consequently, 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 | 0.978316 | Disordered | 0.961360 | Binding | 0.327 | 0.896 | 0.750 | 6-33443455-G-A | 1 | 6.20e-7 | -5.134 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.157 | Likely Benign | -0.48 | Neutral | 0.440 | Benign | 0.198 | Benign | 4.19 | Benign | 0.21 | Tolerated | 4.32 | 2 | 0.1965 | 0.3243 | -1 | 1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||
| c.2942G>A | G981D 2D AIThe SynGAP1 missense variant G981D 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, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Taken together, the balance of evidence leans toward a benign interpretation; there is no ClinVar entry to contradict this assessment. Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.798249 | Disordered | 0.970320 | Binding | 0.275 | 0.897 | 0.625 | -5.280 | Likely Benign | 0.945 | Likely Pathogenic | Ambiguous | 0.159 | Likely Benign | -1.64 | Neutral | 1.000 | Probably Damaging | 0.985 | Probably Damaging | 3.75 | Benign | 0.00 | Affected | 0.1961 | 0.2868 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3041G>A | G1014D 2D AIThe SynGAP1 missense variant G1014D is catalogued in gnomAD (6‑33443593‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports a benign effect, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign impact for G1014D, and this conclusion is not contradicted by any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.914808 | Binding | 0.293 | 0.835 | 0.625 | 6-33443593-G-A | -4.462 | Likely Benign | 0.543 | Ambiguous | Likely Benign | 0.029 | Likely Benign | -1.39 | Neutral | 0.818 | Possibly Damaging | 0.381 | Benign | 2.74 | Benign | 0.77 | Tolerated | 3.77 | 5 | 0.2003 | 0.2942 | -1 | 1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||
| c.308G>A | G103D 2D AIThe SynGAP1 missense variant G103D is not reported in ClinVar and has no entry in gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT each predict a pathogenic impact. The AlphaMissense‑Default tool remains uncertain, and no Foldetta stability assessment is available. High‑accuracy tools specifically highlight benign predictions: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta data are missing. Overall, the balance of evidence points to a benign effect for G103D, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.687376 | Binding | 0.381 | 0.877 | 0.625 | -3.523 | Likely Benign | 0.477 | Ambiguous | Likely Benign | 0.110 | Likely Benign | -0.10 | Neutral | 0.949 | Possibly Damaging | 0.617 | Possibly Damaging | 4.26 | Benign | 0.00 | Affected | 0.2237 | 0.2896 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| 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 | -2.82 | Deleterious | 0.986 | Probably Damaging | 0.787 | Possibly Damaging | -0.74 | Pathogenic | 0.00 | Affected | 0.1677 | 0.2042 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3152G>A | G1051D 2D AISynGAP1 missense variant G1051D is listed in ClinVar as Benign and is present in gnomAD (variant ID 6‑33443704‑G‑A). Prediction tools that classify the variant as benign include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are polyPhen‑2 HumDiv, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign versus two pathogenic votes), and Foldetta stability analysis is unavailable. Overall, the balance of evidence favors a benign effect, consistent with the ClinVar annotation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.900141 | Binding | 0.358 | 0.936 | 0.875 | Benign | 1 | 6-33443704-G-A | 2 | 1.24e-6 | -9.379 | Likely Pathogenic | 0.311 | Likely Benign | Likely Benign | 0.445 | Likely Benign | -0.31 | Neutral | 0.761 | Possibly Damaging | 0.239 | Benign | -0.74 | Pathogenic | 0.39 | Tolerated | 3.77 | 5 | 0.1872 | 0.2235 | -1 | 1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||
| c.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 | -0.26 | Neutral | 0.818 | Possibly Damaging | 0.266 | Benign | 4.07 | Benign | 0.37 | Tolerated | 3.77 | 5 | 0.1824 | 0.2035 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||
| 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 | 0.09 | Neutral | 0.666 | Possibly Damaging | 0.193 | Benign | 1.83 | Pathogenic | 0.92 | Tolerated | 0.1912 | 0.2626 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| 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 | -0.33 | Neutral | 0.077 | Benign | 0.042 | Benign | 5.20 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1889 | 0.2435 | -1 | 1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||
| c.3179G>A | G1060D 2D AIThe SynGAP1 missense variant G1060D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also leans benign (2 benign vs 1 pathogenic). Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.979242 | Disordered | 0.913048 | Binding | 0.407 | 0.928 | 0.875 | -9.824 | Likely Pathogenic | 0.342 | Ambiguous | Likely Benign | 0.391 | Likely Benign | -0.58 | Neutral | 0.905 | Possibly Damaging | 0.538 | Possibly Damaging | 2.63 | Benign | 0.20 | Tolerated | 0.1703 | 0.2035 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3182G>A | G1061D 2D AIThe SynGAP1 missense variant G1061D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and ESM1b, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign prediction (2 benign vs. 1 pathogenic, 1 uncertain). Foldetta results are unavailable. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.978672 | Disordered | 0.926729 | Binding | 0.394 | 0.923 | 0.875 | -9.481 | Likely Pathogenic | 0.346 | Ambiguous | Likely Benign | 0.375 | Likely Benign | -1.32 | Neutral | 0.224 | Benign | 0.120 | Benign | 4.01 | Benign | 0.00 | Affected | 0.1671 | 0.2024 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3188G>A | G1063D 2D AIThe SynGAP1 missense variant G1063D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is likely benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the computational evidence overwhelmingly supports a benign impact for G1063D, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.975134 | Disordered | 0.945784 | Binding | 0.394 | 0.913 | 0.875 | -6.950 | Likely Benign | 0.367 | Ambiguous | Likely Benign | 0.057 | Likely Benign | -0.30 | Neutral | 0.411 | Benign | 0.058 | Benign | 4.24 | Benign | 0.08 | Tolerated | 0.1878 | 0.3026 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.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 | -1.92 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 4.05 | Benign | 0.01 | Affected | 0.1760 | 0.2175 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| 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 | -1.50 | Neutral | 0.901 | Possibly Damaging | 0.540 | Possibly Damaging | 4.00 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1394 | 0.2437 | -1 | 0 | -5.3 | 58.04 | ||||||||||||||||||||||||||||||||||||
| 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 | -1.67 | Neutral | 0.049 | Benign | 0.030 | Benign | 1.93 | Pathogenic | 0.01 | Affected | 0.1924 | 0.3043 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3338G>A | G1113D 2D AIThe SynGAP1 missense variant G1113D is listed in ClinVar with an uncertain significance (ClinVar ID 2766136.0) and is present in gnomAD (variant ID 6‑33443890‑G‑A). Functional prediction tools that agree on a benign outcome include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—all of which classify the substitution as benign. AlphaMissense‑Optimized also predicts a benign effect, whereas AlphaMissense‑Default remains uncertain. No tool predicts a pathogenic effect. The high‑accuracy consensus methods reinforce this benign assessment: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” and AlphaMissense‑Optimized also indicates benign. Foldetta, a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the collective evidence strongly supports a benign impact, and this conclusion does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | Uncertain | 1 | 6-33443890-G-A | -4.638 | Likely Benign | 0.354 | Ambiguous | Likely Benign | 0.061 | Likely Benign | -0.72 | Neutral | 0.029 | Benign | 0.017 | Benign | 2.58 | Benign | 0.34 | Tolerated | 4.32 | 2 | 0.1872 | 0.2452 | -1 | 1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||
| c.3350G>A | G1117D 2D AIThe SynGAP1 missense variant G1117D is catalogued in gnomAD (6‑33443902‑G‑A) but has no ClinVar entry. In silico predictors that agree on benign impact include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic effect, while ESM1b and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it contains two benign and two uncertain calls, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar classification (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.882776 | Disordered | 0.853192 | Binding | 0.323 | 0.914 | 0.750 | 6-33443902-G-A | 1 | 6.61e-7 | -7.594 | In-Between | 0.358 | Ambiguous | Likely Benign | 0.315 | Likely Benign | -0.38 | Neutral | 0.666 | Possibly Damaging | 0.355 | Benign | 4.57 | Benign | 0.24 | Tolerated | 4.32 | 2 | 0.1920 | 0.2635 | -1 | 1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||
| c.3359G>A | G1120D 2D AIThe SynGAP1 missense variant G1120D is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443911‑G‑A). 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. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) resolves to a benign majority (2 benign vs. 1 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact. This conclusion is 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. | 0.871313 | Disordered | 0.804931 | Binding | 0.335 | 0.925 | 0.875 | 6-33443911-G-A | 4 | 2.65e-6 | -9.244 | Likely Pathogenic | 0.378 | Ambiguous | Likely Benign | 0.351 | Likely Benign | -0.82 | Neutral | 0.666 | Possibly Damaging | 0.355 | Benign | 3.60 | Benign | 0.19 | Tolerated | 3.77 | 5 | 0.1659 | 0.1835 | -1 | 1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||
| c.3365G>A | G1122D 2D AIThe SynGAP1 missense variant G1122D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only ESM1b predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also favors benign (2 benign vs. 1 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that G1122D is most likely benign, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.896620 | Disordered | 0.814918 | Binding | 0.357 | 0.932 | 0.875 | -9.991 | Likely Pathogenic | 0.430 | Ambiguous | Likely Benign | 0.332 | Likely Benign | -0.49 | Neutral | 0.411 | Benign | 0.091 | Benign | 4.49 | Benign | 0.10 | Tolerated | 0.1746 | 0.2035 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3368G>A | G1123D 2D AISynGAP1 missense variant G1123D is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443920‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and ESM1b. AlphaMissense‑Default remains uncertain, and Foldetta stability analysis is unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus also benign, while Foldetta provides no result. Overall, the preponderance of evidence points to a benign effect, which does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.837511 | Disordered | 0.827246 | Binding | 0.346 | 0.934 | 0.875 | Uncertain | 2 | 6-33443920-G-A | 2 | 1.33e-6 | -10.321 | Likely Pathogenic | 0.405 | Ambiguous | Likely Benign | 0.360 | Likely Benign | -0.78 | Neutral | 0.500 | Possibly Damaging | 0.157 | Benign | 4.34 | Benign | 0.19 | Tolerated | 3.77 | 5 | 0.1792 | 0.2035 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||
| c.3377G>A | G1126D 2D AISynGAP1 missense variant G1126D is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The AlphaMissense‑Default result is uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.837209 | Binding | 0.345 | 0.918 | 0.875 | Uncertain | 1 | -8.888 | Likely Pathogenic | 0.432 | Ambiguous | Likely Benign | 0.376 | Likely Benign | -0.65 | Neutral | 0.906 | Possibly Damaging | 0.473 | Possibly Damaging | 4.82 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1725 | 0.2224 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||
| c.359G>A | G120D 2D AIThe SynGAP1 missense variant G120D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence overwhelmingly supports a benign classification, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.659993 | Binding | 0.359 | 0.887 | 0.750 | -3.483 | Likely Benign | 0.465 | Ambiguous | Likely Benign | 0.037 | Likely Benign | -0.57 | Neutral | 0.165 | Benign | 0.034 | Benign | 4.25 | Benign | 0.21 | Tolerated | 0.1847 | 0.2024 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.371C>A | A124E 2D AIThe SynGAP1 missense variant A124E is not reported 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 for A124E, 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 | 0.509769 | Disordered | 0.699139 | Binding | 0.340 | 0.883 | 0.750 | -3.444 | Likely Benign | 0.667 | Likely Pathogenic | Likely Benign | 0.208 | Likely Benign | -1.21 | Neutral | 0.993 | Probably Damaging | 0.733 | Possibly Damaging | 4.11 | Benign | 0.01 | Affected | 0.1498 | 0.2233 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3758C>A | A1253E 2D AIThe SynGAP1 missense variant A1253E is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset predicts pathogenicity. High‑accuracy assessments corroborate this benign classification: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.661982 | Disordered | 0.391377 | Uncertain | 0.881 | 0.550 | 0.750 | -1.744 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.059 | Likely Benign | 2.03 | Neutral | 0.301 | Benign | 0.209 | Benign | 3.03 | Benign | 0.98 | Tolerated | 0.0948 | 0.1704 | 0 | -1 | -5.3 | 58.04 | ||||||||||||||||||||||||||||||||||||||
| c.3791G>A | G1264D 2D AIThe SynGAP1 missense variant G1264D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while only AlphaMissense‑Default predicts it as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is also benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -4.725 | Likely Benign | 0.648 | Likely Pathogenic | Likely Benign | 0.097 | Likely Benign | -1.29 | Neutral | 0.012 | Benign | 0.011 | Benign | 2.72 | Benign | 0.23 | Tolerated | 0.1658 | 0.1754 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||
| c.3908G>A | G1303D 2D AIThe SynGAP1 missense variant G1303D is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | -3.825 | Likely Benign | 0.329 | Likely Benign | Likely Benign | 0.103 | Likely Benign | 2.64 | Neutral | 0.002 | Benign | 0.008 | Benign | 3.22 | Benign | 1.00 | Tolerated | 0.1784 | 0.1452 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.392G>A | G131D 2D AIThe SynGAP1 missense variant G131D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. Two tools (ESM1b and AlphaMissense‑Optimized) return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—predicts pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence (four pathogenic, three benign, two uncertain) leans toward pathogenicity. This prediction does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.724779 | Binding | 0.302 | 0.891 | 0.250 | -7.477 | In-Between | 0.950 | Likely Pathogenic | Ambiguous | 0.180 | Likely Benign | -3.29 | Deleterious | 0.888 | Possibly Damaging | 0.435 | Benign | 3.92 | Benign | 0.02 | Affected | 0.2093 | 0.2550 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3950G>A | G1317D 2D AIThe SynGAP1 missense variant G1317D is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33451824‑G‑A). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign prediction (2 benign vs. 1 pathogenic, with one uncertain). Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. 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. | 0.908098 | Disordered | 0.971158 | Binding | 0.385 | 0.879 | 0.750 | 6-33451824-G-A | -4.860 | Likely Benign | 0.520 | Ambiguous | Likely Benign | 0.081 | Likely Benign | -3.54 | Deleterious | 0.588 | Possibly Damaging | 0.212 | Benign | 4.03 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2115 | 0.2859 | -1 | 1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||
| c.4004G>A | G1335D 2D AIThe SynGAP1 missense variant G1335D is reported in ClinVar as “not listed” and is present in gnomAD (variant ID 6‑33451878‑G‑A). Functional prediction tools that agree on a benign effect are REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote) also indicates Likely Pathogenic. Foldetta results are not available for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and the SGM‑Consensus suggests that G1335D 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 | 0.891961 | Disordered | 0.967705 | Binding | 0.323 | 0.724 | 0.750 | 6-33451878-G-A | -5.687 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.404 | Likely Benign | -4.42 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.02 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2120 | 0.3702 | -1 | 1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||
| c.4022C>A | A1341E 2D AIThe SynGAP1 missense variant A1341E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic call comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign consensus. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign. Foldetta stability analysis is not available for this variant. Overall, the majority 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 | 0.823549 | Disordered | 0.980111 | Binding | 0.383 | 0.696 | 1.000 | -3.217 | Likely Benign | 0.307 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -1.18 | Neutral | 0.012 | Benign | 0.015 | Benign | 4.05 | Benign | 0.01 | Affected | 0.1633 | 0.2624 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.44C>A | A15E 2D AIThe SynGAP1 missense variant A15E is reported in gnomAD (ID 6‑33420308‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is provided). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.466055 | Uncertain | 0.330 | 0.912 | 0.375 | 6-33420308-C-A | -3.423 | Likely Benign | 0.277 | Likely Benign | Likely Benign | 0.169 | Likely Benign | 0.46 | Neutral | 0.406 | Benign | 0.040 | Benign | 4.13 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1563 | 0.1908 | -1 | 0 | -5.3 | 58.04 | ||||||||||||||||||||||||||||||||||||
| c.575C>A | A192E 2D AIThe SynGAP1 missense variant A192E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. The protein‑folding stability method Foldetta has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this conclusion 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 | 0.422041 | Structured | 0.428195 | Uncertain | 0.321 | 0.589 | 0.125 | -12.188 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.268 | Likely Benign | -3.52 | Deleterious | 0.997 | Probably Damaging | 0.888 | Possibly Damaging | 3.93 | Benign | 0.01 | Affected | 0.0939 | 0.1628 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.584C>A | A195E 2D AIThe SynGAP1 missense variant A195E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. Foldetta results are unavailable, so they do not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.346032 | Structured | 0.430388 | Uncertain | 0.363 | 0.533 | 0.125 | -10.909 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.237 | Likely Benign | -3.20 | Deleterious | 0.997 | Probably Damaging | 0.879 | Possibly Damaging | 4.12 | Benign | 0.02 | Affected | 0.0855 | 0.1877 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.644G>A | G215D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G215D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SIFT, PolyPhen‑2 (HumDiv and HumVar), PROVEAN, REVEL, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, and FoldX—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta, which evaluates protein‑folding stability, yields an uncertain result. No other high‑confidence tool contradicts the pathogenic prediction. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.155435 | Structured | 0.382818 | Uncertain | 0.791 | 0.291 | 0.000 | -9.884 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.23 | Destabilizing | 0.3 | 0.91 | Ambiguous | 1.57 | Ambiguous | 0.57 | Ambiguous | 0.807 | Likely Pathogenic | -5.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 5.71 | Benign | 0.02 | Affected | 0.1888 | 0.2947 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| c.707C>A | A236E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A236E is not reported in ClinVar and is present in gnomAD (ID 6‑33435558‑C‑A). Functional prediction tools show a split assessment: benign calls come from FATHMM, Rosetta, and the protein‑folding stability method Foldetta; pathogenic calls come from REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score. When grouped by agreement, the benign‑predicting tools (FATHMM, Rosetta, Foldetta) represent one consensus, while the pathogenic‑predicting tools (REVEL, premPS, PROVEAN, polyPhen‑2, SIFT, ESM1b, AlphaMissense‑Default, SGM‑Consensus) form the opposing consensus. High‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain; SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is likely pathogenic; Foldetta, combining FoldX‑MD and Rosetta outputs, is benign. Overall, the majority of predictions lean toward pathogenicity, and this does not contradict the ClinVar status, which has no reported classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | 6-33435558-C-A | 1 | 6.20e-7 | -10.844 | Likely Pathogenic | 0.835 | Likely Pathogenic | Ambiguous | -0.75 | Ambiguous | 0.2 | 0.28 | Likely Benign | -0.24 | Likely Benign | 1.08 | Destabilizing | 0.844 | Likely Pathogenic | -4.24 | Deleterious | 0.998 | Probably Damaging | 0.900 | Possibly Damaging | 6.06 | Benign | 0.02 | Affected | 3.40 | 14 | 0.1075 | 0.1970 | -1 | 0 | -5.3 | 58.04 | ||||||||||||||||||||||||
| c.746C>A | A249E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A249E has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are SIFT and FATHMM. The majority of other in‑silico predictors (SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the variant as pathogenic; FoldX is uncertain and is not counted as evidence for either side. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the preponderance of pathogenic predictions and the absence of benign evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.505461 | Disordered | 0.255452 | Uncertain | 0.810 | 0.336 | 0.125 | -13.519 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 1.60 | Ambiguous | 1.2 | 2.59 | Destabilizing | 2.10 | Destabilizing | 1.02 | Destabilizing | 0.818 | Likely Pathogenic | -3.29 | Deleterious | 0.997 | Probably Damaging | 0.879 | Possibly Damaging | 5.64 | Benign | 0.09 | Tolerated | 0.0799 | 0.1509 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||
| c.875C>A | A292E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292E is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for A292E. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.247041 | Structured | 0.362042 | Uncertain | 0.929 | 0.256 | 0.000 | -14.282 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 6.07 | Destabilizing | 1.2 | 3.82 | Destabilizing | 4.95 | Destabilizing | 1.54 | Destabilizing | 0.475 | Likely Benign | -4.60 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.69 | Pathogenic | 0.02 | Affected | 0.1444 | 0.2205 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||
| c.926G>A | G309D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G309D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are provided by SIFT and Rosetta, whereas the remaining 12 tools (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus) are pathogenic. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta is inconclusive. Taken together, the majority of evidence supports a pathogenic effect. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.338439 | Uncertain | 0.882 | 0.342 | 0.125 | -15.264 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.89 | Destabilizing | 0.5 | -0.03 | Likely Benign | 1.43 | Ambiguous | 0.75 | Ambiguous | 0.523 | Likely Pathogenic | -6.43 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.88 | Pathogenic | 0.06 | Tolerated | 0.1889 | 0.2678 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| c.1046C>G | P349R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P349R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and Rosetta. Uncertain or inconclusive results come from FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for P349R. This conclusion is not contradicted by ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.167087 | Structured | 0.348607 | Uncertain | 0.947 | 0.396 | 0.000 | -14.001 | Likely Pathogenic | 0.791 | Likely Pathogenic | Ambiguous | 0.99 | Ambiguous | 0.1 | 2.15 | Destabilizing | 1.57 | Ambiguous | 0.93 | Ambiguous | 0.335 | Likely Benign | -7.22 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 1.55 | Pathogenic | 0.01 | Affected | 0.1395 | 0.3009 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.1091C>G | P364R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P364R missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic; Foldetta’s stability analysis is uncertain. Overall, the majority of evaluated tools (seven pathogenic vs. three benign) indicate that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.390993 | Structured | 0.439474 | Uncertain | 0.942 | 0.590 | 0.250 | -12.652 | Likely Pathogenic | 0.715 | Likely Pathogenic | Likely Benign | 0.95 | Ambiguous | 0.7 | 0.88 | Ambiguous | 0.92 | Ambiguous | 0.73 | Ambiguous | 0.416 | Likely Benign | -6.76 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 1.57 | Pathogenic | 0.12 | Tolerated | 0.1520 | 0.3977 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.1103C>G | P368R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P368R missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and premPS. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, whereas the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is uncertain. Overall, the majority of evidence—including the SGM‑Consensus and several individual high‑accuracy tools—points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.363090 | Structured | 0.439989 | Uncertain | 0.580 | 0.677 | 0.250 | -9.564 | Likely Pathogenic | 0.736 | Likely Pathogenic | Likely Benign | 1.57 | Ambiguous | 1.0 | 1.54 | Ambiguous | 1.56 | Ambiguous | 0.58 | Ambiguous | 0.263 | Likely Benign | -6.07 | Deleterious | 0.991 | Probably Damaging | 0.881 | Possibly Damaging | 1.78 | Pathogenic | 0.00 | Affected | 0.1439 | 0.3922 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.113C>G | P38R 2D AIThe SynGAP1 missense variant P38R 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 P38R, 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 | 0.497853 | Structured | 0.433285 | Uncertain | 0.344 | 0.791 | 0.375 | -1.799 | Likely Benign | 0.314 | Likely Benign | Likely Benign | 0.168 | Likely Benign | -2.29 | Neutral | 0.989 | Probably Damaging | 0.975 | Probably Damaging | 4.00 | Benign | 0.00 | Affected | 0.1620 | 0.4060 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.1193C>G | P398R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P398R variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include only FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—indicate a pathogenic effect, while Rosetta, premPS, and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.436924 | Structured | 0.401041 | Uncertain | 0.891 | 0.525 | 0.250 | -9.575 | Likely Pathogenic | 0.889 | Likely Pathogenic | Ambiguous | 3.01 | Destabilizing | 0.5 | 1.35 | Ambiguous | 2.18 | Destabilizing | 0.98 | Ambiguous | 0.755 | Likely Pathogenic | -6.55 | Deleterious | 0.988 | Probably Damaging | 0.724 | Possibly Damaging | 5.49 | Benign | 0.00 | Affected | 0.1479 | 0.3472 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.1238C>G | P413R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P413R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The remaining methods, Foldetta and Rosetta, yield uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.332472 | Uncertain | 0.927 | 0.201 | 0.000 | -15.523 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.40 | Destabilizing | 0.2 | 1.34 | Ambiguous | 1.87 | Ambiguous | 1.07 | Destabilizing | 0.562 | Likely Pathogenic | -8.29 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.32 | Benign | 0.01 | Affected | 0.1550 | 0.2199 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.125C>G | P42R 2D AIThe SynGAP1 missense variant P42R is not reported 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 P42R, 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 | 0.308712 | Structured | 0.431487 | Uncertain | 0.420 | 0.771 | 0.375 | -2.498 | Likely Benign | 0.200 | Likely Benign | Likely Benign | 0.087 | Likely Benign | -1.79 | Neutral | 0.972 | Probably Damaging | 0.954 | Probably Damaging | 4.20 | Benign | 0.00 | Affected | 0.1619 | 0.3082 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.1310C>G | P437R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P437R is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, and FATHMM, whereas pathogenic predictions are made by SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. With the majority of tools indicating pathogenicity and the high‑accuracy consensus leaning toward pathogenic, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.306196 | Uncertain | 0.921 | 0.298 | 0.000 | -13.094 | Likely Pathogenic | 0.879 | Likely Pathogenic | Ambiguous | 0.34 | Likely Benign | 0.1 | -3.52 | Stabilizing | -1.59 | Ambiguous | 0.61 | Ambiguous | 0.461 | Likely Benign | -7.72 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.51 | Benign | 0.03 | Affected | 0.1448 | 0.2846 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.137C>G | P46R 2D AIThe SynGAP1 missense variant P46R is catalogued in gnomAD (ID 6‑33423546‑C‑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 (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (FoldX‑MD/Rosetta stability assessment) has no available result. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta data is missing. Overall, the majority of evidence points to a benign effect. There is no ClinVar status to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.390993 | Structured | 0.433588 | Uncertain | 0.549 | 0.741 | 0.375 | 6-33423546-C-G | 1 | 6.20e-7 | -0.520 | Likely Benign | 0.385 | Ambiguous | Likely Benign | 0.155 | Likely Benign | 0.39 | Neutral | 0.972 | Probably Damaging | 0.954 | Probably Damaging | 4.39 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1669 | 0.4543 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||
| c.1583C>G | P528R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P528R missense variant is not reported in ClinVar and is absent from gnomAD. No in silico predictor classifies it as benign; the following tools predict pathogenicity: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Predictions that are uncertain or inconclusive (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -16.367 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.76 | Ambiguous | 0.4 | 0.67 | Ambiguous | 0.72 | Ambiguous | 0.73 | Ambiguous | 0.615 | Likely Pathogenic | -8.58 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.49 | Pathogenic | 0.01 | Affected | 0.1261 | 0.2543 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.1685C>G | P562R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P562R has no ClinVar entry and is not reported in gnomAD. Across the available in‑silico predictors, none classify the change as benign; the majority (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus) predict it to be pathogenic. Two tools (Rosetta and premPS) return uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores it as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic impact. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.022306 | Structured | 0.023606 | Uncertain | 0.893 | 0.200 | 0.000 | -17.309 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.88 | Destabilizing | 1.2 | 0.96 | Ambiguous | 3.42 | Destabilizing | 0.82 | Ambiguous | 0.820 | Likely Pathogenic | -8.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.58 | Pathogenic | 0.02 | Affected | 0.1640 | 0.2489 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.1799C>G | P600R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P600R is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta and premPS, whereas the majority of tools—REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic outcome; FoldX and Foldetta are inconclusive. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the computational evidence strongly favors a pathogenic classification, and this does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009728 | Structured | 0.162960 | Uncertain | 0.947 | 0.147 | 0.000 | -15.304 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.48 | Ambiguous | 0.1 | -2.48 | Stabilizing | -0.50 | Ambiguous | 0.37 | Likely Benign | 0.756 | Likely Pathogenic | -8.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.34 | Pathogenic | 0.00 | Affected | 0.1604 | 0.2734 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.1814C>G | P605R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P605R is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while premPS remains inconclusive. Grouping by consensus, the benign category is empty and the pathogenic category contains all available predictions. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields pathogenic; and Foldetta, integrating FoldX‑MD and Rosetta outputs, reports a destabilizing, pathogenic effect. Consequently, the variant is most likely pathogenic, which does not contradict its current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.023087 | Structured | 0.192737 | Uncertain | 0.929 | 0.231 | 0.000 | Uncertain | 1 | -13.745 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 8.71 | Destabilizing | 2.5 | 6.46 | Destabilizing | 7.59 | Destabilizing | 0.92 | Ambiguous | 0.845 | Likely Pathogenic | -8.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.69 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.1458 | 0.3131 | 0 | -2 | -2.9 | 59.07 | 281.7 | -118.1 | -0.2 | 0.0 | 0.5 | 0.1 | X | X | X | X | Potentially Pathogenic | Pro605 is located in a short turn between an α helix (res. Glu582-Met603) and a short α helical section (res. Ser606-Phe608). The pyrrolidine side chain of Pro605 packs hydrophobically with nearby hydrophobic residues (e.g., Ile514, Leu623, Leu610) in the inter-helix space. Additionally, proline lacks a free backbone amide group, which breaks the α helix and facilitates the turn in the WT structure.In the variant simulations, the guanidinium side chain of Arg605 is bulkier than proline, and its positively charged guanidinium group faces mostly hydrophobic residues (e.g., Ile514, Leu623, Leu610). As a result, it needs to rotate away from the hydrophobic niche. The residue swap could have a more profound effect on the actual folding process, for example, by preventing the bending at the α helix end.Moreover, due to its location at the GAP-Ras interface, the residue swap could affect the GAP-Ras association. | |||||||||||||
| c.1844C>G | P615R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P615R is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, indicates a destabilizing, pathogenic effect. No predictions or stability results are missing or inconclusive. Based on the unanimous pathogenic predictions and the absence of any ClinVar or gnomAD evidence to the contrary, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.179032 | Uncertain | 0.879 | 0.255 | 0.000 | -15.628 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.62 | Destabilizing | 0.5 | 2.69 | Destabilizing | 2.66 | Destabilizing | 1.14 | Destabilizing | 0.871 | Likely Pathogenic | -8.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.29 | Pathogenic | 0.01 | Affected | 0.1463 | 0.2603 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.197C>G | P66R 2D AIThe SynGAP1 missense variant P66R is not reported 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 majority of evidence points toward a benign impact, and there is no ClinVar entry to contradict this assessment. 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 | 0.394753 | Structured | 0.474132 | Uncertain | 0.455 | 0.762 | 0.125 | -2.708 | Likely Benign | 0.940 | Likely Pathogenic | Ambiguous | 0.221 | Likely Benign | -2.23 | Neutral | 0.972 | Probably Damaging | 0.804 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 0.1636 | 0.3928 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2102C>G | P701R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P701R missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Two tools (FoldX and premPS) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta (combining FoldX‑MD and Rosetta outputs) as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation because none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.074921 | Structured | 0.404318 | Uncertain | 0.918 | 0.345 | 0.000 | -11.060 | Likely Pathogenic | 0.779 | Likely Pathogenic | Likely Benign | 0.54 | Ambiguous | 0.0 | -0.19 | Likely Benign | 0.18 | Likely Benign | 0.65 | Ambiguous | 0.088 | Likely Benign | -2.09 | Neutral | 0.784 | Possibly Damaging | 0.278 | Benign | 3.41 | Benign | 0.08 | Tolerated | 0.1365 | 0.2500 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||
| c.2138C>G | P713R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P713R has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, and FATHMM. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The remaining tools, premPS and AlphaMissense‑Optimized, are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of predictions lean toward pathogenicity, while the most accurate methods give conflicting results. Thus, the variant is most likely pathogenic based on the current evidence, and this assessment does not contradict ClinVar status, which has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.393235 | Uncertain | 0.961 | 0.371 | 0.000 | -12.101 | Likely Pathogenic | 0.930 | Likely Pathogenic | Ambiguous | 0.29 | Likely Benign | 0.0 | 0.21 | Likely Benign | 0.25 | Likely Benign | 0.86 | Ambiguous | 0.331 | Likely Benign | -7.42 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.29 | Benign | 0.00 | Affected | 0.1366 | 0.2335 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.2144C>G | P715R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P715R is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors (SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) classify the change as pathogenic. High‑accuracy assessments show that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts a likely pathogenic outcome, AlphaMissense‑Optimized is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Because the pathogenic predictions outnumber the benign ones and the high‑accuracy consensus supports a deleterious effect, the variant is most likely pathogenic. This assessment does not contradict ClinVar, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.243554 | Structured | 0.409757 | Uncertain | 0.956 | 0.362 | 0.000 | -12.191 | Likely Pathogenic | 0.940 | Likely Pathogenic | Ambiguous | 2.19 | Destabilizing | 0.1 | 0.53 | Ambiguous | 1.36 | Ambiguous | 0.87 | Ambiguous | 0.324 | Likely Benign | -8.09 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.53 | Benign | 0.01 | Affected | 0.1389 | 0.2620 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.2183C>G | P728R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P728R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and FoldX, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results are reported by Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments further indicate a likely pathogenic status from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and an uncertain outcome from Foldetta (combining FoldX‑MD and Rosetta). AlphaMissense‑Optimized also remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.632174 | Disordered | 0.434760 | Uncertain | 0.725 | 0.567 | 0.625 | -10.309 | Likely Pathogenic | 0.938 | Likely Pathogenic | Ambiguous | 0.45 | Likely Benign | 0.1 | 0.59 | Ambiguous | 0.52 | Ambiguous | 0.70 | Ambiguous | 0.418 | Likely Benign | -7.46 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 0.66 | Pathogenic | 0.00 | Affected | 0.1728 | 0.2865 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||
| c.2201C>G | P734R 2D AIThe SynGAP1 missense variant P734R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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, 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. 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 | 0.879233 | Disordered | 0.411273 | Uncertain | 0.368 | 0.721 | 0.875 | -6.099 | Likely Benign | 0.288 | Likely Benign | Likely Benign | 0.115 | Likely Benign | -3.00 | Deleterious | 0.984 | Probably Damaging | 0.682 | Possibly Damaging | 2.71 | Benign | 0.07 | Tolerated | 0.1664 | 0.2464 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2222C>G | P741R 2D AIThe SynGAP1 missense variant P741R is not reported 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 | 0.885302 | Disordered | 0.493550 | Uncertain | 0.354 | 0.859 | 0.875 | -4.434 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.070 | Likely Benign | -1.19 | Neutral | 0.642 | Possibly Damaging | 0.393 | Benign | 2.85 | Benign | 0.02 | Affected | 0.1303 | 0.2712 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2228C>G | P743R 2D AIThe SynGAP1 missense variant P743R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.526809 | Binding | 0.317 | 0.862 | 0.875 | -4.295 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.087 | Likely Benign | -1.96 | Neutral | 0.966 | Probably Damaging | 0.494 | Possibly Damaging | 2.73 | Benign | 0.02 | Affected | 0.1488 | 0.2819 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2234C>G | P745R 2D AIThe SynGAP1 missense variant P745R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the conclusion. Overall, the majority of computational evidence points to a benign effect for P745R, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.558331 | Binding | 0.341 | 0.860 | 0.875 | -4.564 | Likely Benign | 0.187 | Likely Benign | Likely Benign | 0.245 | Likely Benign | -2.90 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.51 | Benign | 0.01 | Affected | 0.1571 | 0.2852 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2252C>G | P751R 2D AIThe SynGAP1 missense variant P751R is catalogued in gnomAD (ID 6‑33441717‑C‑G) but has no ClinVar entry. Functional 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 outcome are PROVEAN and polyPhen‑2 HumDiv. 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, SGM‑Consensus is likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.667683 | Binding | 0.386 | 0.866 | 0.625 | 6-33441717-C-G | 1 | 6.20e-7 | -5.646 | Likely Benign | 0.296 | Likely Benign | Likely Benign | 0.157 | Likely Benign | -2.61 | Deleterious | 0.719 | Possibly Damaging | 0.295 | Benign | 2.68 | Benign | 0.06 | Tolerated | 3.99 | 5 | 0.1390 | 0.3644 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||
| c.2360C>G | P787R 2D AIThe SynGAP1 missense variant P787R is not 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, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of conventional tools lean toward pathogenicity, whereas the single high‑accuracy tool indicates benign and the consensus is unresolved. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.901269 | Disordered | 0.613211 | Binding | 0.377 | 0.899 | 0.750 | -5.013 | Likely Benign | 0.784 | Likely Pathogenic | Likely Benign | 0.268 | Likely Benign | -4.41 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.50 | Benign | 0.03 | Affected | 0.1373 | 0.2741 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2366C>G | P789R 2D AIThe SynGAP1 missense variant P789R 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. In contrast, the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all indicate pathogenicity, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also 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 preponderance of evidence points to a pathogenic effect, and this conclusion does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.963420 | Disordered | 0.541575 | Binding | 0.398 | 0.903 | 0.750 | -2.503 | Likely Benign | 0.668 | Likely Pathogenic | Likely Benign | 0.354 | Likely Benign | -5.04 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.03 | Pathogenic | 0.00 | Affected | 0.1353 | 0.2129 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||
| c.2381C>G | P794R 2D AIThe SynGAP1 missense variant P794R 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 from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign effect for P794R, 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 | SH3-binding motif | 0.979741 | Disordered | 0.408951 | Uncertain | 0.550 | 0.898 | 0.875 | -5.136 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -0.73 | Neutral | 0.918 | Possibly Damaging | 0.522 | Possibly Damaging | 4.25 | Benign | 0.02 | Affected | 0.1467 | 0.3662 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||
| c.2384C>G | P795R 2D AIThe SynGAP1 missense variant P795R 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 classifies the change as pathogenic, but this is the sole discordant call. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that P795R 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 | SH3-binding motif | 0.972450 | Disordered | 0.410339 | Uncertain | 0.457 | 0.903 | 0.875 | -6.536 | Likely Benign | 0.221 | Likely Benign | Likely Benign | 0.059 | Likely Benign | -1.02 | Neutral | 0.290 | Benign | 0.114 | Benign | 4.25 | Benign | 0.05 | Affected | 0.1430 | 0.4065 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||
| c.2387C>G | P796R 2D AIThe SynGAP1 P796R missense change is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as “Likely Benign.” Only SIFT predicts a pathogenic outcome, and ESM1b remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Taken together, the overwhelming majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.936162 | Disordered | 0.426363 | Uncertain | 0.427 | 0.900 | 0.875 | -7.053 | In-Between | 0.191 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -0.57 | Neutral | 0.002 | Benign | 0.002 | Benign | 4.28 | Benign | 0.01 | Affected | 0.1558 | 0.2934 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||
| c.2390C>G | P797R 2D AIThe SynGAP1 missense variant P797R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports “Likely Benign.” No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome; Foldetta results are not available. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.926919 | Disordered | 0.449970 | Uncertain | 0.561 | 0.902 | 0.875 | -5.642 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.045 | Likely Benign | 0.00 | Neutral | 0.006 | Benign | 0.026 | Benign | 4.28 | Benign | 0.20 | Tolerated | 0.1549 | 0.3085 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||
| c.2393C>G | P798R 2D AIThe SynGAP1 missense variant P798R is not reported 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 points to a benign effect for P798R, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.871313 | Disordered | 0.492709 | Uncertain | 0.426 | 0.899 | 0.875 | -5.232 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -0.83 | Neutral | 0.976 | Probably Damaging | 0.780 | Possibly Damaging | 4.25 | Benign | 0.00 | Affected | 0.1397 | 0.2840 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||
| c.2396C>G | P799R 2D AIThe SynGAP1 missense variant P799R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a “Likely Benign” outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) likewise indicates benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the preponderance of evidence points to the variant being most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.871313 | Disordered | 0.537892 | Binding | 0.400 | 0.894 | 0.750 | -5.100 | Likely Benign | 0.141 | Likely Benign | Likely Benign | 0.029 | Likely Benign | -0.49 | Neutral | 0.029 | Benign | 0.022 | Benign | 4.27 | Benign | 0.00 | Affected | 0.1425 | 0.2905 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||
| c.2432C>G | P811R 2D AIThe SynGAP1 missense variant P811R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT; AlphaMissense‑Default remains uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome (2 benign vs. 1 pathogenic, with one uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as benign, while Foldetta (combining FoldX‑MD and Rosetta) has no available result. Overall, the preponderance of evidence points to a benign impact for P811R, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -5.273 | Likely Benign | 0.557 | Ambiguous | Likely Benign | 0.065 | Likely Benign | -2.69 | Deleterious | 0.100 | Benign | 0.066 | Benign | 2.73 | Benign | 0.01 | Affected | 0.1448 | 0.3817 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2435C>G | P812R 2D AIThe SynGAP1 P812R missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, the majority of standard predictors indicate a pathogenic impact, while the most accurate tools provide no definitive evidence. Thus, the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.414856 | Structured | 0.842442 | Binding | 0.388 | 0.901 | 0.125 | -6.784 | Likely Benign | 0.799 | Likely Pathogenic | Ambiguous | 0.222 | Likely Benign | -2.70 | Deleterious | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.77 | Benign | 0.01 | Affected | 0.1285 | 0.3525 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2453C>G | P818R 2D AIThe SynGAP1 missense variant P818R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated predictors—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. ESM1b is uncertain and does not contribute to a consensus. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Pathogenic” designation. AlphaMissense‑Optimized independently predicts pathogenicity, while Foldetta results are unavailable. Based on the preponderance of pathogenic predictions and the SGM consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.599170 | Disordered | 0.715889 | Binding | 0.371 | 0.893 | 0.625 | -7.267 | In-Between | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.374 | Likely Benign | -5.12 | Deleterious | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 1.97 | Pathogenic | 0.03 | Affected | 0.1499 | 0.4547 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2489C>G | P830R 2D AIThe SynGAP1 missense variant P830R is not 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 favors 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 reliable predictors and the high‑accuracy consensus indicate a benign impact. This conclusion is not contradicted by any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.590140 | Disordered | 0.618152 | Binding | 0.333 | 0.874 | 0.500 | -5.919 | Likely Benign | 0.515 | Ambiguous | Likely Benign | 0.227 | Likely Benign | -3.51 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.72 | Benign | 0.00 | Affected | 0.1277 | 0.2984 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.2552C>G | P851R 2D AIThe SynGAP1 missense variant P851R 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 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, 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 | 0.648219 | Disordered | 0.526893 | Binding | 0.347 | 0.819 | 0.625 | -4.154 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -0.56 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 4.22 | Benign | 0.09 | Tolerated | 0.1252 | 0.3873 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2654C>G | P885R 2D AIThe SynGAP1 missense variant P885R is reported in gnomAD (ID 6‑33443206‑C‑G) 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 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 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 | 0.690604 | Disordered | 0.636133 | Binding | 0.344 | 0.917 | 0.250 | 6-33443206-C-G | 1 | 6.20e-7 | -4.166 | Likely Benign | 0.308 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -1.99 | Neutral | 0.586 | Possibly Damaging | 0.377 | Benign | 2.84 | Benign | 0.00 | Affected | 4.32 | 4 | 0.1311 | 0.3505 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||
| c.2660C>G | P887R 2D AIThe SynGAP1 missense variant P887R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence supports a benign classification for P887R, 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 | 0.716283 | Disordered | 0.602269 | Binding | 0.348 | 0.925 | 0.500 | -4.759 | Likely Benign | 0.201 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -1.06 | Neutral | 0.802 | Possibly Damaging | 0.413 | Benign | 2.76 | Benign | 1.00 | Tolerated | 0.1306 | 0.2238 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.266C>G | P89R 2D AIThe SynGAP1 missense variant P89R is not 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, and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign). Foldetta results are unavailable. Overall, the balance of evidence (five pathogenic vs. four benign predictions) indicates the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.703578 | Disordered | 0.545797 | Binding | 0.316 | 0.865 | 0.500 | -3.636 | Likely Benign | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.116 | Likely Benign | -3.00 | Deleterious | 0.642 | Possibly Damaging | 0.097 | Benign | 3.83 | Benign | 0.00 | Affected | 0.1720 | 0.3362 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.2750C>G | P917R 2D AIThe SynGAP1 missense variant P917R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (gnomAD ID 6‑33443302‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). 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 (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also 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 | 0.599170 | Disordered | 0.863949 | Binding | 0.314 | 0.862 | 0.375 | Uncertain | 1 | 6-33443302-C-G | 5 | 3.10e-6 | -4.475 | Likely Benign | 0.363 | Ambiguous | Likely Benign | 0.142 | Likely Benign | -1.70 | Neutral | 0.642 | Possibly Damaging | 0.316 | Benign | 2.68 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1270 | 0.3012 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||
| c.2771C>G | P924R 2D AIThe SynGAP1 missense variant P924R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls from REVEL and ESM1b, whereas the remaining seven tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict pathogenicity. Grouping by consensus, the pathogenic group outweighs the benign group. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores the variant as pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. Foldetta data are unavailable. Overall, the preponderance of evidence indicates that P924R 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 | 0.521092 | Disordered | 0.971858 | Binding | 0.293 | 0.846 | 0.250 | -6.024 | Likely Benign | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.420 | Likely Benign | -6.20 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.66 | Pathogenic | 0.00 | Affected | 0.1314 | 0.2083 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2789C>G | P930R 2D AIThe SynGAP1 missense variant P930R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset predicts a benign outcome. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the consensus of available predictions indicates that P930R is most likely pathogenic, and this conclusion is consistent with the absence of a ClinVar entry (i.e., no contradictory status). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.538167 | Disordered | 0.988036 | Binding | 0.304 | 0.855 | 0.375 | -9.474 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.505 | Likely Pathogenic | -6.67 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.66 | Pathogenic | 0.00 | Affected | 0.1460 | 0.3515 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2816C>G | P939R 2D AIThe SynGAP1 missense variant P939R is reported in gnomAD (ID 6‑33443368‑C‑G) but has no ClinVar entry. Functional prediction tools show mixed results: benign calls come from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Grouping by consensus, the benign‑predicted tools outnumbered the pathogenic ones by one, but the overall tally favors pathogenicity (5 pathogenic vs 4 benign). High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is benign, but the SGM Consensus (a 2‑vs‑2 majority among AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields no clear verdict, and Foldetta data are unavailable. Consequently, the variant is most likely pathogenic according to the available predictions, and this assessment does not contradict any ClinVar status because none is reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.935841 | Binding | 0.397 | 0.897 | 0.625 | 6-33443368-C-G | 1 | 6.20e-7 | -4.863 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.199 | Likely Benign | -3.79 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.18 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1360 | 0.3336 | -2 | 0 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.281C>G | P94R 2D AIThe SynGAP1 missense variant P94R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.570978 | Binding | 0.350 | 0.869 | 0.625 | -3.272 | Likely Benign | 0.281 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -2.31 | Neutral | 0.110 | Benign | 0.012 | Benign | 4.11 | Benign | 0.00 | Affected | 0.1445 | 0.2780 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2822C>G | P941R 2D AIThe SynGAP1 missense variant P941R is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the only pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta results are not available, so they do not influence the assessment. Overall, the majority of evidence points to a benign impact for P941R, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.900790 | Binding | 0.403 | 0.906 | 0.625 | -5.463 | Likely Benign | 0.181 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -0.34 | Neutral | 0.144 | Benign | 0.062 | Benign | 2.75 | Benign | 0.01 | Affected | 0.1487 | 0.3775 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2825C>G | P942R 2D AIThe SynGAP1 missense variant P942R 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 | 0.919029 | Disordered | 0.878102 | Binding | 0.365 | 0.915 | 0.625 | -5.405 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.78 | Neutral | 0.411 | Benign | 0.139 | Benign | 2.36 | Pathogenic | 0.00 | Affected | 0.1307 | 0.3693 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2858C>G | P953R 2D AIThe SynGAP1 missense variant P953R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic outcome, creating a single discordant signal. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence supports a benign classification, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.920633 | Binding | 0.403 | 0.926 | 0.750 | -6.036 | Likely Benign | 0.174 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -1.50 | Neutral | 0.611 | Possibly Damaging | 0.185 | Benign | 2.78 | Benign | 0.31 | Tolerated | 0.1771 | 0.4525 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2861C>G | P954R 2D AIThe SynGAP1 missense variant P954R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that P954R is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984159 | Disordered | 0.932268 | Binding | 0.465 | 0.926 | 0.750 | -6.329 | Likely Benign | 0.160 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -1.19 | Neutral | 0.954 | Possibly Damaging | 0.826 | Possibly Damaging | 2.78 | Benign | 0.11 | Tolerated | 0.1548 | 0.3940 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2912C>G | P971R 2D AIThe SynGAP1 missense variant P971R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.950334 | Disordered | 0.951523 | Binding | 0.545 | 0.905 | 0.625 | -4.407 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.042 | Likely Benign | -1.01 | Neutral | 0.453 | Possibly Damaging | 0.078 | Benign | 3.91 | Benign | 0.00 | Affected | 0.1306 | 0.3818 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2915C>G | P972R 2D AIThe SynGAP1 missense variant P972R is reported in gnomAD (ID 6‑33443467‑C‑G) but has no ClinVar entry. All evaluated in silico predictors classify it as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Based on the unanimous benign predictions and lack of ClinVar pathogenic annotation, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.954150 | Binding | 0.472 | 0.904 | 0.625 | 6-33443467-C-G | -4.483 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -1.44 | Neutral | 0.290 | Benign | 0.114 | Benign | 4.23 | Benign | 0.12 | Tolerated | 4.32 | 2 | 0.1379 | 0.3931 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||
| c.2933C>G | P978R 2D AIThe SynGAP1 missense variant P978R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, all of which classify the variant as benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence from multiple independent predictors indicates that P978R 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 | 0.819762 | Disordered | 0.975775 | Binding | 0.425 | 0.892 | 0.625 | -2.852 | Likely Benign | 0.487 | Ambiguous | Likely Benign | 0.105 | Likely Benign | -2.10 | Neutral | 0.970 | Probably Damaging | 0.726 | Possibly Damaging | 4.15 | Benign | 0.01 | Affected | 0.1530 | 0.4590 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2978C>G | P993R 2D AIThe SynGAP1 missense variant P993R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.923979 | Binding | 0.319 | 0.908 | 0.750 | -3.508 | Likely Benign | 0.158 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -0.85 | Neutral | 0.586 | Possibly Damaging | 0.478 | Possibly Damaging | 4.14 | Benign | 0.01 | Affected | 0.1469 | 0.3122 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2984C>G | P995R 2D AIThe SynGAP1 missense variant P995R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv and SIFT predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.935305 | Binding | 0.338 | 0.902 | 0.750 | -4.605 | Likely Benign | 0.141 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -1.06 | Neutral | 0.586 | Possibly Damaging | 0.304 | Benign | 4.18 | Benign | 0.00 | Affected | 0.1370 | 0.3424 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2987C>G | P996R 2D AIThe SynGAP1 missense variant P996R is listed in ClinVar (ID 2808854.0) as benign and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the consensus of the majority of tools, including the high‑accuracy methods, indicates a benign impact. This prediction aligns with the ClinVar benign classification and does not contradict the existing clinical annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.775545 | Disordered | 0.942262 | Binding | 0.312 | 0.900 | 0.750 | Benign | 1 | -4.457 | Likely Benign | 0.141 | Likely Benign | Likely Benign | 0.040 | Likely Benign | -1.04 | Neutral | 0.144 | Benign | 0.085 | Benign | 4.26 | Benign | 0.01 | Affected | 4.32 | 4 | 0.1297 | 0.3385 | -2 | 0 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.3035C>G | P1012R 2D AIThe SynGAP1 missense variant P1012R is not reported in ClinVar and is absent from gnomAD, indicating no documented population frequency. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the consensus of all available predictions strongly supports a benign classification, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.894674 | Binding | 0.319 | 0.866 | 0.625 | -4.413 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.034 | Likely Benign | 1.24 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.89 | Benign | 0.88 | Tolerated | 0.1339 | 0.3083 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.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 | -3.04 | Deleterious | 0.002 | Benign | 0.005 | Benign | 2.40 | Pathogenic | 0.02 | Affected | 0.1366 | 0.4182 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| 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 | 1.07 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 2.89 | Benign | 0.93 | Tolerated | 0.1424 | 0.4201 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| 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 | -3.33 | Deleterious | 0.986 | Probably Damaging | 0.787 | Possibly Damaging | 5.46 | Benign | 0.07 | Tolerated | 0.1401 | 0.4292 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3131C>G | P1044R 2D AIThe SynGAP1 missense variant P1044R is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the collective evidence strongly supports a benign classification, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.979741 | Disordered | 0.952126 | Binding | 0.331 | 0.855 | 0.750 | -3.969 | Likely Benign | 0.242 | Likely Benign | Likely Benign | 0.368 | Likely Benign | 0.79 | Neutral | 0.259 | Benign | 0.140 | Benign | 5.45 | Benign | 1.00 | Tolerated | 0.1451 | 0.4270 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3137C>G | P1046R 2D AIThe SynGAP1 missense variant P1046R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all classify the change as benign or likely benign. Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized returns a benign prediction, and the SGM‑Consensus also indicates a likely benign status. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.970265 | Disordered | 0.942366 | Binding | 0.364 | 0.898 | 0.750 | -4.929 | Likely Benign | 0.222 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -1.79 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.38 | Pathogenic | 0.07 | Tolerated | 0.1267 | 0.3841 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3146C>G | P1049R 2D AIThe SynGAP1 missense variant P1049R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978316 | Disordered | 0.917915 | Binding | 0.428 | 0.920 | 0.750 | -5.144 | Likely Benign | 0.145 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -1.90 | Neutral | 0.791 | Possibly Damaging | 0.500 | Possibly Damaging | 2.74 | Benign | 0.03 | Affected | 0.1376 | 0.3769 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3194C>G | P1065R 2D AIThe SynGAP1 missense variant P1065R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence from multiple independent predictors indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.979741 | Disordered | 0.959518 | Binding | 0.424 | 0.917 | 0.875 | -3.237 | Likely Benign | 0.228 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -2.46 | Neutral | 0.102 | Benign | 0.052 | Benign | 2.00 | Pathogenic | 0.00 | Affected | 0.1439 | 0.4369 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.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 | -2.89 | Deleterious | 0.992 | Probably Damaging | 0.873 | Possibly Damaging | 2.63 | Benign | 0.00 | Affected | 0.1523 | 0.4742 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| 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 | -2.74 | Deleterious | 0.971 | Probably Damaging | 0.580 | Possibly Damaging | 2.78 | Benign | 0.01 | Affected | 0.1300 | 0.3651 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||||
| 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 | -2.87 | Deleterious | 0.970 | Probably Damaging | 0.637 | Possibly Damaging | 3.99 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1370 | 0.4153 | -2 | 0 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| 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 | -3.42 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.86 | Benign | 0.00 | Affected | 0.1319 | 0.3551 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||||
| 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 | -1.93 | Neutral | 0.922 | Possibly Damaging | 0.528 | Possibly Damaging | 2.77 | Benign | 0.04 | Affected | 0.1513 | 0.4576 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| 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 | -1.75 | Neutral | 0.918 | Possibly Damaging | 0.525 | Possibly Damaging | 2.58 | Benign | 0.07 | Tolerated | 0.1517 | 0.4027 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| 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 | -1.28 | Neutral | 0.960 | Probably Damaging | 0.761 | Possibly Damaging | 4.27 | Benign | 0.36 | Tolerated | 0.1497 | 0.4644 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3311C>G | P1104R 2D AIThe SynGAP1 missense variant P1104R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus likewise indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.936162 | Disordered | 0.954801 | Binding | 0.440 | 0.863 | 0.875 | -3.864 | Likely Benign | 0.328 | Likely Benign | Likely Benign | 0.099 | Likely Benign | -0.64 | Neutral | 0.986 | Probably Damaging | 0.761 | Possibly Damaging | 2.68 | Benign | 0.06 | Tolerated | 0.1387 | 0.3703 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.332C>G | P111R 2D AIThe SynGAP1 missense variant P111R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are unavailable 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 | 0.707965 | Disordered | 0.650020 | Binding | 0.438 | 0.858 | 0.750 | -4.811 | Likely Benign | 0.782 | Likely Pathogenic | Likely Benign | 0.100 | Likely Benign | -2.34 | Neutral | 0.421 | Benign | 0.075 | Benign | 4.06 | Benign | 0.00 | Affected | 0.1578 | 0.3015 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3392C>G | P1131R 2D AIThe SynGAP1 P1131R missense variant has no ClinVar record and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta data are unavailable. With five benign versus four pathogenic calls and a benign result from the most accurate tool, the variant is most likely benign. This assessment does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.919029 | Disordered | 0.855155 | Binding | 0.360 | 0.899 | 0.750 | -3.792 | Likely Benign | 0.702 | Likely Pathogenic | Likely Benign | 0.416 | Likely Benign | -2.58 | Deleterious | 0.918 | Possibly Damaging | 0.420 | Benign | 5.26 | Benign | 0.00 | Affected | 0.1252 | 0.4010 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3422C>G | P1141R 2D AIThe SynGAP1 missense variant P1141R is not 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 comprise 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 as benign, while the SGM‑Consensus indicates a likely pathogenic outcome; a Foldetta stability analysis is unavailable. Overall, the majority of computational predictions (seven pathogenic vs. three benign) support a pathogenic classification. This consensus 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 | 0.930790 | Disordered | 0.716087 | Binding | 0.364 | 0.852 | 1.000 | -4.768 | Likely Benign | 0.626 | Likely Pathogenic | Likely Benign | 0.120 | Likely Benign | -3.90 | Deleterious | 0.913 | Possibly Damaging | 0.690 | Possibly Damaging | 0.97 | Pathogenic | 0.00 | Affected | 0.1329 | 0.3614 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3437C>G | P1146R 2D AIThe SynGAP1 missense variant P1146R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. Tools that agree on a benign effect are ESM1b, FATHMM, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of available predictions (seven pathogenic versus three benign) indicate that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, as the variant has no existing ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.919029 | Disordered | 0.732173 | Binding | 0.415 | 0.837 | 1.000 | -3.826 | Likely Benign | 0.729 | Likely Pathogenic | Likely Benign | 0.603 | Likely Pathogenic | -4.81 | Deleterious | 0.996 | Probably Damaging | 0.967 | Probably Damaging | 5.50 | Benign | 0.00 | Affected | 0.1315 | 0.3193 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3446C>G | P1149R 2D AIThe SynGAP1 missense variant P1149R 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 stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for P1149R, 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 | 0.762850 | Disordered | 0.786938 | Binding | 0.424 | 0.837 | 0.625 | -4.340 | Likely Benign | 0.706 | Likely Pathogenic | Likely Benign | 0.101 | Likely Benign | -1.94 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 2.67 | Benign | 0.01 | Affected | 0.1525 | 0.3671 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3485C>G | P1162R 2D AIThe SynGAP1 missense variant P1162R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of predictions (5 pathogenic vs 4 benign) and the pathogenic call from AlphaMissense‑Optimized suggest the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.599170 | Disordered | 0.858809 | Binding | 0.366 | 0.823 | 0.375 | -2.657 | Likely Benign | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.208 | Likely Benign | -2.68 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.70 | Benign | 0.14 | Tolerated | 0.1269 | 0.3439 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.365C>G | P122R 2D AIThe SynGAP1 missense variant P122R has no ClinVar record and is not listed in gnomAD. 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) which reports “Likely Benign.” Pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: 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 balance of evidence favors a benign effect for P122R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.672358 | Binding | 0.400 | 0.887 | 0.750 | -4.981 | Likely Benign | 0.572 | Likely Pathogenic | Likely Benign | 0.132 | Likely Benign | -1.74 | Neutral | 0.952 | Possibly Damaging | 0.521 | Possibly Damaging | 4.18 | Benign | 0.05 | Affected | 0.1796 | 0.2804 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.374C>G | P125R 2D AIThe SynGAP1 missense variant P125R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs 2 benign), and Foldetta data are unavailable. Consequently, the overall computational evidence is split evenly between benign and pathogenic predictions, with no decisive support from the most accurate methods. Based on these predictions, the variant’s impact remains inconclusive; it is neither clearly benign nor pathogenic, and this lack of consensus does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.704227 | Binding | 0.373 | 0.878 | 0.625 | -5.658 | Likely Benign | 0.792 | Likely Pathogenic | Ambiguous | 0.159 | Likely Benign | -4.33 | Deleterious | 0.952 | Possibly Damaging | 0.521 | Possibly Damaging | 2.83 | Benign | 0.09 | Tolerated | 0.1461 | 0.2913 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3833C>G | P1278R 2D AIThe SynGAP1 missense variant P1278R 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 P1278R, 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 | 0.806955 | Binding | 0.532 | 0.722 | 0.750 | -4.246 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -1.11 | Neutral | 0.586 | Possibly Damaging | 0.114 | Benign | 2.69 | Benign | 0.05 | Affected | 0.1640 | 0.2282 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.383C>G | P128R 2D AIThe SynGAP1 missense variant P128R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. When predictions are grouped by consensus, the majority of methods (six) predict benign, while three predict pathogenic. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a likely benign effect. Foldetta results are unavailable. Overall, the computational evidence favors a benign classification for P128R, and this conclusion is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.497853 | Structured | 0.713069 | Binding | 0.376 | 0.878 | 0.625 | -5.048 | Likely Benign | 0.748 | Likely Pathogenic | Likely Benign | 0.188 | Likely Benign | -1.76 | Neutral | 0.984 | Probably Damaging | 0.601 | Possibly Damaging | 4.19 | Benign | 0.08 | Tolerated | 0.1810 | 0.2401 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3848C>G | P1283R 2D AIThe SynGAP1 missense variant P1283R 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 | 0.762850 | Disordered | 0.819686 | Binding | 0.484 | 0.732 | 0.875 | -3.643 | Likely Benign | 0.130 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -1.40 | Neutral | 0.911 | Possibly Damaging | 0.567 | Possibly Damaging | 2.72 | Benign | 0.05 | Affected | 0.1377 | 0.2211 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3854C>G | P1285R 2D AIThe SynGAP1 missense variant P1285R is reported in gnomAD (variant ID 6‑33447902‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the majority of evidence points to a benign impact. There is no ClinVar classification to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.821643 | Binding | 0.557 | 0.759 | 0.750 | 6-33447902-C-G | -3.417 | Likely Benign | 0.157 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -2.10 | Neutral | 0.977 | Probably Damaging | 0.632 | Possibly Damaging | 4.22 | Benign | 0.14 | Tolerated | 4.32 | 2 | 0.1564 | 0.2194 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||
| c.3860C>G | P1287R 2D AIThe SynGAP1 missense variant P1287R 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 reinforce this view: 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 P1287R, 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 | 0.813701 | Binding | 0.538 | 0.777 | 0.750 | -2.180 | Likely Benign | 0.165 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -1.37 | Neutral | 0.586 | Possibly Damaging | 0.172 | Benign | 2.77 | Benign | 0.01 | Affected | 0.1337 | 0.2427 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3899C>G | P1300R 2D AIThe SynGAP1 missense variant P1300R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized returns “Benign” and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates “Likely Benign.” No Foldetta stability analysis is available, so it does not influence the conclusion. Overall, the majority of evidence points to a benign effect for P1300R, 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 | 0.788093 | Disordered | 0.885826 | Binding | 0.400 | 0.834 | 0.875 | -3.930 | Likely Benign | 0.195 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -1.27 | Neutral | 0.901 | Possibly Damaging | 0.516 | Possibly Damaging | 2.82 | Benign | 0.05 | Affected | 0.1516 | 0.2733 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3902C>G | P1301R 2D AIThe SynGAP1 missense variant P1301R is listed in ClinVar with an uncertain significance (ClinVar ID 2092739.0) and is present in gnomAD (ID 6‑33451776‑C‑G). Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign effects. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. In summary, all available predictions agree on a benign impact, and this consensus does not contradict the ClinVar uncertain status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.885064 | Binding | 0.447 | 0.841 | 0.875 | Uncertain | 1 | 6-33451776-C-G | 15 | 9.30e-6 | -4.753 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -1.13 | Neutral | 0.077 | Benign | 0.059 | Benign | 2.81 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.1352 | 0.1929 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||
| c.3911C>G | P1304R 2D AIThe SynGAP1 missense variant P1304R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 HumDiv and SIFT predict pathogenicity, but these two tools represent a minority of the evidence. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of predictions supports a benign classification for P1304R, 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 | 0.885302 | Disordered | 0.886417 | Binding | 0.475 | 0.866 | 0.875 | -4.518 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 0.108 | Likely Benign | -1.21 | Neutral | 0.586 | Possibly Damaging | 0.172 | Benign | 2.93 | Benign | 0.04 | Affected | 0.1717 | 0.3150 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3920C>G | P1307R 2D AIThe SynGAP1 missense variant P1307R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy methods further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the available predictions indicates that P1307R is most likely benign, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.798249 | Disordered | 0.913511 | Binding | 0.491 | 0.901 | 0.875 | -4.022 | Likely Benign | 0.183 | Likely Benign | Likely Benign | 0.225 | Likely Benign | -1.17 | Neutral | 0.887 | Possibly Damaging | 0.664 | Possibly Damaging | 2.82 | Benign | 0.06 | Tolerated | 0.1552 | 0.2763 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3938C>G | P1313R 2D AIThe SynGAP1 missense variant P1313R is not reported in ClinVar and has no entry in gnomAD. Prediction tools that assess pathogenicity are unanimous: all listed algorithms (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a benign effect, while none predict pathogenicity. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized scores the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign,” and the protein‑folding stability tool Foldetta provides no result, so it does not influence the assessment. Based on the collective predictions, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.970301 | Binding | 0.452 | 0.902 | 0.750 | -4.634 | Likely Benign | 0.161 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -0.52 | Neutral | 0.324 | Benign | 0.172 | Benign | 4.25 | Benign | 0.22 | Tolerated | 0.1659 | 0.4742 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3941C>G | P1314R 2D AIThe SynGAP1 missense variant P1314R is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign likelihood. Foldetta results are not available, so they do not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.971592 | Binding | 0.467 | 0.903 | 0.750 | -4.234 | Likely Benign | 0.168 | Likely Benign | Likely Benign | 0.036 | Likely Benign | 0.01 | Neutral | 0.618 | Possibly Damaging | 0.206 | Benign | 4.25 | Benign | 0.09 | Tolerated | 0.1634 | 0.3405 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3959C>G | P1320R 2D AIThe SynGAP1 missense variant P1320R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.946297 | Binding | 0.510 | 0.833 | 0.750 | -5.204 | Likely Benign | 0.160 | Likely Benign | Likely Benign | 0.142 | Likely Benign | -1.39 | Neutral | 0.994 | Probably Damaging | 0.987 | Probably Damaging | 4.25 | Benign | 0.00 | Affected | 0.1558 | 0.4052 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3962C>G | P1321R 2D AIThe SynGAP1 missense variant P1321R is reported in gnomAD (ID 6‑33451836‑C‑G) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool examined—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classifies the substitution as benign. No pathogenic predictions are present. Grouping the results, the benign consensus is unanimous; the pathogenic group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign status. Foldetta stability analysis is not available for this variant. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.933505 | Binding | 0.463 | 0.828 | 0.875 | 6-33451836-C-G | 1 | 6.58e-7 | -5.310 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.034 | Likely Benign | -1.10 | Neutral | 0.389 | Benign | 0.024 | Benign | 4.25 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.1722 | 0.3635 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||
| c.3968C>G | P1323R 2D AIThe SynGAP1 missense variant P1323R is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that P1323R is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.901269 | Disordered | 0.907659 | Binding | 0.489 | 0.814 | 0.875 | -5.785 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -0.67 | Neutral | 0.002 | Benign | 0.003 | Benign | 3.82 | Benign | 0.00 | Affected | 0.1725 | 0.3015 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3971C>G | P1324R 2D AIThe SynGAP1 missense variant P1324R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.899181 | Binding | 0.432 | 0.793 | 0.875 | -5.718 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -0.80 | Neutral | 0.414 | Benign | 0.133 | Benign | 4.28 | Benign | 0.00 | Affected | 0.1723 | 0.3613 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3974C>G | P1325R 2D AIThe SynGAP1 missense variant P1325R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta 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 | 0.876521 | Disordered | 0.893621 | Binding | 0.439 | 0.791 | 0.875 | -5.427 | Likely Benign | 0.173 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -0.33 | Neutral | 0.182 | Benign | 0.029 | Benign | 4.06 | Benign | 0.00 | Affected | 0.1668 | 0.3081 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3977C>G | P1326R 2D AIThe SynGAP1 missense variant P1326R is listed in ClinVar (ID 2429486.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) also benign; 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 | 0.948786 | Disordered | 0.887377 | Binding | 0.393 | 0.782 | 0.875 | Uncertain | 1 | -5.097 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.133 | Likely Benign | -0.82 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 3.62 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1710 | 0.2808 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.3980C>G | P1327R 2D AIThe SynGAP1 missense variant P1327R is reported in gnomAD (variant ID 6‑33451854‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict the variant to be pathogenic. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a likely benign outcome. No Foldetta stability analysis is available, so it does not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | 6-33451854-C-G | -4.724 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.137 | Likely Benign | -0.95 | Neutral | 0.994 | Probably Damaging | 0.937 | Probably Damaging | 4.12 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.1442 | 0.2798 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||
| c.41C>G | P14R 2D AIThe SynGAP1 missense variant P14R is not reported 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 methods give a benign verdict: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” No result is available from Foldetta, so its folding‑stability assessment is not considered. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of any 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 | 0.433034 | Structured | 0.471596 | Uncertain | 0.399 | 0.909 | 0.375 | -2.794 | Likely Benign | 0.253 | Likely Benign | Likely Benign | 0.183 | Likely Benign | 0.13 | Neutral | 0.486 | Possibly Damaging | 0.032 | Benign | 4.20 | Benign | 0.00 | Affected | 0.1597 | 0.3536 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.443C>G | P148R 2D AIThe SynGAP1 missense variant P148R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from multiple in silico predictors and high‑accuracy tools suggests that P148R is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.653063 | Disordered | 0.500109 | Binding | 0.372 | 0.837 | 0.625 | -12.079 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 0.174 | Likely Benign | -3.17 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.92 | Benign | 0.01 | Affected | 0.1615 | 0.3100 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.482C>G | P161R 2D AIThe SynGAP1 missense variant P161R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. Foldetta results are unavailable, so they do not influence the overall assessment. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.509769 | Disordered | 0.520000 | Binding | 0.256 | 0.713 | 0.375 | -13.014 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.302 | Likely Benign | -4.16 | Deleterious | 0.700 | Possibly Damaging | 0.483 | Possibly Damaging | 3.93 | Benign | 0.00 | Affected | 0.1716 | 0.2900 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.566C>G | P189R 2D AIThe SynGAP1 missense variant P189R has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL and FATHMM, whereas the remaining eight tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—indicate pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus confirms a likely pathogenic status. 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 pathogenic effect for P189R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.497853 | Structured | 0.428590 | Uncertain | 0.331 | 0.602 | 0.250 | -13.503 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.331 | Likely Benign | -6.45 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.05 | Benign | 0.01 | Affected | 0.1363 | 0.3894 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.59C>G | P20R 2D AIThe SynGAP1 missense variant P20R is listed in ClinVar (ID 566521.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.529623 | Disordered | 0.442804 | Uncertain | 0.448 | 0.899 | 0.500 | Uncertain | 1 | -3.548 | Likely Benign | 0.434 | Ambiguous | Likely Benign | 0.146 | Likely Benign | -0.15 | Neutral | 0.972 | Probably Damaging | 0.804 | Possibly Damaging | 4.33 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1509 | 0.3272 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.623C>G | P208R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P208R missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and FATHMM. The majority of other in silico predictors (FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score (Likely Pathogenic) all indicate a pathogenic impact, while Rosetta remains uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the preponderance of pathogenic predictions and the absence of any benign consensus, the variant is most likely pathogenic, with no contradiction to ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.271506 | Structured | 0.399506 | Uncertain | 0.864 | 0.345 | 0.125 | -11.929 | Likely Pathogenic | 0.966 | Likely Pathogenic | Likely Pathogenic | 5.25 | Destabilizing | 1.6 | 1.39 | Ambiguous | 3.32 | Destabilizing | 1.16 | Destabilizing | 0.472 | Likely Benign | -7.50 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.75 | Benign | 0.00 | Affected | 0.1676 | 0.3118 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.755C>G | P252R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P252R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Computational predictors that classify the variant as benign are FoldX and FATHMM, whereas the majority of tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. Predictions that are inconclusive are Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic; Foldetta remains uncertain. Overall, the preponderance of evidence indicates that P252R is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.461924 | Structured | 0.211606 | Uncertain | 0.753 | 0.304 | 0.250 | -14.648 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 0.1 | 1.23 | Ambiguous | 0.82 | Ambiguous | 0.81 | Ambiguous | 0.890 | Likely Pathogenic | -8.27 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 5.80 | Benign | 0.00 | Affected | 0.1413 | 0.2848 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.80C>G | P27R 2D AIThe SynGAP1 missense variant P27R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for P27R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.437871 | Uncertain | 0.430 | 0.881 | 0.375 | -3.260 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.146 | Likely Benign | -2.28 | Neutral | 0.972 | Probably Damaging | 0.954 | Probably Damaging | 3.82 | Benign | 0.00 | Affected | 0.1744 | 0.4203 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.824C>G | P275R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P275R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify the change as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments further support this view: the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. AlphaMissense‑Optimized remains uncertain, but its result does not counter the overall consensus. Consequently, the variant is most likely pathogenic, and this conclusion is consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.059222 | Structured | 0.353469 | Uncertain | 0.811 | 0.208 | 0.250 | -13.557 | Likely Pathogenic | 0.915 | Likely Pathogenic | Ambiguous | 2.10 | Destabilizing | 0.6 | 2.11 | Destabilizing | 2.11 | Destabilizing | 0.82 | Ambiguous | 0.645 | Likely Pathogenic | -6.36 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.75 | Pathogenic | 0.01 | Affected | 0.1637 | 0.3039 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.827C>G | P276R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P276R missense variant is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (gnomAD ID 6‑33437732‑C‑G). Prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Stability‑based predictors (FoldX, Rosetta, premPS, Foldetta) are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification; this conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.037156 | Structured | 0.338937 | Uncertain | 0.724 | 0.230 | 0.250 | 6-33437732-C-G | 7 | 4.34e-6 | -10.983 | Likely Pathogenic | 0.714 | Likely Pathogenic | Likely Benign | 1.78 | Ambiguous | 0.2 | 1.02 | Ambiguous | 1.40 | Ambiguous | 0.78 | Ambiguous | 0.498 | Likely Benign | -4.52 | Deleterious | 0.994 | Probably Damaging | 0.892 | Possibly Damaging | 1.89 | Pathogenic | 0.01 | Affected | 3.38 | 19 | 0.1445 | 0.2828 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||
| c.893C>G | P298R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P298R has no ClinVar entry and is not reported in gnomAD. Computational predictors fall into two consensus groups: benign predictions come from REVEL, FoldX, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported only by Foldetta and premPS. High‑accuracy tools give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta reports an uncertain stability change. Overall, the majority of evidence points toward a pathogenic effect, and this assessment is not contradicted by ClinVar, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.268765 | Uncertain | 0.860 | 0.283 | 0.500 | -11.427 | Likely Pathogenic | 0.733 | Likely Pathogenic | Likely Benign | 0.45 | Likely Benign | 0.0 | 2.08 | Destabilizing | 1.27 | Ambiguous | 0.61 | Ambiguous | 0.280 | Likely Benign | -1.83 | Neutral | 0.997 | Probably Damaging | 0.952 | Probably Damaging | 2.03 | Pathogenic | 0.09 | Tolerated | 0.1299 | 0.3872 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.953C>G | P318R 2D 3DClick to see structure in 3D Viewer AISynGAP1 P318R is not reported in ClinVar and is absent from gnomAD. In silico predictors that classify the variant as benign: none. Those that predict pathogenicity include SGM‑Consensus (Likely Pathogenic), REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions from FoldX, Rosetta, and Foldetta are uncertain. High‑accuracy tools give a consistent pathogenic signal: AlphaMissense‑Optimized reports pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; Foldetta remains inconclusive. Overall, the consensus of the majority of predictors supports a pathogenic effect. This conclusion is not contradicted by ClinVar status, which is currently unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.111485 | Structured | 0.400936 | Uncertain | 0.858 | 0.234 | 0.000 | -14.132 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 1.20 | Ambiguous | 0.1 | 0.70 | Ambiguous | 0.95 | Ambiguous | 1.01 | Destabilizing | 0.643 | Likely Pathogenic | -8.01 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.84 | Pathogenic | 0.01 | Affected | 0.1308 | 0.3310 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.1190G>A | C397Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C397Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, Rosetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and the combined Foldetta method. Uncertain results come from AlphaMissense‑Default and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as pathogenic. Overall, the majority of tools and the high‑accuracy consensus lean toward a benign interpretation, and this does not contradict any ClinVar classification (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.429200 | Structured | 0.395774 | Uncertain | 0.778 | 0.551 | 0.250 | -7.213 | In-Between | 0.397 | Ambiguous | Likely Benign | 2.01 | Destabilizing | 2.3 | 8.64 | Destabilizing | 5.33 | Destabilizing | 0.12 | Likely Benign | 0.455 | Likely Benign | -1.82 | Neutral | 0.952 | Possibly Damaging | 0.497 | Possibly Damaging | 4.64 | Benign | 0.07 | Tolerated | 0.1299 | 0.5084 | 0 | -2 | -3.8 | 60.04 | ||||||||||||||||||||||||||||||
| c.1295G>A | C432Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant C432Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while benign predictions are reported by REVEL, Rosetta, FATHMM, and Foldetta. Tools with uncertain or missing results (FoldX, premPS) are not considered evidence. High‑accuracy methods give mixed signals: AlphaMissense‑Optimized and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predict pathogenicity, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect. Overall, the majority of predictions support a pathogenic impact, and this conclusion does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.362533 | Uncertain | 0.960 | 0.285 | 0.000 | -13.720 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.62 | Ambiguous | 0.3 | 0.31 | Likely Benign | 0.47 | Likely Benign | 0.71 | Ambiguous | 0.441 | Likely Benign | -10.50 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.45 | Benign | 0.02 | Affected | 0.0857 | 0.3438 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.146G>A | C49Y 2D AIThe SynGAP1 missense variant C49Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is classified as Likely Pathogenic, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for C49Y. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -11.097 | Likely Pathogenic | 0.949 | Likely Pathogenic | Ambiguous | 0.312 | Likely Benign | -3.38 | Deleterious | 0.676 | Possibly Damaging | 0.761 | Possibly Damaging | 3.85 | Benign | 0.00 | Affected | 0.1016 | 0.3172 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||||||||||||
| c.1571G>A | C524Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C524Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess the variant’s effect largely agree on a deleterious outcome: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic, while premPS is the sole tool predicting a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. With the overwhelming majority of evidence pointing to a damaging effect and no ClinVar annotation to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.024729 | Uncertain | 0.916 | 0.385 | 0.125 | -11.032 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.20 | Destabilizing | 1.4 | 6.24 | Destabilizing | 4.72 | Destabilizing | 0.18 | Likely Benign | 0.863 | Likely Pathogenic | -10.94 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.36 | Pathogenic | 0.00 | Affected | 0.1496 | 0.3911 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.1592G>A | C531Y 2D AIThe SynGAP1 missense variant C531Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only Rosetta, whereas the remaining tools—REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus—consistently predict a pathogenic impact. Uncertain or inconclusive results come from AlphaMissense‑Optimized, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for C531Y. This prediction does not contradict ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.017941 | Uncertain | 0.878 | 0.401 | 0.000 | -11.667 | Likely Pathogenic | 0.914 | Likely Pathogenic | Ambiguous | 3.09 | Destabilizing | 4.6 | 0.15 | Likely Benign | 1.62 | Ambiguous | 0.65 | Ambiguous | 0.551 | Likely Pathogenic | -8.95 | Deleterious | 0.976 | Probably Damaging | 0.480 | Possibly Damaging | -1.24 | Pathogenic | 0.00 | Affected | 0.0843 | 0.3266 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.1637G>A | C546Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C546Y is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that classify the variant as benign include FoldX, premPS, and SIFT, whereas the remaining tools—SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports a pathogenic effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic impact. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.027463 | Structured | 0.009041 | Uncertain | 0.960 | 0.288 | 0.000 | -10.771 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | -0.08 | Likely Benign | 1.8 | 4.75 | Destabilizing | 2.34 | Destabilizing | 0.09 | Likely Benign | 0.794 | Likely Pathogenic | -8.74 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.07 | Pathogenic | 0.29 | Tolerated | 0.1433 | 0.3015 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.1640G>A | C547Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C547Y (ClinVar ID 1404191.0) is listed as Pathogenic in ClinVar and is not reported in gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Taken together, the overwhelming majority of computational evidence indicates a pathogenic effect, which is in agreement with the ClinVar classification. Thus, the variant is most likely pathogenic and does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.007912 | Uncertain | 0.971 | 0.275 | 0.000 | Pathogenic | 1 | -15.871 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 8.53 | Destabilizing | 1.8 | 6.20 | Destabilizing | 7.37 | Destabilizing | 0.62 | Ambiguous | 0.874 | Likely Pathogenic | -10.57 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.33 | Pathogenic | 0.06 | Tolerated | 3.37 | 35 | 0.1393 | 0.2742 | 0 | -2 | -3.8 | 60.04 | 280.1 | -54.8 | 0.0 | 0.0 | 0.0 | 0.0 | X | X | X | Potentially Pathogenic | Cys547 is located in an α-helix (res. Ala533-Val560). The thiol side chain of Cys547 is situated in a hydrophobic inter-helix space, where it packs hydrophobically with other residues such as Ile626, Leu551, and Phe652. Additionally, the thiol side chain of Cys weakly hydrogen bonds with the carbonyl group of Leu543 in the same α-helix. In the variant simulations, the bulkier phenol ring of Tyr547, with its polar hydroxyl group, is less suited for the hydrophobic space. Consequently, it moves outside and forms a hydrogen bond with the carbonyl group of Phe652 in the neighboring α-helix (res. Glu666-Asp644). This causes the two helices to slightly separate, negatively affecting the secondary structure integrity of the latter helix. These negative structural effects could be more pronounced during protein folding and are likely to be undermined in the MD simulations. | ||||||||||||||
| c.1655G>A | C552Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C552Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from premPS and SIFT, and pathogenic predictions from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, while Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence points to a pathogenic impact for C552Y. This conclusion is consistent with the absence of ClinVar annotation and does not contradict any existing database status. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.013265 | Structured | 0.005714 | Uncertain | 0.955 | 0.256 | 0.000 | -13.195 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | -0.96 | Ambiguous | 0.1 | -0.57 | Ambiguous | -0.77 | Ambiguous | 0.41 | Likely Benign | 0.750 | Likely Pathogenic | -9.37 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.23 | Pathogenic | 0.07 | Tolerated | 0.0988 | 0.2563 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.1676G>A | C559Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant C559Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM. Those that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Because the evidence is split evenly between benign and pathogenic predictions and the high‑accuracy tools disagree, the variant is best classified as of uncertain significance. 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 Pathogenic | GAP | 0.016021 | Structured | 0.010460 | Uncertain | 0.842 | 0.204 | 0.000 | -11.767 | Likely Pathogenic | 0.868 | Likely Pathogenic | Ambiguous | -0.37 | Likely Benign | 0.0 | -0.19 | Likely Benign | -0.28 | Likely Benign | 0.36 | Likely Benign | 0.561 | Likely Pathogenic | -8.39 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.45 | Benign | 0.10 | Tolerated | 0.2094 | 0.2135 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.1727G>A | C576Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C576Y is not reported in ClinVar and has no gnomAD allele. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, whereas SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized all classify the change as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also indicates pathogenicity. No tool yields an inconclusive result. Based on the consensus of available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.017684 | Uncertain | 0.913 | 0.245 | 0.000 | -13.891 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 8.77 | Destabilizing | 0.5 | 3.90 | Destabilizing | 6.34 | Destabilizing | 0.63 | Ambiguous | 0.612 | Likely Pathogenic | -9.98 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.38 | Benign | 0.00 | Affected | 0.1398 | 0.3009 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.1796G>A | C599Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C599Y is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that indicate a benign effect include only premPS, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among the majority of tools, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009865 | Structured | 0.151725 | Uncertain | 0.960 | 0.151 | 0.000 | -13.563 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 4.00 | Destabilizing | 1.4 | 2.80 | Destabilizing | 3.40 | Destabilizing | -0.29 | Likely Benign | 0.905 | Likely Pathogenic | -10.95 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.49 | Pathogenic | 0.00 | Affected | 0.1092 | 0.2555 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.2462G>A | C821Y 2D AIThe SynGAP1 missense variant C821Y is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, seven tools support pathogenicity while three support benignity, and no high‑accuracy consensus contradicts this trend. Therefore, the variant is most likely pathogenic based on the available predictions, and this assessment does not conflict with the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.745909 | Disordered | 0.672821 | Binding | 0.351 | 0.883 | 0.750 | -1.007 | Likely Benign | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.342 | Likely Benign | -3.11 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.66 | Benign | 0.01 | Affected | 0.1288 | 0.3187 | 0 | -2 | -3.8 | 60.04 | ||||||||||||||||||||||||||||||||||||||||
| c.656G>A | C219Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219Y is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic effect. High‑accuracy assessments further support this view: AlphaMissense‑Optimized returns a pathogenic prediction; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Based on the preponderance of evidence, the variant is most likely pathogenic, a conclusion that does not contradict its ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | Uncertain | 1 | -14.797 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 8.98 | Destabilizing | 2.0 | 2.84 | Destabilizing | 5.91 | Destabilizing | 0.55 | Ambiguous | 0.812 | Likely Pathogenic | -9.09 | Deleterious | 0.990 | Probably Damaging | 0.758 | Possibly Damaging | 5.81 | Benign | 0.00 | Affected | 0.0772 | 0.3285 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||
| c.689G>A | C230Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230Y is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that indicate a benign effect include FoldX, Rosetta, premPS, SIFT, and FATHMM, whereas those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score is “Likely Pathogenic,” and the Foldetta stability assessment is “Uncertain.” High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.268042 | Structured | 0.308076 | Uncertain | 0.870 | 0.308 | 0.000 | -8.978 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | -0.03 | Likely Benign | 0.1 | -2.24 | Stabilizing | -1.14 | Ambiguous | 0.00 | Likely Benign | 0.816 | Likely Pathogenic | -8.46 | Deleterious | 0.940 | Possibly Damaging | 0.641 | Possibly Damaging | 6.17 | Benign | 0.14 | Tolerated | 0.1159 | 0.3655 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.698G>A | C233Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233Y is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are Rosetta and FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; premPS is uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic (3 pathogenic vs. 1 benign); and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Thus, the variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -17.893 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 13.15 | Destabilizing | 4.6 | 0.04 | Likely Benign | 6.60 | Destabilizing | 0.71 | Ambiguous | 0.904 | Likely Pathogenic | -9.79 | Deleterious | 0.940 | Possibly Damaging | 0.459 | Possibly Damaging | 5.71 | Benign | 0.00 | Affected | 4.29 | 391 | 0.1324 | 0.5284 | 0 | -2 | -3.8 | 60.04 | 248.9 | -63.0 | 0.0 | 0.3 | 0.0 | 0.4 | X | X | Potentially Pathogenic | The introduced residue Tyr233 is located in a β-α loop between an anti-parallel β sheet strand (res. Gly227-Ala232) and an α helix (residues Ala236-Val250). Although the thiol group of a cysteine side chain is not a strong hydrogen bond acceptor or donor, it facilitates hydrogen bonding between Cys233 and the backbone carbonyl of Ala232 in the WT simulations. In the variant simulations, the bulky phenol ring of the Tyr233 side chain stacks with the indole ring of the Trp242 side chain. This interaction could alter the tertiary assembly of the β sheet and α helix due to the residue swap. Indeed, in the second replica simulation, the protein structure begins to unfold to accommodate the introduced Tyr233 side chain. | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||
| c.845G>A | C282Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282Y resides in the C2 domain. ClinVar has no entry for this variant, and it is not listed in gnomAD. Prediction tools that indicate a benign effect are REVEL and premPS. All other evaluated algorithms—FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.098513 | Structured | 0.348535 | Uncertain | 0.942 | 0.250 | 0.000 | -13.438 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 8.50 | Destabilizing | 1.1 | 2.91 | Destabilizing | 5.71 | Destabilizing | 0.41 | Likely Benign | 0.419 | Likely Benign | -10.11 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.63 | Pathogenic | 0.00 | Affected | 0.1069 | 0.3089 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.854G>A | C285Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C285Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and Rosetta. Those that agree on a pathogenic effect include SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive are Foldetta, premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact for C285Y. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.144935 | Structured | 0.375400 | Uncertain | 0.946 | 0.250 | 0.000 | -7.210 | In-Between | 0.895 | Likely Pathogenic | Ambiguous | 3.66 | Destabilizing | 1.1 | -2.33 | Stabilizing | 0.67 | Ambiguous | 0.53 | Ambiguous | 0.484 | Likely Benign | -8.67 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.88 | Pathogenic | 0.18 | Tolerated | 0.1413 | 0.3689 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.110C>T | S37F 2D  AIThe SynGAP1 missense variant S37F 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). AlphaMissense‑Default is uncertain, while the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is 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 from both general and high‑accuracy predictors points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.433492 | Uncertain | 0.317 | 0.806 | 0.500 | -4.258 | Likely Benign | 0.412 | Ambiguous | Likely Benign | 0.131 | Likely Benign | -1.77 | Neutral | 0.676 | Possibly Damaging | 0.828 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 0.1060 | 0.5552 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.1121C>T | S374F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S374F missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 HumDiv and SIFT. Uncertain or inconclusive results are reported for FoldX, Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also indicates a likely benign outcome, while Foldetta’s stability analysis remains uncertain. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.642678 | Disordered | 0.428948 | Uncertain | 0.333 | 0.812 | 0.625 | -7.907 | In-Between | 0.268 | Likely Benign | Likely Benign | 0.55 | Ambiguous | 0.8 | 0.60 | Ambiguous | 0.58 | Ambiguous | -0.19 | Likely Benign | 0.202 | Likely Benign | -1.19 | Neutral | 0.875 | Possibly Damaging | 0.271 | Benign | 6.29 | Benign | 0.00 | Affected | 0.1045 | 0.6427 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.11C>T | S4F 2D AIThe SynGAP1 missense variant S4F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for S4F, 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 | 0.608892 | Disordered | 0.547364 | Binding | 0.390 | 0.924 | 0.750 | -4.880 | Likely Benign | 0.317 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -0.17 | Neutral | 0.676 | Possibly Damaging | 0.485 | Possibly Damaging | 4.13 | Benign | 0.00 | Affected | 0.0686 | 0.6270 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.1412C>T | S471F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and AlphaMissense‑Optimized, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The remaining tools—AlphaMissense‑Default, FoldX, Rosetta, and Foldetta—return uncertain or inconclusive results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts a benign effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Taken together, the majority of evidence points toward a pathogenic impact for S471F, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | -10.777 | Likely Pathogenic | 0.492 | Ambiguous | Likely Benign | -0.54 | Ambiguous | 0.1 | -1.51 | Ambiguous | -1.03 | Ambiguous | 0.12 | Likely Benign | 0.423 | Likely Benign | -4.75 | Deleterious | 0.942 | Possibly Damaging | 0.487 | Possibly Damaging | -1.26 | Pathogenic | 0.02 | Affected | 0.0553 | 0.4691 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.1559C>T | S520F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520F is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include Rosetta, Foldetta, and premPS. Those that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX gives an uncertain result. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, whereas Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign impact. Overall, the majority of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | Uncertain | 1 | -12.541 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | -1.20 | Ambiguous | 0.4 | 0.39 | Likely Benign | -0.41 | Likely Benign | 0.25 | Likely Benign | 0.833 | Likely Pathogenic | -5.57 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.36 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.0668 | 0.4779 | -2 | -3 | 3.6 | 60.10 | |||||||||||||||||||||||||
| c.1601C>T | S534F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, FoldX, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. Tools with uncertain results are AlphaMissense‑Default and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic. Overall, the majority of predictions lean toward a benign effect, and this is consistent with the lack of ClinVar evidence; thus 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. | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | -10.948 | Likely Pathogenic | 0.492 | Ambiguous | Likely Benign | -0.03 | Likely Benign | 0.1 | 0.88 | Ambiguous | 0.43 | Likely Benign | 0.43 | Likely Benign | 0.313 | Likely Benign | -5.09 | Deleterious | 0.998 | Probably Damaging | 0.998 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | 0.0621 | 0.5379 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||
| c.1670C>T | S557F 2D AIThe SynGAP1 missense variant S557F is not reported in ClinVar and has no gnomAD entry. Prediction tools cluster into two groups: the single benign prediction from premPS versus a consensus of pathogenic predictions from the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized). High‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta—all indicate pathogenicity. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic based on the aggregate computational evidence, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.028107 | Structured | 0.010261 | Uncertain | 0.924 | 0.215 | 0.000 | -12.523 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 15.55 | Destabilizing | 5.2 | 9.95 | Destabilizing | 12.75 | Destabilizing | 0.08 | Likely Benign | 0.958 | Likely Pathogenic | -5.38 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.77 | Pathogenic | 0.00 | Affected | 0.1073 | 0.5931 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.1910C>T | S637F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S637F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, FoldX, Foldetta, premPS, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by Rosetta and AlphaMissense‑Optimized. The high‑accuracy consensus (SGM‑Consensus) aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and yields a pathogenic verdict. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, predicts a benign effect. AlphaMissense‑Optimized remains inconclusive. Overall, the majority of evidence points toward a pathogenic impact, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.076542 | Structured | 0.083482 | Uncertain | 0.920 | 0.253 | 0.000 | -13.266 | Likely Pathogenic | 0.831 | Likely Pathogenic | Ambiguous | 0.01 | Likely Benign | 0.1 | 0.96 | Ambiguous | 0.49 | Likely Benign | 0.49 | Likely Benign | 0.222 | Likely Benign | -3.92 | Deleterious | 0.985 | Probably Damaging | 0.681 | Possibly Damaging | 3.35 | Benign | 0.01 | Affected | 0.0780 | 0.4126 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.1976C>T | S659F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S659F is listed in ClinVar with an uncertain significance and is absent from gnomAD. Functional prediction tools that provide definitive calls cluster into two groups: benign predictions come from REVEL, Rosetta, premPS, polyPhen2_HumVar, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen2_HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, SGM Consensus predicts pathogenic, and Foldetta (which integrates FoldX‑MD and Rosetta outputs) yields an uncertain result and is therefore unavailable. Overall, the majority of reliable tools favor a pathogenic effect. Thus, the variant is most likely pathogenic, a conclusion that does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.154597 | Uncertain | 0.954 | 0.283 | 0.000 | Uncertain | 1 | -10.925 | Likely Pathogenic | 0.662 | Likely Pathogenic | Likely Benign | -0.81 | Ambiguous | 0.1 | -0.25 | Likely Benign | -0.53 | Ambiguous | 0.32 | Likely Benign | 0.194 | Likely Benign | -4.59 | Deleterious | 0.806 | Possibly Damaging | 0.171 | Benign | 3.39 | Benign | 0.05 | Affected | 3.38 | 28 | 0.0897 | 0.5828 | -3 | -2 | 3.6 | 60.10 | 221.3 | -61.2 | 0.0 | 0.0 | 0.6 | 0.4 | X | Potentially Benign | In the WT simulations, the hydroxyl group of Ser659, located in a kink in the middle of the long α-helix (res. Ser641-Glu666), forms a hydrogen bond with the carboxylate group of Glu656. However, the phenol ring of the Phe659 side chain cannot form a similar hydrogen bond. Instead, it interacts with the hydrophobic isopropyl side chain of Val555 from the opposing α-helix (res. Ala533-Val560). This residue swap may therefore cause issues during protein folding. | ||||||||||||||||
| c.2003C>T | S668F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S668F is reported in ClinVar as Pathogenic (ClinVar ID 1309930.0) and is not found in gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from premPS and FATHMM, while the remaining 12 tools (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also Pathogenic. No predictions are inconclusive. Overall, the computational evidence strongly supports a pathogenic effect, consistent with the ClinVar classification. Therefore, the variant is most likely pathogenic based on the consensus of prediction tools, and this assessment aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.247041 | Structured | 0.084935 | Uncertain | 0.922 | 0.370 | 0.000 | Likely Pathogenic | 1 | -15.047 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 16.72 | Destabilizing | 5.0 | 11.07 | Destabilizing | 13.90 | Destabilizing | 0.00 | Likely Benign | 0.643 | Likely Pathogenic | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.18 | Benign | 0.00 | Affected | 3.38 | 28 | 0.0656 | 0.5849 | -3 | -2 | 3.6 | 60.10 | 250.9 | -59.6 | -0.1 | 0.1 | 0.0 | 0.1 | X | X | X | Potentially Pathogenic | In the WT simulations, the hydroxyl side chain of Ser668, located on an α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), forms hydrogen bonds with the backbone carbonyl groups of Leu664, Tyr665, and Glu666, as well as the guanidinium group of Arg573 on a nearby α-helix (res. Arg563-Glu578). In the variant simulations, the side chain of Phe668 cannot maintain the same hydrogen-bond network. Due to its larger size, it moves away to avoid steric hindrance. In the WT simulations, a network of hydrogen bonds between several residues (e.g., Asn669, Lys566, and Glu666) keeps both α-helices and the proceeding loop (res. Asn669-Asp684) tightly connected, but this setup is not present in the variant simulations. Additionally, in the variant simulations, the side chain of Arg573 shifts to form a more stable salt bridge with the carboxylate group of Glu582 instead of hydrogen bonding with Ser668 as in the WT simulations. | ||||||||||||||
| c.2069C>T | S690F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S690F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of algorithms predict a pathogenic outcome: FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). The high‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No predictions are inconclusive or missing. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.055536 | Structured | 0.247926 | Uncertain | 0.944 | 0.253 | 0.000 | -14.325 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 9.85 | Destabilizing | 2.4 | 2.17 | Destabilizing | 6.01 | Destabilizing | 0.51 | Ambiguous | 0.384 | Likely Benign | -5.76 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.39 | Benign | 0.00 | Affected | 0.0498 | 0.4800 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.20C>T | S7F 2D AIThe SynGAP1 missense variant S7F is not reported 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, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. AlphaMissense‑Optimized independently predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the majority of 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 | 0.590140 | Disordered | 0.548467 | Binding | 0.386 | 0.922 | 0.750 | -4.346 | Likely Benign | 0.250 | Likely Benign | Likely Benign | 0.171 | Likely Benign | -0.24 | Neutral | 0.296 | Benign | 0.032 | Benign | 4.06 | Benign | 0.00 | Affected | 0.0622 | 0.5177 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.227C>T | S76F 2D AIThe SynGAP1 missense variant S76F is reported in ClinVar as “Not submitted” and is present in gnomAD (variant ID 6-33425835-C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently contains no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.444487 | Uncertain | 0.279 | 0.826 | 0.500 | 6-33425835-C-T | 4 | 2.48e-6 | -4.557 | Likely Benign | 0.197 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -2.40 | Neutral | 0.972 | Probably Damaging | 0.831 | Possibly Damaging | 3.71 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0501 | 0.4887 | -2 | -3 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||
| c.2297C>T | S766F 2D AIThe SynGAP1 missense variant S766F is listed in gnomAD (ID 6‑33442455‑C‑T) but has no ClinVar entry. Functional prediction tools show a split verdict: benign calls come from REVEL, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments further reveal AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains pathogenic; Foldetta results are unavailable. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.405110 | Structured | 0.923125 | Binding | 0.338 | 0.874 | 0.250 | 6-33442455-C-T | -8.944 | Likely Pathogenic | 0.709 | Likely Pathogenic | Likely Benign | 0.233 | Likely Benign | -2.87 | Deleterious | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 4.08 | Benign | 0.00 | Affected | 3.64 | 6 | 0.0770 | 0.5887 | -2 | -3 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||
| c.2312C>T | S771F 2D AIThe SynGAP1 missense variant S771F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools—ESM1b and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is uncertain, and Foldetta stability analysis is unavailable. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not conflict with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.436924 | Structured | 0.922503 | Binding | 0.306 | 0.883 | 0.250 | -7.988 | In-Between | 0.525 | Ambiguous | Likely Benign | 0.189 | Likely Benign | -2.29 | Neutral | 0.990 | Probably Damaging | 0.892 | Possibly Damaging | 4.02 | Benign | 0.04 | Affected | 0.0624 | 0.5428 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||||
| c.2339C>T | S780F 2D AIThe SynGAP1 missense variant S780F is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic) and therefore unavailable as evidence. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is also unavailable for this variant. Overall, the majority of available predictions (five benign vs. four pathogenic) lean toward a benign impact. There is no ClinVar annotation 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. | 0.599170 | Disordered | 0.812415 | Binding | 0.283 | 0.883 | 0.500 | -8.055 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 0.104 | Likely Benign | -1.42 | Neutral | 0.995 | Probably Damaging | 0.925 | Probably Damaging | 2.61 | Benign | 0.10 | Tolerated | 0.0768 | 0.6706 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||||
| c.2363C>T | S788F 2D AIThe SynGAP1 missense variant S788F is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; Foldetta stability analysis is unavailable. Overall, the preponderance of predictions points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.956248 | Disordered | 0.573557 | Binding | 0.349 | 0.895 | 0.750 | -7.870 | In-Between | 0.749 | Likely Pathogenic | Likely Benign | 0.275 | Likely Benign | -4.73 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 1.50 | Pathogenic | 0.00 | Affected | 0.0781 | 0.5824 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||
| c.2447C>T | S816F 2D AIThe SynGAP1 missense variant S816F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls from REVEL and FATHMM, while pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. When predictions are grouped, two tools predict benign and six predict pathogenic. High‑accuracy assessment further supports a pathogenic interpretation: AlphaMissense‑Optimized is uncertain, but the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both conventional and high‑accuracy predictors indicates that S816F is most likely pathogenic, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -8.804 | Likely Pathogenic | 0.903 | Likely Pathogenic | Ambiguous | 0.232 | Likely Benign | -3.21 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.59 | Benign | 0.03 | Affected | 0.0605 | 0.5014 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.2525C>T | S842F 2D AIThe SynGAP1 missense variant S842F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls from REVEL, polyPhen‑2 HumDiv and HumVar, whereas pathogenic calls come from PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default and AlphaMissense‑Optimized. The consensus predictor SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus result is consistent with this. Foldetta, a protein‑folding stability method that combines FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.604312 | Disordered | 0.617281 | Binding | 0.274 | 0.861 | 0.250 | -14.590 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.188 | Likely Benign | -4.12 | Deleterious | 0.029 | Benign | 0.043 | Benign | 1.98 | Pathogenic | 0.00 | Affected | 0.0584 | 0.5692 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.260C>T | S87F 2D AIThe SynGAP1 missense variant S87F is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM. Tools that agree on a pathogenic effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign). 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 (six out of nine) indicate a pathogenic impact, whereas three predict benign. Therefore, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.690604 | Disordered | 0.550904 | Binding | 0.302 | 0.878 | 0.500 | -9.673 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.054 | Likely Benign | -2.34 | Neutral | 0.676 | Possibly Damaging | 0.485 | Possibly Damaging | 3.74 | Benign | 0.00 | Affected | 0.0493 | 0.4937 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||||
| c.2675C>T | S892F 2D AIThe SynGAP1 missense variant S892F is not 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, 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 the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.754692 | Disordered | 0.473390 | Uncertain | 0.319 | 0.926 | 0.875 | -4.709 | Likely Benign | 0.605 | Likely Pathogenic | Likely Benign | 0.090 | Likely Benign | -3.07 | Deleterious | 0.998 | Probably Damaging | 0.959 | Probably Damaging | 2.55 | Benign | 0.00 | Affected | 0.0715 | 0.5124 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||||
| c.2693C>T | S898F 2D AIThe SynGAP1 missense variant S898F is not 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 and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) 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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.690604 | Disordered | 0.426070 | Uncertain | 0.305 | 0.922 | 0.500 | -5.242 | Likely Benign | 0.673 | Likely Pathogenic | Likely Benign | 0.181 | Likely Benign | -2.87 | Deleterious | 0.998 | Probably Damaging | 0.959 | Probably Damaging | 2.44 | Pathogenic | 0.00 | Affected | 0.1183 | 0.6643 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.2777C>T | S926F 2D AIThe SynGAP1 missense variant S926F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. Foldetta results are not available for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that S926F is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.461924 | Structured | 0.981753 | Binding | 0.295 | 0.854 | 0.250 | -6.157 | Likely Benign | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.458 | Likely Benign | -4.57 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.50 | Pathogenic | 0.00 | Affected | 0.0585 | 0.5220 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.2864C>T | S955F 2D AISynGAP1 missense variant S955F is listed in ClinVar as uncertain and is present in gnomAD (ID 6‑33443416‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM; ESM1b is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also returns benign, and Foldetta results are unavailable. Overall, the majority of high‑confidence predictions favor a benign impact, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.984871 | Disordered | 0.945325 | Binding | 0.350 | 0.924 | 0.750 | Conflicting | 4 | 6-33443416-C-T | 95 | 5.89e-5 | -7.374 | In-Between | 0.176 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -1.73 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1246 | 0.4943 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||
| c.2867C>T | S956F 2D AIThe SynGAP1 missense variant S956F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The predictions do not contradict any ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984871 | Disordered | 0.957345 | Binding | 0.364 | 0.917 | 0.750 | -6.654 | Likely Benign | 0.226 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -1.04 | Neutral | 0.832 | Possibly Damaging | 0.398 | Benign | 1.93 | Pathogenic | 0.39 | Tolerated | 0.1315 | 0.4943 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.2966C>T | S989F 2D AIThe SynGAP1 missense variant S989F is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, and Foldetta results are unavailable. Overall, the majority of reliable predictors and the consensus high‑accuracy tools indicate a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.795062 | Disordered | 0.908835 | Binding | 0.296 | 0.911 | 0.750 | -4.115 | Likely Benign | 0.435 | Ambiguous | Likely Benign | 0.109 | Likely Benign | -3.35 | Deleterious | 0.986 | Probably Damaging | 0.876 | Possibly Damaging | 2.60 | Benign | 0.00 | Affected | 0.0598 | 0.5103 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||||
| c.2969C>T | S990F 2D AIThe SynGAP1 missense variant S990F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; no Foldetta stability result is available. Overall, the majority of evidence points to a benign impact for S990F. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.816150 | Disordered | 0.902387 | Binding | 0.301 | 0.919 | 0.750 | -4.253 | Likely Benign | 0.290 | Likely Benign | Likely Benign | 0.107 | Likely Benign | -2.65 | Deleterious | 0.710 | Possibly Damaging | 0.272 | Benign | 2.75 | Benign | 0.00 | Affected | 0.0814 | 0.6021 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.2996C>T | S999F 2D AIThe SynGAP1 missense variant S999F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized independently predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect; this is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.950682 | Binding | 0.262 | 0.897 | 0.625 | -6.206 | Likely Benign | 0.368 | Ambiguous | Likely Benign | 0.072 | Likely Benign | -1.79 | Neutral | 0.966 | Probably Damaging | 0.837 | Possibly Damaging | 2.64 | Benign | 0.01 | Affected | 0.0865 | 0.6337 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.3038C>T | S1013F 2D AIThe SynGAP1 missense variant S1013F is catalogued in gnomAD (ID 6‑33443590‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen2_HumVar, ESM1b, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen2_HumDiv, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign; the SGM Consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive due to mixed signals, and Foldetta results are unavailable. Overall, the balance of evidence, including the benign call from AlphaMissense‑Optimized, points to a likely benign effect. This conclusion does not conflict with ClinVar, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.823549 | Disordered | 0.899570 | Binding | 0.308 | 0.846 | 0.625 | 6-33443590-C-T | 1 | 6.20e-7 | -5.370 | Likely Benign | 0.353 | Ambiguous | Likely Benign | 0.057 | Likely Benign | -2.54 | Deleterious | 0.453 | Possibly Damaging | 0.272 | Benign | 2.65 | Benign | 0.03 | Affected | 3.77 | 5 | 0.0922 | 0.5803 | -2 | -3 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||
| c.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 | -1.02 | Neutral | 0.440 | Benign | 0.185 | Benign | 2.70 | Benign | 0.05 | Affected | 0.0699 | 0.5546 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| 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 | -2.58 | Deleterious | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 3.81 | Benign | 0.00 | Affected | 0.0952 | 0.5957 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||||
| 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 | -2.75 | Deleterious | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.56 | Benign | 0.03 | Affected | 3.77 | 5 | 0.0645 | 0.6029 | -2 | -3 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||
| 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 | -2.17 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.45 | Pathogenic | 0.02 | Affected | 0.0925 | 0.5851 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||||
| c.3395C>T | S1132F 2D AIThe SynGAP1 missense variant S1132F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, 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 both general and high‑accuracy predictors 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 | 0.845506 | Binding | 0.289 | 0.894 | 0.750 | -5.458 | Likely Benign | 0.385 | Ambiguous | Likely Benign | 0.310 | Likely Benign | -2.02 | Neutral | 0.006 | Benign | 0.006 | Benign | 5.41 | Benign | 0.05 | Affected | 0.0921 | 0.5506 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.3413C>T | S1138F 2D AIThe SynGAP1 missense variant S1138F is not reported in ClinVar and is present in gnomAD (ID 6‑33444448‑C‑T). 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. The high‑accuracy AlphaMissense‑Optimized score is benign. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b (benign), FATHMM (benign), and PROVEAN (pathogenic), resolves to 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 a benign effect. This conclusion is consistent with the absence of a ClinVar classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.891961 | Disordered | 0.738250 | Binding | 0.346 | 0.869 | 1.000 | 6-33444448-C-T | 1 | 6.20e-7 | -6.298 | Likely Benign | 0.379 | Ambiguous | Likely Benign | 0.407 | Likely Benign | -2.88 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 5.42 | Benign | 0.03 | Affected | 4.32 | 4 | 0.0991 | 0.5623 | -2 | -3 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||
| c.3425C>T | S1142F 2D AIThe SynGAP1 missense variant S1142F has no ClinVar record and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority, and Foldetta data are unavailable. Overall, the balance of evidence—especially from the high‑accuracy tools—suggests that the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.919029 | Disordered | 0.719935 | Binding | 0.276 | 0.844 | 1.000 | -5.074 | Likely Benign | 0.508 | Ambiguous | Likely Benign | 0.206 | Likely Benign | -3.70 | Deleterious | 0.918 | Possibly Damaging | 0.827 | Possibly Damaging | 2.65 | Benign | 0.00 | Affected | 0.0861 | 0.5603 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||||
| c.3452C>T | S1151F 2D AIThe SynGAP1 missense variant S1151F is 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 based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.741537 | Disordered | 0.805072 | Binding | 0.394 | 0.839 | 0.625 | -4.433 | Likely Benign | 0.661 | Likely Pathogenic | Likely Benign | 0.170 | Likely Benign | -0.60 | Neutral | 0.995 | Probably Damaging | 0.925 | Probably Damaging | 2.70 | Benign | 0.19 | Tolerated | 0.0749 | 0.5370 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.3476C>T | S1159F 2D AIThe SynGAP1 missense variant S1159F 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 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) remains benign; Foldetta stability analysis is unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.626927 | Disordered | 0.867068 | Binding | 0.343 | 0.846 | 0.375 | -5.627 | Likely Benign | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.181 | Likely Benign | -1.11 | Neutral | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 2.66 | Benign | 0.20 | Tolerated | 0.0527 | 0.5211 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.3635C>T | S1212F 2D AIThe SynGAP1 missense variant S1212F is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) score—predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely pathogenic. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence from multiple independent predictors indicates that the variant is most likely pathogenic, which is consistent with its ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.566480 | Disordered | 0.548409 | Binding | 0.852 | 0.565 | 0.500 | Conflicting | 2 | -14.445 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.271 | Likely Benign | -4.52 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.03 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.0503 | 0.4579 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||
| c.3674C>T | S1225F 2D AIThe SynGAP1 missense variant S1225F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. ESM1b is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S1225F, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.513880 | Disordered | 0.441915 | Uncertain | 0.891 | 0.544 | 0.500 | -7.938 | In-Between | 0.328 | Likely Benign | Likely Benign | 0.423 | Likely Benign | -2.34 | Neutral | 0.927 | Possibly Damaging | 0.690 | Possibly Damaging | 5.37 | Benign | 0.06 | Tolerated | 0.0505 | 0.4979 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||
| c.3770C>T | S1257F 2D AIThe SynGAP1 missense variant S1257F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors a benign outcome. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.541878 | Disordered | 0.482380 | Uncertain | 0.889 | 0.572 | 0.375 | -8.584 | Likely Pathogenic | 0.379 | Ambiguous | Likely Benign | 0.141 | Likely Benign | -2.41 | Neutral | 0.966 | Probably Damaging | 0.837 | Possibly Damaging | 2.55 | Benign | 0.08 | Tolerated | 0.0453 | 0.4747 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.419C>T | S140F 2D AIThe SynGAP1 missense variant S140F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic or likely pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports “Likely Pathogenic.” High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote) also indicates likely pathogenic. Foldetta results are unavailable. Overall, the consensus of the available predictions points to a pathogenic effect for S140F, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.476583 | Structured | 0.587898 | Binding | 0.321 | 0.896 | 0.625 | -10.824 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.246 | Likely Benign | -3.83 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 3.48 | Benign | 0.00 | Affected | 0.0565 | 0.5988 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.50C>T | S17F 2D AIThe SynGAP1 missense variant S17F is listed in ClinVar (ID 3451958) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33420314‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.452228 | Uncertain | 0.341 | 0.910 | 0.375 | Conflicting | 2 | 6-33420314-C-T | 10 | 6.49e-6 | -3.888 | Likely Benign | 0.637 | Likely Pathogenic | Likely Benign | 0.048 | Likely Benign | -0.99 | Neutral | 0.486 | Possibly Damaging | 0.032 | Benign | 3.99 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0729 | 0.6468 | -2 | -3 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||
| c.545C>T | S182F 2D AIThe SynGAP1 missense variant S182F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic, and the Foldetta stability analysis is unavailable. Based on the preponderance of pathogenic predictions and the corroborating high‑accuracy tools, the variant is most likely pathogenic, with no conflict with ClinVar status (which is absent). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.501700 | Disordered | 0.436016 | Uncertain | 0.368 | 0.619 | 0.625 | -12.027 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.227 | Likely Benign | -4.30 | Deleterious | 0.838 | Possibly Damaging | 0.466 | Possibly Damaging | 3.64 | Benign | 0.00 | Affected | 0.0597 | 0.5482 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.554C>T | S185F 2D AIThe SynGAP1 missense variant S185F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic outcome. The SGM‑Consensus, a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus as Likely Pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for S185F. This conclusion is consistent with the absence of a ClinVar classification, so there is no contradiction with existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.545602 | Disordered | 0.430485 | Uncertain | 0.365 | 0.623 | 0.500 | -13.327 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.356 | Likely Benign | -5.03 | Deleterious | 0.838 | Possibly Damaging | 0.466 | Possibly Damaging | 3.55 | Benign | 0.00 | Affected | 0.0628 | 0.5563 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.611C>T | S204F 2D AIThe SynGAP1 missense variant S204F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, and FATHMM, whereas a majority of tools (FoldX, Rosetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. 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, predicts a pathogenic effect. Overall, the balance of evidence—seven pathogenic versus four benign predictions, with high‑accuracy tools supporting pathogenicity—suggests that the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.268042 | Structured | 0.420667 | Uncertain | 0.816 | 0.405 | 0.125 | -8.693 | Likely Pathogenic | 0.842 | Likely Pathogenic | Ambiguous | 7.35 | Destabilizing | 6.1 | 4.21 | Destabilizing | 5.78 | Destabilizing | -0.09 | Likely Benign | 0.161 | Likely Benign | -0.88 | Neutral | 0.978 | Probably Damaging | 0.694 | Possibly Damaging | 4.16 | Benign | 0.03 | Affected | 0.0468 | 0.5764 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||
| c.635C>T | S212F 2D AIThe SynGAP1 missense variant S212F is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FoldX, FATHMM, and premPS, whereas the majority of other in‑silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score (Likely Pathogenic) predict a pathogenic outcome. The remaining tools, Foldetta and Rosetta, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Based on the overall consensus of the majority of predictors and the high‑accuracy tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.381517 | Uncertain | 0.846 | 0.278 | 0.125 | -14.029 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.11 | Likely Benign | 1.6 | 0.88 | Ambiguous | 0.50 | Ambiguous | -0.02 | Likely Benign | 0.820 | Likely Pathogenic | -5.15 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 5.76 | Benign | 0.00 | Affected | 0.0503 | 0.6259 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.704C>T | S235F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235F is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FATHMM and Rosetta, whereas the majority of other in silico predictors (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the variant as pathogenic. Two tools give inconclusive results: Foldetta (protein‑folding stability) and premPS. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | -14.456 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 3.03 | Destabilizing | 1.7 | 0.46 | Likely Benign | 1.75 | Ambiguous | 0.56 | Ambiguous | 0.919 | Likely Pathogenic | -5.14 | Deleterious | 0.917 | Possibly Damaging | 0.548 | Possibly Damaging | 5.45 | Benign | 0.00 | Affected | 0.0617 | 0.5393 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.83C>T | S28F 2D AIThe SynGAP1 missense variant S28F is not reported 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 | 0.545602 | Disordered | 0.438157 | Uncertain | 0.354 | 0.884 | 0.125 | -4.548 | Likely Benign | 0.255 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -1.13 | Neutral | 0.009 | Benign | 0.002 | Benign | 4.13 | Benign | 0.05 | Affected | 0.0748 | 0.5340 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.887C>T | S296F 2D AIThe SynGAP1 missense variant S296F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, and premPS. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive and therefore unavailable as evidence. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, 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. | Likely Pathogenic | C2 | 0.444081 | Structured | 0.282669 | Uncertain | 0.887 | 0.284 | 0.250 | -11.721 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 1.29 | Ambiguous | 1.6 | 0.24 | Likely Benign | 0.77 | Ambiguous | 0.29 | Likely Benign | 0.494 | Likely Benign | -4.34 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.94 | Pathogenic | 0.04 | Affected | 0.0720 | 0.5905 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.899C>T | S300F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S300F is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The remaining tool, AlphaMissense‑Default, gives an uncertain result. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions lean toward pathogenicity, while two high‑accuracy methods support a benign effect. Thus, the variant is most likely pathogenic based on the current computational evidence, which does not contradict its ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.356642 | Structured | 0.256848 | Uncertain | 0.742 | 0.280 | 0.375 | Uncertain | 1 | -10.222 | Likely Pathogenic | 0.353 | Ambiguous | Likely Benign | -0.29 | Likely Benign | 0.4 | 0.16 | Likely Benign | -0.07 | Likely Benign | 0.04 | Likely Benign | 0.117 | Likely Benign | -2.66 | Deleterious | 0.975 | Probably Damaging | 0.596 | Possibly Damaging | 1.52 | Pathogenic | 0.01 | Affected | 3.47 | 19 | 0.0579 | 0.5701 | -3 | -2 | 3.6 | 60.10 | 233.6 | -67.6 | -0.1 | 0.0 | 0.4 | 0.2 | X | X | Potentially Pathogenic | The hydroxyl group of the Ser300 side chain, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), hydrogen bonds with the guanidinium group of Arg299 and the backbone amide group and side chain of Ser302. Thus, in the WT simulations, it contributes to the β hairpin stability. In the variant simulations, the phenol ring of Phe300 cannot form any side chain-related hydrogen bonds, and Arg299 is moved away from its central hairpin loop position.β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Due to its location near the membrane surface, the residue swap could also affect the C2 loop dynamics and SynGAP-membrane association. However, this is beyond the scope of the solvent-only simulations to unravel. | |||||||||||||||
| c.905C>T | S302F 2D AIThe SynGAP1 missense variant S302F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and ESM1b; Rosetta’s output is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Benign. Taken together, the majority of evidence supports a benign impact for S302F, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.263489 | Uncertain | 0.616 | 0.258 | 0.375 | -9.483 | Likely Pathogenic | 0.321 | Likely Benign | Likely Benign | -0.04 | Likely Benign | 0.5 | 0.71 | Ambiguous | 0.34 | Likely Benign | -0.21 | Likely Benign | 0.073 | Likely Benign | -0.92 | Neutral | 0.570 | Possibly Damaging | 0.383 | Benign | 4.06 | Benign | 0.01 | Affected | 0.0705 | 0.6092 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.1111A>C | S371R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change S371R is catalogued in gnomAD (ID 6‑33438016‑A‑C) but has no ClinVar entry. Functional prediction programs largely agree on a benign effect: REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, Foldetta, and the SGM‑Consensus score (Likely Benign) all report a non‑pathogenic outcome. Only AlphaMissense‑Default predicts a pathogenic effect, while FoldX and premPS are inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta) is benign. Taken together, the majority of evidence supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.444081 | Structured | 0.432086 | Uncertain | 0.294 | 0.746 | 0.375 | 6-33438016-A-C | -6.415 | Likely Benign | 0.762 | Likely Pathogenic | Likely Benign | 0.51 | Ambiguous | 1.2 | -0.25 | Likely Benign | 0.13 | Likely Benign | 0.57 | Ambiguous | 0.295 | Likely Benign | -1.17 | Neutral | 0.396 | Benign | 0.099 | Benign | 5.35 | Benign | 0.26 | Tolerated | 3.52 | 18 | 0.1362 | 0.4131 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||
| c.1113T>A | S371R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S371R is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all classify the substitution as benign, while AlphaMissense‑Optimized also predicts benign. Only AlphaMissense‑Default indicates a pathogenic outcome; FoldX and premPS are inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Overall, the majority of evidence supports a benign impact, 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 | C2 | 0.444081 | Structured | 0.432086 | Uncertain | 0.294 | 0.746 | 0.375 | -6.415 | Likely Benign | 0.762 | Likely Pathogenic | Likely Benign | 0.51 | Ambiguous | 1.2 | -0.25 | Likely Benign | 0.13 | Likely Benign | 0.57 | Ambiguous | 0.344 | Likely Benign | -1.17 | Neutral | 0.396 | Benign | 0.099 | Benign | 5.35 | Benign | 0.26 | Tolerated | 3.52 | 18 | 0.1362 | 0.4131 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||
| c.1113T>G | S371R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S371R is reported in gnomAD (variant ID 6‑33438018‑T‑G) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves as “Likely Benign” (3 benign vs. 1 pathogenic). High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM‑Consensus is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No prediction or stability result is missing or inconclusive. Overall, the evidence strongly favors a benign classification, and this is consistent with the absence of a ClinVar pathogenic report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.444081 | Structured | 0.432086 | Uncertain | 0.294 | 0.746 | 0.375 | 6-33438018-T-G | 1 | 1.18e-6 | -6.415 | Likely Benign | 0.762 | Likely Pathogenic | Likely Benign | 0.51 | Ambiguous | 1.2 | -0.25 | Likely Benign | 0.13 | Likely Benign | 0.57 | Ambiguous | 0.340 | Likely Benign | -1.17 | Neutral | 0.396 | Benign | 0.099 | Benign | 5.35 | Benign | 0.26 | Tolerated | 3.52 | 18 | 0.1362 | 0.4131 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||
| c.1228A>C | S410R 2D 3DClick to see structure in 3D Viewer AIClinVar contains no record for the SynGAP1 S410R variant, and it is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, premPS, AlphaMissense‑Optimized) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, Foldetta predicts a benign impact, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive. Taken together, the majority of evidence points to a benign outcome. This conclusion does not contradict ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.098513 | Structured | 0.349627 | Uncertain | 0.908 | 0.206 | 0.000 | -8.203 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | -0.67 | Ambiguous | 0.2 | 0.56 | Ambiguous | -0.06 | Likely Benign | 0.62 | Ambiguous | 0.242 | Likely Benign | -2.47 | Neutral | 0.871 | Possibly Damaging | 0.298 | Benign | 4.20 | Benign | 0.40 | Tolerated | 0.0955 | 0.3927 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||
| c.1230C>A | S410R 2D 3DClick to see structure in 3D Viewer AIClinVar contains no record for the SynGAP1 S410R variant, and it is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, premPS, AlphaMissense‑Optimized) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, Foldetta predicts a benign impact, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive. Taken together, the majority of evidence points to a benign outcome. This conclusion does not contradict ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.098513 | Structured | 0.349627 | Uncertain | 0.908 | 0.206 | 0.000 | -8.203 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | -0.67 | Ambiguous | 0.2 | 0.56 | Ambiguous | -0.06 | Likely Benign | 0.62 | Ambiguous | 0.148 | Likely Benign | -2.47 | Neutral | 0.871 | Possibly Damaging | 0.298 | Benign | 4.20 | Benign | 0.40 | Tolerated | 0.0955 | 0.3927 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||
| c.1230C>G | S410R 2D 3DClick to see structure in 3D Viewer AIClinVar contains no record for the SynGAP1 S410R variant, and it is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, premPS, AlphaMissense‑Optimized) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, Foldetta predicts a benign impact, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive. Taken together, the majority of evidence points to a benign outcome. This conclusion does not contradict ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.098513 | Structured | 0.349627 | Uncertain | 0.908 | 0.206 | 0.000 | -8.203 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | -0.67 | Ambiguous | 0.2 | 0.56 | Ambiguous | -0.06 | Likely Benign | 0.62 | Ambiguous | 0.146 | Likely Benign | -2.47 | Neutral | 0.871 | Possibly Damaging | 0.298 | Benign | 4.20 | Benign | 0.40 | Tolerated | 0.0955 | 0.3927 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||
| c.1345A>C | S449R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S449R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are SGM Consensus, PROVEAN, polyPhen‑2 HumDiv, AlphaMissense‑Default, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifying it as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yielding an uncertain stability change. No folding‑stability prediction is definitive. Overall, the majority of tools predict a benign outcome, and this does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -8.486 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | -0.69 | Ambiguous | 0.2 | -1.33 | Ambiguous | -1.01 | Ambiguous | 0.50 | Likely Benign | 0.145 | Likely Benign | -3.36 | Deleterious | 0.950 | Possibly Damaging | 0.214 | Benign | 3.40 | Benign | 0.18 | Tolerated | 0.0762 | 0.3250 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1347T>A | S449R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449R is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, SIFT, FATHMM, and polyPhen‑2 HumVar, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments provide a mixed picture: AlphaMissense‑Optimized predicts a benign effect, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an inconclusive result. FoldX and Rosetta predictions are also uncertain and are treated as unavailable. Overall, the evidence is balanced, with an equal number of benign and pathogenic calls, and the high‑accuracy tools do not converge on a single conclusion. Consequently, the variant is most likely pathogenic based on the preponderance of pathogenic predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -8.486 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | -0.69 | Ambiguous | 0.2 | -1.33 | Ambiguous | -1.01 | Ambiguous | 0.50 | Likely Benign | 0.168 | Likely Benign | -3.36 | Deleterious | 0.950 | Possibly Damaging | 0.214 | Benign | 3.40 | Benign | 0.18 | Tolerated | 0.0762 | 0.3250 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1347T>G | S449R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449R is not reported in ClinVar (ClinVar status: None) and has no entry in gnomAD (gnomAD ID: None). Prediction tools that classify the variant as benign include REVEL, premPS, SIFT, FATHMM, and polyPhen‑2 HumVar. Those that predict pathogenicity are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicting a benign effect, while the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; Foldetta’s stability prediction is uncertain and therefore treated as unavailable. Overall, the predictions are split, with an equal number of benign and pathogenic calls and conflicting high‑accuracy results. Consequently, the variant’s impact remains inconclusive, and there is no contradiction with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -8.486 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | -0.69 | Ambiguous | 0.2 | -1.33 | Ambiguous | -1.01 | Ambiguous | 0.50 | Likely Benign | 0.167 | Likely Benign | -3.36 | Deleterious | 0.950 | Possibly Damaging | 0.214 | Benign | 3.40 | Benign | 0.18 | Tolerated | 0.0762 | 0.3250 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1369A>C | S457R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S457R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign calls come from REVEL, Rosetta, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX, Foldetta, and premPS are inconclusive. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenic, whereas Foldetta’s stability analysis is uncertain. Overall, the majority of evidence points toward a pathogenic impact. This conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -10.882 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | -1.04 | Ambiguous | 0.0 | -0.06 | Likely Benign | -0.55 | Ambiguous | 0.74 | Ambiguous | 0.468 | Likely Benign | -4.47 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.30 | Benign | 0.05 | Affected | 0.0781 | 0.3426 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1371T>A | S457R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S457R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, SGM‑Consensus confirms a likely pathogenic status, and Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. No other high‑confidence stability predictions are available. Overall, the preponderance of evidence from multiple independent predictors indicates that S457R is most likely pathogenic, and this assessment does not contradict any existing ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -10.882 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | -1.04 | Ambiguous | 0.0 | -0.06 | Likely Benign | -0.55 | Ambiguous | 0.74 | Ambiguous | 0.343 | Likely Benign | -4.47 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.30 | Benign | 0.05 | Affected | 0.0781 | 0.3426 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1371T>G | S457R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S457R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, SGM‑Consensus confirms a likely pathogenic status, and Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. No other high‑confidence stability predictions are available. Overall, the preponderance of evidence from multiple independent predictors indicates that S457R is most likely pathogenic, and this assessment does not contradict any existing ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -10.882 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | -1.04 | Ambiguous | 0.0 | -0.06 | Likely Benign | -0.55 | Ambiguous | 0.74 | Ambiguous | 0.343 | Likely Benign | -4.47 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.30 | Benign | 0.05 | Affected | 0.0781 | 0.3426 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1603A>C | S535R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S535R is not reported in ClinVar and is present in gnomAD (ID 6‑33438846‑A‑C). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results come from AlphaMissense‑Optimized, Foldetta, Rosetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the balance of evidence, especially the SGM Consensus, points to a pathogenic interpretation. 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. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | 6-33438846-A-C | 3 | 1.86e-6 | -9.363 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | -0.37 | Likely Benign | 0.0 | -0.97 | Ambiguous | -0.67 | Ambiguous | 0.64 | Ambiguous | 0.390 | Likely Benign | -1.99 | Neutral | 0.830 | Possibly Damaging | 0.274 | Benign | -1.23 | Pathogenic | 0.19 | Tolerated | 3.37 | 35 | 0.1086 | 0.3743 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||
| c.1605T>A | S535R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S535R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, and SIFT, while pathogenic calls come from polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments indicate that AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta is also inconclusive. Overall, the balance of evidence, particularly the SGM Consensus, points to a pathogenic effect. This conclusion does not conflict with ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | -9.363 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | -0.37 | Likely Benign | 0.0 | -0.97 | Ambiguous | -0.67 | Ambiguous | 0.64 | Ambiguous | 0.432 | Likely Benign | -1.99 | Neutral | 0.830 | Possibly Damaging | 0.274 | Benign | -1.23 | Pathogenic | 0.19 | Tolerated | 3.37 | 35 | 0.1086 | 0.3743 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||
| c.1605T>G | S535R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S535R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, and SIFT, while pathogenic calls come from polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments indicate that AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta is also inconclusive. Overall, the balance of evidence, particularly the SGM Consensus, points to a pathogenic effect. This conclusion does not conflict with ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | -9.363 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | -0.37 | Likely Benign | 0.0 | -0.97 | Ambiguous | -0.67 | Ambiguous | 0.64 | Ambiguous | 0.432 | Likely Benign | -1.99 | Neutral | 0.830 | Possibly Damaging | 0.274 | Benign | -1.23 | Pathogenic | 0.19 | Tolerated | 3.37 | 35 | 0.1086 | 0.3743 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||
| c.1768A>C | S590R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S590R is not reported in ClinVar (status: None) and has no entries in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus (likely pathogenic), REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions are inconclusive or missing. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.022667 | Structured | 0.088943 | Uncertain | 0.918 | 0.199 | 0.000 | -18.228 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.69 | Ambiguous | 0.6 | 3.21 | Destabilizing | 2.45 | Destabilizing | 1.28 | Destabilizing | 0.640 | Likely Pathogenic | -4.88 | Deleterious | 1.000 | Probably Damaging | 0.979 | Probably Damaging | 3.11 | Benign | 0.01 | Affected | 0.0983 | 0.3388 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1770C>A | S590R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S590R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools (AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, Rosetta, and Foldetta) all predict a pathogenic impact; FoldX is uncertain and therefore not counted. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.022667 | Structured | 0.088943 | Uncertain | 0.918 | 0.199 | 0.000 | -18.228 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.69 | Ambiguous | 0.6 | 3.21 | Destabilizing | 2.45 | Destabilizing | 1.28 | Destabilizing | 0.391 | Likely Benign | -4.88 | Deleterious | 1.000 | Probably Damaging | 0.979 | Probably Damaging | 3.11 | Benign | 0.01 | Affected | 0.0983 | 0.3388 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1770C>G | S590R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S590R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools (AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, Rosetta, and Foldetta) all predict a pathogenic impact; FoldX is uncertain and therefore not counted. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.022667 | Structured | 0.088943 | Uncertain | 0.918 | 0.199 | 0.000 | -18.228 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.69 | Ambiguous | 0.6 | 3.21 | Destabilizing | 2.45 | Destabilizing | 1.28 | Destabilizing | 0.389 | Likely Benign | -4.88 | Deleterious | 1.000 | Probably Damaging | 0.979 | Probably Damaging | 3.11 | Benign | 0.01 | Affected | 0.0983 | 0.3388 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1816A>C | S606R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S606R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, and FATHMM, whereas a separate group predicts pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Tools with uncertain outcomes are Foldetta, premPS, and Rosetta. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta remains inconclusive. Overall, the majority of high‑confidence predictions and the consensus vote indicate a pathogenic effect. Because ClinVar contains no entry for this variant, there is no contradiction between the computational evidence and clinical annotation. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.191720 | Uncertain | 0.875 | 0.247 | 0.000 | -12.900 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.15 | Likely Benign | 0.4 | 1.80 | Ambiguous | 0.98 | Ambiguous | 0.82 | Ambiguous | 0.252 | Likely Benign | -4.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 3.38 | Benign | 0.08 | Tolerated | 0.0819 | 0.2750 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1818T>A | S606R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S606R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, and FATHMM, whereas a separate group predicts pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Tools with uncertain outcomes are Foldetta, premPS, and Rosetta. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta remains inconclusive. Overall, the majority of high‑confidence predictions and the consensus vote indicate a pathogenic effect. Because ClinVar contains no entry for this variant, there is no contradiction between the computational evidence and clinical annotation. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.191720 | Uncertain | 0.875 | 0.247 | 0.000 | -12.900 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.15 | Likely Benign | 0.4 | 1.80 | Ambiguous | 0.98 | Ambiguous | 0.82 | Ambiguous | 0.246 | Likely Benign | -4.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 3.38 | Benign | 0.08 | Tolerated | 0.0819 | 0.2750 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1818T>G | S606R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S606R is not reported in ClinVar or gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, SIFT, and FATHMM, whereas a majority predict pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. High‑accuracy methods confirm the pathogenic trend: AlphaMissense‑Optimized is pathogenic, SGM Consensus is Likely Pathogenic, and Foldetta remains uncertain. Overall, the evidence points to the variant being most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.191720 | Uncertain | 0.875 | 0.247 | 0.000 | -12.900 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.15 | Likely Benign | 0.4 | 1.80 | Ambiguous | 0.98 | Ambiguous | 0.82 | Ambiguous | 0.246 | Likely Benign | -4.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 3.38 | Benign | 0.08 | Tolerated | 0.0819 | 0.2750 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.2026A>C | S676R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S676R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, FATHMM, and polyPhen‑2 HumVar, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or folding stability result is missing; all available data are reported. Overall, the balance of evidence (six benign versus four pathogenic predictions, with the high‑accuracy Foldetta supporting benign) indicates that the variant is most likely benign. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.209395 | Structured | 0.113632 | Uncertain | 0.551 | 0.338 | 0.125 | -10.665 | Likely Pathogenic | 0.936 | Likely Pathogenic | Ambiguous | 0.22 | Likely Benign | 0.3 | 0.74 | Ambiguous | 0.48 | Likely Benign | 0.45 | Likely Benign | 0.136 | Likely Benign | -2.34 | Neutral | 0.891 | Possibly Damaging | 0.278 | Benign | 3.40 | Benign | 0.02 | Affected | 0.0962 | 0.3454 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||
| c.2028C>A | S676R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S676R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, FATHMM, and polyPhen‑2 HumVar, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or folding stability result is missing; all available data are included. Overall, the balance of evidence (six benign versus four pathogenic predictions, with the high‑accuracy Foldetta supporting benign) indicates that the variant is most likely benign. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.209395 | Structured | 0.113632 | Uncertain | 0.551 | 0.338 | 0.125 | -10.665 | Likely Pathogenic | 0.936 | Likely Pathogenic | Ambiguous | 0.22 | Likely Benign | 0.3 | 0.74 | Ambiguous | 0.48 | Likely Benign | 0.45 | Likely Benign | 0.157 | Likely Benign | -2.34 | Neutral | 0.891 | Possibly Damaging | 0.278 | Benign | 3.40 | Benign | 0.02 | Affected | 0.0962 | 0.3454 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||
| c.2028C>G | S676R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S676R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, FATHMM, and polyPhen‑2 HumVar, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or folding stability result is missing; all available data are included. Overall, the balance of evidence (six benign versus four pathogenic predictions, with the high‑accuracy Foldetta supporting benign) indicates that the variant is most likely benign. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.209395 | Structured | 0.113632 | Uncertain | 0.551 | 0.338 | 0.125 | -10.665 | Likely Pathogenic | 0.936 | Likely Pathogenic | Ambiguous | 0.22 | Likely Benign | 0.3 | 0.74 | Ambiguous | 0.48 | Likely Benign | 0.45 | Likely Benign | 0.156 | Likely Benign | -2.34 | Neutral | 0.891 | Possibly Damaging | 0.278 | Benign | 3.40 | Benign | 0.02 | Affected | 0.0962 | 0.3454 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||
| c.2029A>C | S677R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S677R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Those that predict a pathogenic effect are FoldX, ESM1b, and AlphaMissense‑Default. Uncertain results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta is also inconclusive. Overall, the majority of tools and the high‑accuracy benign prediction suggest the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.194234 | Structured | 0.115685 | Uncertain | 0.555 | 0.338 | 0.125 | -9.388 | Likely Pathogenic | 0.714 | Likely Pathogenic | Likely Benign | 2.59 | Destabilizing | 0.1 | 0.73 | Ambiguous | 1.66 | Ambiguous | 0.71 | Ambiguous | 0.104 | Likely Benign | -2.49 | Neutral | 0.385 | Benign | 0.037 | Benign | 3.31 | Benign | 0.12 | Tolerated | 0.1120 | 0.4195 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||
| c.2031T>A | S677R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S677R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are FoldX, ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are Rosetta, Foldetta, and premPS. High‑accuracy methods give mixed signals: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta is uncertain. Overall, the majority of consensus tools (six benign vs. three pathogenic) lean toward a benign interpretation. This prediction does not contradict any ClinVar status, as none is available. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.194234 | Structured | 0.115685 | Uncertain | 0.555 | 0.338 | 0.125 | -9.388 | Likely Pathogenic | 0.714 | Likely Pathogenic | Likely Benign | 2.59 | Destabilizing | 0.1 | 0.73 | Ambiguous | 1.66 | Ambiguous | 0.71 | Ambiguous | 0.150 | Likely Benign | -2.49 | Neutral | 0.385 | Benign | 0.037 | Benign | 3.31 | Benign | 0.12 | Tolerated | 0.1120 | 0.4195 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||
| c.2031T>G | S677R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S677R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are FoldX, ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are Rosetta, Foldetta, and premPS. High‑accuracy methods give mixed signals: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta is uncertain. Overall, the majority of consensus tools (six benign vs. three pathogenic) lean toward a benign interpretation. This prediction does not contradict any ClinVar status, as none is available. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.194234 | Structured | 0.115685 | Uncertain | 0.555 | 0.338 | 0.125 | -9.388 | Likely Pathogenic | 0.714 | Likely Pathogenic | Likely Benign | 2.59 | Destabilizing | 0.1 | 0.73 | Ambiguous | 1.66 | Ambiguous | 0.71 | Ambiguous | 0.150 | Likely Benign | -2.49 | Neutral | 0.385 | Benign | 0.037 | Benign | 3.31 | Benign | 0.12 | Tolerated | 0.1120 | 0.4195 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||
| c.2032A>C | S678R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S678R is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign), and Foldetta predicts a benign effect. Overall, the majority of tools (8 benign vs. 4 pathogenic) support a benign classification. 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. | GAP | 0.301917 | Structured | 0.123585 | Uncertain | 0.660 | 0.321 | 0.000 | -9.708 | Likely Pathogenic | 0.878 | Likely Pathogenic | Ambiguous | -0.37 | Likely Benign | 0.2 | 0.48 | Likely Benign | 0.06 | Likely Benign | 0.32 | Likely Benign | 0.106 | Likely Benign | -2.07 | Neutral | 0.454 | Possibly Damaging | 0.057 | Benign | 3.44 | Benign | 0.02 | Affected | 0.0950 | 0.3519 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||
| c.2034C>A | S678R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S678R is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SIFT, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is classified as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign), and Foldetta predicts a benign effect. Overall, the majority of evidence (8 benign vs. 4 pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.301917 | Structured | 0.123585 | Uncertain | 0.660 | 0.321 | 0.000 | -9.708 | Likely Pathogenic | 0.878 | Likely Pathogenic | Ambiguous | -0.37 | Likely Benign | 0.2 | 0.48 | Likely Benign | 0.06 | Likely Benign | 0.32 | Likely Benign | 0.158 | Likely Benign | -2.07 | Neutral | 0.454 | Possibly Damaging | 0.057 | Benign | 3.44 | Benign | 0.02 | Affected | 0.0950 | 0.3519 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||
| c.2034C>G | S678R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S678R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is classified as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta predicts a benign stability change. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.301917 | Structured | 0.123585 | Uncertain | 0.660 | 0.321 | 0.000 | -9.708 | Likely Pathogenic | 0.878 | Likely Pathogenic | Ambiguous | -0.37 | Likely Benign | 0.2 | 0.48 | Likely Benign | 0.06 | Likely Benign | 0.32 | Likely Benign | 0.157 | Likely Benign | -2.07 | Neutral | 0.454 | Possibly Damaging | 0.057 | Benign | 3.44 | Benign | 0.02 | Affected | 0.0950 | 0.3519 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||
| c.2110A>C | S704R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704R is not reported in gnomAD and has no ClinVar entry. Prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely pathogenic. FoldX, Rosetta, and Foldetta provide uncertain stability results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the evidence points to the variant being most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.096677 | Structured | 0.383620 | Uncertain | 0.928 | 0.363 | 0.000 | -9.417 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.81 | Ambiguous | 0.1 | 0.92 | Ambiguous | 0.87 | Ambiguous | 0.31 | Likely Benign | 0.178 | Likely Benign | -2.65 | Deleterious | 0.997 | Probably Damaging | 0.822 | Possibly Damaging | 3.53 | Benign | 0.05 | Affected | 0.0714 | 0.3038 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.2112C>A | S704R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, the SGM Consensus confirms Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result, providing no additional evidence. Overall, the preponderance of evidence from multiple independent predictors indicates that S704R is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.096677 | Structured | 0.383620 | Uncertain | 0.928 | 0.363 | 0.000 | -9.417 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.81 | Ambiguous | 0.1 | 0.92 | Ambiguous | 0.87 | Ambiguous | 0.31 | Likely Benign | 0.200 | Likely Benign | -2.65 | Deleterious | 0.997 | Probably Damaging | 0.822 | Possibly Damaging | 3.53 | Benign | 0.05 | Affected | 0.0714 | 0.3038 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.2112C>G | S704R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). FoldX and Rosetta give uncertain results, and Foldetta (a combined FoldX‑MD/Rosetta stability assessment) is also uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as unavailable. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic; this conclusion does not contradict any ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.096677 | Structured | 0.383620 | Uncertain | 0.928 | 0.363 | 0.000 | -9.417 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.81 | Ambiguous | 0.1 | 0.92 | Ambiguous | 0.87 | Ambiguous | 0.31 | Likely Benign | 0.200 | Likely Benign | -2.65 | Deleterious | 0.997 | Probably Damaging | 0.822 | Possibly Damaging | 3.53 | Benign | 0.05 | Affected | 0.0714 | 0.3038 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.2164A>C | S722R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools and the high‑accuracy methods lean toward a pathogenic effect. Thus, the variant is most likely pathogenic based on current predictions, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | -10.731 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.05 | Likely Benign | 0.1 | -0.03 | Likely Benign | 0.01 | Likely Benign | 0.72 | Ambiguous | 0.306 | Likely Benign | -2.66 | Deleterious | 0.999 | Probably Damaging | 0.948 | Probably Damaging | 2.52 | Benign | 0.09 | Tolerated | 0.0886 | 0.2797 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.2166C>A | S722R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722R is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus (SGM Consensus) derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN is pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | -10.731 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.05 | Likely Benign | 0.1 | -0.03 | Likely Benign | 0.01 | Likely Benign | 0.72 | Ambiguous | 0.221 | Likely Benign | -2.66 | Deleterious | 0.999 | Probably Damaging | 0.948 | Probably Damaging | 2.52 | Benign | 0.09 | Tolerated | 0.0886 | 0.2797 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.2166C>G | S722R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign stability. Overall, the balance of evidence leans toward pathogenicity, and this conclusion does not contradict any ClinVar annotation (none is available). Thus, based on the current computational predictions, the S722R variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | -10.731 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.05 | Likely Benign | 0.1 | -0.03 | Likely Benign | 0.01 | Likely Benign | 0.72 | Ambiguous | 0.220 | Likely Benign | -2.66 | Deleterious | 0.999 | Probably Damaging | 0.948 | Probably Damaging | 2.52 | Benign | 0.09 | Tolerated | 0.0886 | 0.2797 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.2203A>C | S735R 2D AIThe SynGAP1 missense variant S735R is not reported 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. 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 classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, while the SGM‑Consensus (majority vote) remains 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 is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.916840 | Disordered | 0.412174 | Uncertain | 0.290 | 0.752 | 0.875 | -6.318 | Likely Benign | 0.784 | Likely Pathogenic | Ambiguous | 0.126 | Likely Benign | -1.25 | Neutral | 0.997 | Probably Damaging | 0.933 | Probably Damaging | 2.66 | Benign | 0.72 | Tolerated | 0.0913 | 0.2861 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2205C>A | S735R 2D AIThe SynGAP1 missense variant S735R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, whereas the SGM‑Consensus (majority vote) supports a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.916840 | Disordered | 0.412174 | Uncertain | 0.290 | 0.752 | 0.875 | -6.318 | Likely Benign | 0.784 | Likely Pathogenic | Ambiguous | 0.108 | Likely Benign | -1.25 | Neutral | 0.997 | Probably Damaging | 0.933 | Probably Damaging | 2.66 | Benign | 0.72 | Tolerated | 0.0913 | 0.2861 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2205C>G | S735R 2D AIThe SynGAP1 missense variant S735R has no ClinVar record and is not listed in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, whereas the SGM‑Consensus (majority vote) remains Benign; Foldetta results are unavailable. Overall, the balance of evidence—five benign versus three pathogenic predictions, a benign SGM‑Consensus, and no contradictory ClinVar annotation—indicates that the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.916840 | Disordered | 0.412174 | Uncertain | 0.290 | 0.752 | 0.875 | -6.318 | Likely Benign | 0.784 | Likely Pathogenic | Ambiguous | 0.108 | Likely Benign | -1.25 | Neutral | 0.997 | Probably Damaging | 0.933 | Probably Damaging | 2.66 | Benign | 0.72 | Tolerated | 0.0913 | 0.2861 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.220A>C | S74R 2D AIThe SynGAP1 missense variant S74R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified 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 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 | 0.505461 | Disordered | 0.450156 | Uncertain | 0.294 | 0.831 | 0.500 | -3.271 | Likely Benign | 0.418 | Ambiguous | Likely Benign | 0.065 | Likely Benign | -1.34 | Neutral | 0.361 | Benign | 0.019 | Benign | 4.08 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0943 | 0.3562 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.2212A>C | S738R 2D AIThe SynGAP1 missense variant S738R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S738R, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.441162 | Uncertain | 0.284 | 0.827 | 0.875 | -4.241 | Likely Benign | 0.570 | Likely Pathogenic | Likely Benign | 0.066 | Likely Benign | -1.55 | Neutral | 0.473 | Possibly Damaging | 0.193 | Benign | 2.69 | Benign | 0.01 | Affected | 4.32 | 2 | 0.0887 | 0.2891 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.2214T>A | S738R 2D AIThe SynGAP1 missense variant S738R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus (majority vote) as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.441162 | Uncertain | 0.284 | 0.827 | 0.875 | -4.241 | Likely Benign | 0.570 | Likely Pathogenic | Likely Benign | 0.068 | Likely Benign | -1.55 | Neutral | 0.473 | Possibly Damaging | 0.193 | Benign | 2.69 | Benign | 0.01 | Affected | 4.32 | 2 | 0.0887 | 0.2891 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.2214T>G | S738R 2D AIThe SynGAP1 missense variant S738R is listed in ClinVar (ID 1592652.0) as Benign and is present in gnomAD (variant ID 6‑33441679‑T‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Benign; Foldetta’s protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar designation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.441162 | Uncertain | 0.284 | 0.827 | 0.875 | Benign | 1 | 6-33441679-T-G | 1 | 6.20e-7 | -4.241 | Likely Benign | 0.570 | Likely Pathogenic | Likely Benign | 0.068 | Likely Benign | -1.55 | Neutral | 0.473 | Possibly Damaging | 0.193 | Benign | 2.69 | Benign | 0.01 | Affected | 4.32 | 2 | 0.0887 | 0.2891 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||
| c.222C>A | S74R 2D AIThe SynGAP1 missense variant S74R is catalogued in gnomAD (ID 6‑33425830‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all report benign or likely benign. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments confirm the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus, derived from the majority of the high‑confidence predictors, is benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that S74R is most likely benign, and this assessment does not contradict any ClinVar status, as none is reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.450156 | Uncertain | 0.294 | 0.831 | 0.500 | 6-33425830-C-A | 1 | 6.20e-7 | -3.271 | Likely Benign | 0.418 | Ambiguous | Likely Benign | 0.070 | Likely Benign | -1.34 | Neutral | 0.361 | Benign | 0.019 | Benign | 4.08 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0943 | 0.3562 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||
| c.222C>G | S74R 2D AIThe SynGAP1 missense variant S74R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority of the high‑accuracy tools) is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that 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 | 0.505461 | Disordered | 0.450156 | Uncertain | 0.294 | 0.831 | 0.500 | -3.271 | Likely Benign | 0.418 | Ambiguous | Likely Benign | 0.070 | Likely Benign | -1.34 | Neutral | 0.361 | Benign | 0.019 | Benign | 4.08 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0943 | 0.3562 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.2293A>C | S765R 2D AIThe SynGAP1 missense variant S765R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus (majority vote) as Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this conclusion, so the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.370445 | Structured | 0.922652 | Binding | 0.335 | 0.865 | 0.250 | -5.422 | Likely Benign | 0.791 | Likely Pathogenic | Ambiguous | 0.157 | Likely Benign | -1.57 | Neutral | 0.996 | Probably Damaging | 0.985 | Probably Damaging | 4.16 | Benign | 0.07 | Tolerated | 3.64 | 6 | 0.0741 | 0.3859 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.2295C>A | S765R 2D AIThe SynGAP1 missense variant S765R is reported in gnomAD (ID 6‑33442453‑C‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM. Those that predict a pathogenic impact are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Taken together, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status because none is assigned. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.370445 | Structured | 0.922652 | Binding | 0.335 | 0.865 | 0.250 | 6-33442453-C-A | -5.422 | Likely Benign | 0.791 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | -1.57 | Neutral | 0.996 | Probably Damaging | 0.985 | Probably Damaging | 4.16 | Benign | 0.07 | Tolerated | 3.64 | 6 | 0.0741 | 0.3859 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| c.2295C>G | S765R 2D AIThe SynGAP1 missense variant S765R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence points to a benign impact for S765R, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.370445 | Structured | 0.922652 | Binding | 0.335 | 0.865 | 0.250 | -5.422 | Likely Benign | 0.791 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | -1.57 | Neutral | 0.996 | Probably Damaging | 0.985 | Probably Damaging | 4.16 | Benign | 0.07 | Tolerated | 3.64 | 6 | 0.0741 | 0.3859 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.229A>C | S77R 2D AIThe SynGAP1 missense variant S77R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified 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 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 S77R, 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 | 0.490133 | Structured | 0.446124 | Uncertain | 0.310 | 0.855 | 0.375 | -2.823 | Likely Benign | 0.482 | Ambiguous | Likely Benign | 0.011 | Likely Benign | -1.22 | Neutral | 0.198 | Benign | 0.015 | Benign | 4.09 | Benign | 0.00 | Affected | 0.0752 | 0.3247 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.231T>A | S77R 2D AIThe SynGAP1 missense variant S77R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority of the high‑accuracy tools) is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that 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 | 0.490133 | Structured | 0.446124 | Uncertain | 0.310 | 0.855 | 0.375 | -2.823 | Likely Benign | 0.482 | Ambiguous | Likely Benign | 0.026 | Likely Benign | -1.22 | Neutral | 0.198 | Benign | 0.015 | Benign | 4.09 | Benign | 0.00 | Affected | 0.0752 | 0.3247 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.231T>G | S77R 2D AIThe SynGAP1 missense variant S77R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority of the high‑accuracy tools) is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that 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 | 0.490133 | Structured | 0.446124 | Uncertain | 0.310 | 0.855 | 0.375 | -2.823 | Likely Benign | 0.482 | Ambiguous | Likely Benign | 0.026 | Likely Benign | -1.22 | Neutral | 0.198 | Benign | 0.015 | Benign | 4.09 | Benign | 0.00 | Affected | 0.0752 | 0.3247 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2335A>C | S779R 2D AIThe SynGAP1 missense variant S779R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it yields a 2‑to‑2 split. High‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain, and both the SGM Consensus and Foldetta (which would combine FoldX‑MD and Rosetta outputs) are unavailable. Consequently, the overall prediction is ambiguous. The variant is most likely benign based on the balance of evidence, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.509769 | Disordered | 0.834974 | Binding | 0.321 | 0.890 | 0.375 | -4.044 | Likely Benign | 0.950 | Likely Pathogenic | Ambiguous | 0.103 | Likely Benign | -0.74 | Neutral | 0.846 | Possibly Damaging | 0.627 | Possibly Damaging | 2.29 | Pathogenic | 0.12 | Tolerated | 0.0961 | 0.4046 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.2337C>A | S779R 2D AIThe SynGAP1 missense variant S779R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it yields a 2‑to‑2 split. High‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain, and both the SGM Consensus and Foldetta (which would combine FoldX‑MD and Rosetta outputs) are unavailable. Consequently, the overall prediction is ambiguous. The variant is most likely benign based on the balance of evidence, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.509769 | Disordered | 0.834974 | Binding | 0.321 | 0.890 | 0.375 | -4.044 | Likely Benign | 0.950 | Likely Pathogenic | Ambiguous | 0.119 | Likely Benign | -0.74 | Neutral | 0.846 | Possibly Damaging | 0.627 | Possibly Damaging | 2.29 | Pathogenic | 0.12 | Tolerated | 0.0961 | 0.4046 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.2337C>G | S779R 2D AIThe SynGAP1 missense variant S779R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it yields a 2‑to‑2 split. High‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain, and both the SGM Consensus and Foldetta (which would combine FoldX‑MD and Rosetta outputs) are unavailable. Consequently, the overall prediction is ambiguous. The variant is most likely benign based on the balance of evidence, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.509769 | Disordered | 0.834974 | Binding | 0.321 | 0.890 | 0.375 | -4.044 | Likely Benign | 0.950 | Likely Pathogenic | Ambiguous | 0.124 | Likely Benign | -0.74 | Neutral | 0.846 | Possibly Damaging | 0.627 | Possibly Damaging | 2.29 | Pathogenic | 0.12 | Tolerated | 0.0961 | 0.4046 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.2425A>C | S809R 2D AIThe SynGAP1 missense variant S809R is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into three groups: benign predictions from REVEL, PROVEAN, and FATHMM; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; and uncertain predictions from ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward benign. Protein‑folding stability analysis with Foldetta is unavailable. Overall, the balance of evidence, particularly the benign consensus from high‑accuracy tools, suggests the variant is most likely benign, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -7.062 | In-Between | 0.935 | Likely Pathogenic | Ambiguous | 0.085 | Likely Benign | -1.50 | Neutral | 0.784 | Possibly Damaging | 0.472 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.0954 | 0.3702 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2427C>A | S809R 2D AIThe SynGAP1 missense variant S809R is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into three groups: benign predictions from REVEL, PROVEAN, and FATHMM; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; and uncertain predictions from ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward benign. Protein‑folding stability analysis with Foldetta is unavailable. Overall, the balance of evidence, particularly the benign consensus from high‑accuracy tools, suggests the variant is most likely benign, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -7.062 | In-Between | 0.935 | Likely Pathogenic | Ambiguous | 0.091 | Likely Benign | -1.50 | Neutral | 0.784 | Possibly Damaging | 0.472 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.0954 | 0.3702 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2427C>G | S809R 2D AIThe SynGAP1 missense variant S809R is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into three groups: benign predictions from REVEL, PROVEAN, and FATHMM; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; and uncertain predictions from ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward benign. Protein‑folding stability analysis with Foldetta is unavailable. Overall, the balance of evidence, particularly the benign consensus from high‑accuracy tools, suggests the variant is most likely benign, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -7.062 | In-Between | 0.935 | Likely Pathogenic | Ambiguous | 0.091 | Likely Benign | -1.50 | Neutral | 0.784 | Possibly Damaging | 0.472 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.0954 | 0.3702 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2467A>C | S823R 2D AIThe SynGAP1 missense variant S823R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all indicate likely pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus also reports it as likely pathogenic. Foldetta results are not available for this variant. Overall, the preponderance of evidence from both general and high‑accuracy prediction tools points to a pathogenic effect for S823R, 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 | 0.685117 | Disordered | 0.627336 | Binding | 0.358 | 0.884 | 0.750 | -6.612 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.293 | Likely Benign | -3.47 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.93 | Pathogenic | 0.00 | Affected | 0.0893 | 0.4046 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2469C>A | S823R 2D AIThe SynGAP1 missense variant S823R is not 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 remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.685117 | Disordered | 0.627336 | Binding | 0.358 | 0.884 | 0.750 | -6.612 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.196 | Likely Benign | -3.47 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.93 | Pathogenic | 0.00 | Affected | 0.0893 | 0.4046 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2469C>G | S823R 2D AIThe SynGAP1 missense variant S823R is not 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 remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.685117 | Disordered | 0.627336 | Binding | 0.358 | 0.884 | 0.750 | -6.612 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.196 | Likely Benign | -3.47 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.93 | Pathogenic | 0.00 | Affected | 0.0893 | 0.4046 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2470A>C | S824R 2D AIThe SynGAP1 missense variant S824R 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 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 classifying the variant as pathogenic, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome; Foldetta stability analysis is unavailable. Overall, the majority of predictions lean toward a benign interpretation, but the split in high‑accuracy tools introduces uncertainty. The variant is therefore 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 | 0.728858 | Disordered | 0.611272 | Binding | 0.314 | 0.884 | 0.750 | -5.589 | Likely Benign | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.131 | Likely Benign | -1.67 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.61 | Benign | 0.23 | Tolerated | 0.1096 | 0.4255 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2472C>A | S824R 2D AIThe SynGAP1 missense variant S824R has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, whereas the SGM‑Consensus remains benign; Foldetta results are unavailable. Overall, the majority of tools lean toward a benign interpretation, but the presence of a pathogenic prediction from a high‑accuracy model introduces uncertainty. Thus, the variant is most likely benign based on the current predictions, and this assessment does not contradict the ClinVar status, which has no reported classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.611272 | Binding | 0.314 | 0.884 | 0.750 | -5.589 | Likely Benign | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.154 | Likely Benign | -1.67 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.61 | Benign | 0.23 | Tolerated | 0.1096 | 0.4255 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2472C>G | S824R 2D AIThe SynGAP1 missense variant S824R is not reported in ClinVar and has no gnomAD entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus score, which is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (majority vote) is benign; Foldetta, a protein‑folding stability predictor, 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, as none exists for S824R. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.611272 | Binding | 0.314 | 0.884 | 0.750 | -5.589 | Likely Benign | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.154 | Likely Benign | -1.67 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.61 | Benign | 0.23 | Tolerated | 0.1096 | 0.4255 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2506A>C | S836R 2D AIThe SynGAP1 missense variant S836R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic outcome. 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, whereas the SGM‑Consensus remains benign; Foldetta results are unavailable. Overall, the balance of evidence (five benign versus three pathogenic predictions, with the high‑accuracy consensus leaning benign) indicates that the variant is most likely benign. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | -6.050 | Likely Benign | 0.935 | Likely Pathogenic | Ambiguous | 0.120 | Likely Benign | -2.06 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.54 | Benign | 0.08 | Tolerated | 0.0731 | 0.3210 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2508T>A | S836R 2D AIThe SynGAP1 missense variant S836R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus (majority vote) as Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. 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 | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | -6.050 | Likely Benign | 0.935 | Likely Pathogenic | Ambiguous | 0.159 | Likely Benign | -2.06 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.54 | Benign | 0.08 | Tolerated | 0.0731 | 0.3210 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2508T>G | S836R 2D AIThe SynGAP1 missense variant S836R is not reported in ClinVar and has no gnomAD entry. Consensus from multiple in silico predictors shows a split: benign calls come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Grouping by agreement, the benign‑predicating tools outnumber the pathogenic ones. 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) is classified as Likely Benign, and no Foldetta stability data are available. Overall, the preponderance of evidence leans toward a benign effect for S836R, 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 | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | -6.050 | Likely Benign | 0.935 | Likely Pathogenic | Ambiguous | 0.159 | Likely Benign | -2.06 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.54 | Benign | 0.08 | Tolerated | 0.0731 | 0.3210 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2518A>C | S840R 2D AIThe SynGAP1 missense variant S840R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: REVEL classifies it as benign, whereas the remaining 11 predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as Likely Pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus result is consistent. Foldetta, a protein‑folding stability method that combines FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the preponderance of evidence indicates that S840R is most likely pathogenic, and this conclusion does not conflict with the current ClinVar status, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.622677 | Disordered | 0.611356 | Binding | 0.259 | 0.865 | 0.250 | -9.366 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.282 | Likely Benign | -3.27 | Deleterious | 0.993 | Probably Damaging | 0.904 | Possibly Damaging | 1.51 | Pathogenic | 0.00 | Affected | 0.0726 | 0.3328 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2520T>A | S840R 2D AIThe SynGAP1 missense variant S840R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity largely agree: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict a deleterious effect. Only REVEL classifies the variant as benign, representing the sole benign prediction. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized returns a pathogenic score, and the SGM‑Consensus indicates “Likely Pathogenic.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the preponderance of evidence from multiple in silico tools and high‑accuracy predictors indicates that S840R 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 | 0.622677 | Disordered | 0.611356 | Binding | 0.259 | 0.865 | 0.250 | -9.366 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.244 | Likely Benign | -3.27 | Deleterious | 0.993 | Probably Damaging | 0.904 | Possibly Damaging | 1.51 | Pathogenic | 0.00 | Affected | 0.0726 | 0.3328 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2520T>G | S840R 2D AIThe SynGAP1 missense variant S840R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity largely agree: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict a deleterious effect. Only REVEL classifies the variant as benign, representing the sole benign prediction. High‑accuracy assessments further support a pathogenic outcome: AlphaMissense‑Optimized returns a pathogenic score, and the SGM‑Consensus indicates “Likely Pathogenic.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the preponderance of evidence from multiple in silico tools and high‑accuracy predictors indicates that S840R is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.622677 | Disordered | 0.611356 | Binding | 0.259 | 0.865 | 0.250 | -9.366 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.244 | Likely Benign | -3.27 | Deleterious | 0.993 | Probably Damaging | 0.904 | Possibly Damaging | 1.51 | Pathogenic | 0.00 | Affected | 0.0726 | 0.3328 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2569A>C | S857R 2D AIThe SynGAP1 missense variant S857R is 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, REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those 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 from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S857R, 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 | 0.728858 | Disordered | 0.475747 | Uncertain | 0.288 | 0.826 | 0.375 | -4.490 | Likely Benign | 0.718 | Likely Pathogenic | Likely Benign | 0.138 | Likely Benign | -1.09 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 4.07 | Benign | 0.18 | Tolerated | 0.1030 | 0.4112 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2571C>A | S857R 2D AIThe SynGAP1 missense variant S857R is not reported in ClinVar and has no entry in gnomAD, indicating it is not catalogued in these databases. Prediction tools that agree on a benign effect include 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 further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion 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 | 0.728858 | Disordered | 0.475747 | Uncertain | 0.288 | 0.826 | 0.375 | -4.490 | Likely Benign | 0.718 | Likely Pathogenic | Likely Benign | 0.132 | Likely Benign | -1.09 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 4.07 | Benign | 0.18 | Tolerated | 0.1030 | 0.4112 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2571C>G | S857R 2D AIThe SynGAP1 missense variant S857R is not reported in ClinVar and has no entry in gnomAD, indicating it is not catalogued in these databases. Prediction tools that agree on a benign effect include 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 further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion 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 | 0.728858 | Disordered | 0.475747 | Uncertain | 0.288 | 0.826 | 0.375 | -4.490 | Likely Benign | 0.718 | Likely Pathogenic | Likely Benign | 0.132 | Likely Benign | -1.09 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 4.07 | Benign | 0.18 | Tolerated | 0.1030 | 0.4112 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2572A>C | S858R 2D AIThe SynGAP1 missense variant S858R is reported in ClinVar as “None” and is not present in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a likely benign classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.482724 | Uncertain | 0.305 | 0.833 | 0.375 | -3.924 | Likely Benign | 0.753 | Likely Pathogenic | Likely Benign | 0.189 | Likely Benign | -1.18 | Neutral | 0.818 | Possibly Damaging | 0.899 | Possibly Damaging | 4.12 | Benign | 0.02 | Affected | 0.0996 | 0.3778 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2574C>A | S858R 2D AIThe SynGAP1 missense variant S858R is reported as “Likely Benign” in ClinVar and is not present in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus, REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.482724 | Uncertain | 0.305 | 0.833 | 0.375 | -3.924 | Likely Benign | 0.753 | Likely Pathogenic | Likely Benign | 0.165 | Likely Benign | -1.18 | Neutral | 0.818 | Possibly Damaging | 0.899 | Possibly Damaging | 4.12 | Benign | 0.02 | Affected | 0.0996 | 0.3778 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2574C>G | S858R 2D AIThe SynGAP1 missense variant S858R is reported as “Likely Benign” in ClinVar and is not present in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus, REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.482724 | Uncertain | 0.305 | 0.833 | 0.375 | -3.924 | Likely Benign | 0.753 | Likely Pathogenic | Likely Benign | 0.165 | Likely Benign | -1.18 | Neutral | 0.818 | Possibly Damaging | 0.899 | Possibly Damaging | 4.12 | Benign | 0.02 | Affected | 0.0996 | 0.3778 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2575A>C | S859R 2D AIThe SynGAP1 missense variant S859R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Uncertain predictions come from ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows that AlphaMissense‑Optimized is uncertain, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward benign (two benign versus one pathogenic vote). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, 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. | 0.648219 | Disordered | 0.497075 | Uncertain | 0.288 | 0.819 | 0.375 | -7.810 | In-Between | 0.844 | Likely Pathogenic | Ambiguous | 0.127 | Likely Benign | -1.42 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 4.00 | Benign | 0.06 | Tolerated | 0.0945 | 0.4061 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.2577T>A | S859R 2D AIThe SynGAP1 missense variant S859R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Uncertain predictions come from ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows that the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans benign (2 benign vs. 1 pathogenic, 1 uncertain). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence 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. | 0.648219 | Disordered | 0.497075 | Uncertain | 0.288 | 0.819 | 0.375 | -7.810 | In-Between | 0.844 | Likely Pathogenic | Ambiguous | 0.120 | Likely Benign | -1.42 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 4.00 | Benign | 0.06 | Tolerated | 0.0945 | 0.4061 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.2577T>G | S859R 2D AIThe SynGAP1 missense variant S859R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Uncertain predictions come from ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows that AlphaMissense‑Optimized remains uncertain, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward benign (two benign versus one pathogenic vote). Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.648219 | Disordered | 0.497075 | Uncertain | 0.288 | 0.819 | 0.375 | -7.810 | In-Between | 0.844 | Likely Pathogenic | Ambiguous | 0.120 | Likely Benign | -1.42 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 4.00 | Benign | 0.06 | Tolerated | 0.0945 | 0.4061 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.2617A>C | S873R 2D AIThe SynGAP1 missense variant S873R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the balance of evidence (five pathogenic vs four benign predictions) suggests the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | -5.856 | Likely Benign | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.218 | Likely Benign | -2.74 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.67 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0.0970 | 0.3667 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.2619C>A | S873R 2D AIThe SynGAP1 missense variant S873R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the balance of evidence (five pathogenic vs. four benign predictions, with a pathogenic high‑accuracy tool) suggests the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as the variant has not yet been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | -5.856 | Likely Benign | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.192 | Likely Benign | -2.74 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.67 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0.0970 | 0.3667 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.2619C>G | S873R 2D AIThe SynGAP1 missense variant S873R is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443171‑C‑G). Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, ESM1b, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic versus two benign votes), and Foldetta stability analysis is unavailable. Overall, the balance of evidence favors 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. | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | Uncertain | 1 | 6-33443171-C-G | 1 | 6.20e-7 | -5.856 | Likely Benign | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.192 | Likely Benign | -2.74 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.67 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0.0970 | 0.3667 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||
| c.2683A>C | S895R 2D AIThe SynGAP1 missense variant S895R is reported in ClinVar as not yet classified and is present in gnomAD (ID 6‑33443235‑A‑C). Consensus from multiple in silico predictors shows a split: benign calls come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. When grouping by agreement, the benign group contains five tools, whereas the pathogenic group contains four. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts pathogenicity, whereas the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points toward a benign effect, and this conclusion does not conflict with the current ClinVar status, which remains unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.414977 | Uncertain | 0.294 | 0.925 | 0.750 | 6-33443235-A-C | 1 | 6.20e-7 | -4.746 | Likely Benign | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.167 | Likely Benign | -1.72 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.64 | Benign | 0.10 | Tolerated | 4.32 | 4 | 0.0949 | 0.4046 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||
| c.2685T>A | S895R 2D AIThe SynGAP1 missense variant S895R is not reported in ClinVar and has no gnomAD entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect, and this is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.414977 | Uncertain | 0.294 | 0.925 | 0.750 | -4.746 | Likely Benign | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.123 | Likely Benign | -1.72 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.64 | Benign | 0.10 | Tolerated | 4.32 | 4 | 0.0949 | 0.4046 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.2685T>G | S895R 2D AIThe SynGAP1 missense variant S895R is not reported in ClinVar and has no gnomAD entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus score (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 (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.414977 | Uncertain | 0.294 | 0.925 | 0.750 | -4.746 | Likely Benign | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.123 | Likely Benign | -1.72 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.64 | Benign | 0.10 | Tolerated | 4.32 | 4 | 0.0949 | 0.4046 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.2719A>C | S907R 2D AIThe SynGAP1 missense variant S907R 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 the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, while the SGM‑Consensus (a majority vote of the same four high‑accuracy tools) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.661854 | Binding | 0.336 | 0.920 | 0.250 | -3.852 | Likely Benign | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.082 | Likely Benign | -0.71 | Neutral | 0.998 | Probably Damaging | 0.951 | Probably Damaging | 2.73 | Benign | 0.34 | Tolerated | 0.0964 | 0.3441 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2721C>A | S907R 2D AIThe SynGAP1 missense variant S907R has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic outcome. AlphaMissense‑Optimized also classifies the variant as pathogenic, whereas the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely benign. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus as benign; Foldetta results are unavailable. Overall, the majority of tools (five benign vs. four pathogenic) lean toward a benign interpretation, and there is no ClinVar evidence contradicting this assessment. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.661854 | Binding | 0.336 | 0.920 | 0.250 | -3.852 | Likely Benign | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.089 | Likely Benign | -0.71 | Neutral | 0.998 | Probably Damaging | 0.951 | Probably Damaging | 2.73 | Benign | 0.34 | Tolerated | 0.0964 | 0.3441 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2721C>G | S907R 2D AIThe SynGAP1 missense variant S907R is not 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 FATHMM, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, whereas the SGM‑Consensus remains benign; Foldetta results are unavailable. Overall, the predictions are mixed but lean toward a benign interpretation, with no conflict with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.661854 | Binding | 0.336 | 0.920 | 0.250 | -3.852 | Likely Benign | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.089 | Likely Benign | -0.71 | Neutral | 0.998 | Probably Damaging | 0.951 | Probably Damaging | 2.73 | Benign | 0.34 | Tolerated | 0.0964 | 0.3441 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2947A>C | S983R 2D AIThe SynGAP1 missense variant S983R is reported in ClinVar as “Not submitted” and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and also indicates a likely pathogenic outcome. AlphaMissense‑Optimized independently predicts pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple in silico predictors points to a pathogenic effect for S983R, and this conclusion does not contradict any ClinVar annotation, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.707965 | Disordered | 0.960212 | Binding | 0.277 | 0.889 | 0.625 | -4.733 | Likely Benign | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.156 | Likely Benign | -2.66 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.03 | Pathogenic | 0.00 | Affected | 0.1163 | 0.3740 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2949C>A | S983R 2D AIThe SynGAP1 missense variant S983R is reported in ClinVar as “Not submitted” and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (3 pathogenic vs. 1 benign) is likely pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that S983R is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently lacks a classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.707965 | Disordered | 0.960212 | Binding | 0.277 | 0.889 | 0.625 | -4.733 | Likely Benign | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.190 | Likely Benign | -2.66 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.03 | Pathogenic | 0.00 | Affected | 0.1163 | 0.3740 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2949C>G | S983R 2D AIThe SynGAP1 missense variant S983R is reported in ClinVar as “Not submitted” and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (3 pathogenic vs. 1 benign) is likely pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that S983R is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently lacks a pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.707965 | Disordered | 0.960212 | Binding | 0.277 | 0.889 | 0.625 | -4.733 | Likely Benign | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.190 | Likely Benign | -2.66 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.03 | Pathogenic | 0.00 | Affected | 0.1163 | 0.3740 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2953A>C | S985R 2D AIThe SynGAP1 missense variant S985R has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains benign; Foldetta, a protein‑folding stability method, has no available result for this variant. Consequently, the evidence is split evenly between benign and pathogenic predictions, with no contradiction to ClinVar status. The variant’s impact remains uncertain, and no definitive benign or pathogenic classification can be assigned based solely on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.941547 | Binding | 0.302 | 0.896 | 0.750 | -6.148 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.174 | Likely Benign | -2.40 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.52 | Benign | 0.00 | Affected | 0.1213 | 0.3905 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2955T>A | S985R 2D AIThe SynGAP1 missense variant S985R has no ClinVar entry and is not reported in gnomAD. Consensus predictions from multiple in‑silico tools are split: benign calls come from REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) which reports a likely benign outcome. Pathogenic calls arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments are mixed: AlphaMissense‑Optimized predicts pathogenic, whereas the SGM‑Consensus (a majority‑vote aggregator) predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the predictions are evenly divided, leaving the variant’s clinical significance uncertain; it does not contradict any ClinVar status because none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.941547 | Binding | 0.302 | 0.896 | 0.750 | -6.148 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.203 | Likely Benign | -2.40 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.52 | Benign | 0.00 | Affected | 0.1213 | 0.3905 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2955T>G | S985R 2D AISynGAP1 missense variant S985R has no ClinVar record and is not present in gnomAD. Computational predictions are mixed: benign calls come from REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy tools give a split result: AlphaMissense‑Optimized predicts pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely benign; Foldetta data are unavailable. Consequently, the variant’s predicted impact is ambiguous, with an equal number of benign and pathogenic scores. No ClinVar evidence contradicts these predictions. Thus, the variant is best classified as of uncertain significance, with no clear bias toward benign or pathogenic status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.941547 | Binding | 0.302 | 0.896 | 0.750 | -6.148 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.203 | Likely Benign | -2.40 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.52 | Benign | 0.00 | Affected | 0.1213 | 0.3905 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3007A>C | S1003R 2D AIThe SynGAP1 missense variant S1003R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of evaluated tools (six pathogenic vs. three benign) indicate a pathogenic impact. This prediction aligns with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | -5.113 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.110 | Likely Benign | -1.88 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1151 | 0.3746 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3009C>A | S1003R 2D AIThe SynGAP1 missense variant S1003R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of evaluated tools (six pathogenic vs. three benign) indicate a pathogenic impact. This prediction aligns with the lack of ClinVar annotation and does not contradict any existing clinical classification. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | -5.113 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.141 | Likely Benign | -1.88 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1151 | 0.3746 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3009C>G | S1003R 2D AIThe SynGAP1 missense variant S1003R (ClinVar ID 1798770.0) is listed as Uncertain in ClinVar and is not present in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and ESM1b, while pathogenic predictions are reported by polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessment shows AlphaMissense‑Optimized classifying the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic), and Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a pathogenic effect, which contrasts with the ClinVar designation of Uncertain. Thus, the variant is most likely pathogenic, contradicting the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | Uncertain | 1 | -5.113 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.141 | Likely Benign | -1.88 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1151 | 0.3746 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| c.3013A>C | S1005R 2D AIThe SynGAP1 missense variant S1005R has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign calls from REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign); pathogenic calls from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicting pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Benign. Foldetta stability analysis is unavailable. Overall, the evidence is split, with an equal number of benign and pathogenic predictions and no ClinVar status to contradict. Thus, the variant is most likely pathogenic based on the majority of high‑confidence tools, and this assessment is not contradicted by ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.936602 | Binding | 0.261 | 0.897 | 0.750 | -3.300 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.135 | Likely Benign | -2.29 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.66 | Benign | 0.00 | Affected | 3.77 | 5 | 0.0994 | 0.2856 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.3015C>A | S1005R 2D AISynGAP1 missense variant S1005R has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign); pathogenic predictions include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains benign; Foldetta stability analysis is unavailable. The overall evidence is split, with five tools favoring benign and five favoring pathogenic, and the two high‑accuracy methods disagree. Consequently, the variant’s impact is uncertain; it is not contradicted by any ClinVar status because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.936602 | Binding | 0.261 | 0.897 | 0.750 | -3.300 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.165 | Likely Benign | -2.29 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.66 | Benign | 0.00 | Affected | 3.77 | 5 | 0.0994 | 0.2856 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.3015C>G | S1005R 2D AIThe SynGAP1 missense variant S1005R is catalogued in gnomAD (ID 6‑33443567‑C‑G) but has no ClinVar entry. Prediction tools cluster into two groups: benign calls include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, and FATHMM; pathogenic calls include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts pathogenic, while the SGM consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the predictions are split, with an equal number of benign and pathogenic calls and a mixed outcome from the high‑accuracy tools. Consequently, the variant is most likely of uncertain significance; there is no contradiction with ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.936602 | Binding | 0.261 | 0.897 | 0.750 | 6-33443567-C-G | 2 | 1.24e-6 | -3.300 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.165 | Likely Benign | -2.29 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.66 | Benign | 0.00 | Affected | 3.77 | 5 | 0.0994 | 0.2856 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||
| c.3019A>C | S1007R 2D AIThe SynGAP1 missense variant S1007R is not reported in ClinVar and has no gnomAD entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give opposing results: AlphaMissense‑Optimized classifies the variant as pathogenic, whereas the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the predictions are split, with an equal number of benign and pathogenic calls, and the high‑accuracy tools disagree. Thus, the variant is most likely pathogenic based on the majority of predictions, and this assessment does not contradict ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.925648 | Binding | 0.295 | 0.899 | 0.750 | -5.441 | Likely Benign | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.211 | Likely Benign | -1.93 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.65 | Benign | 0.01 | Affected | 0.1121 | 0.3237 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3021T>A | S1007R 2D AIThe SynGAP1 missense variant S1007R has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign); pathogenic predictions include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, whereas the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the evidence leans toward a pathogenic interpretation, with no ClinVar status to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.925648 | Binding | 0.295 | 0.899 | 0.750 | -5.441 | Likely Benign | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.219 | Likely Benign | -1.93 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.65 | Benign | 0.01 | Affected | 0.1121 | 0.3237 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3021T>G | S1007R 2D AISynGAP1 missense variant S1007R has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, while the SGM‑Consensus (a majority vote of four high‑accuracy predictors) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the evidence is split, with an equal number of benign and pathogenic predictions. The variant is most likely pathogenic based on the presence of several high‑confidence pathogenic calls, and this assessment does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.925648 | Binding | 0.295 | 0.899 | 0.750 | -5.441 | Likely Benign | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.219 | Likely Benign | -1.93 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.65 | Benign | 0.01 | Affected | 0.1121 | 0.3237 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.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 | 0.43 | Neutral | 0.969 | Probably Damaging | 0.581 | Possibly Damaging | 5.33 | Benign | 0.59 | Tolerated | 3.77 | 5 | 0.1321 | 0.3820 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| 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 | 0.43 | Neutral | 0.969 | Probably Damaging | 0.581 | Possibly Damaging | 5.33 | Benign | 0.59 | Tolerated | 3.77 | 5 | 0.1321 | 0.3820 | -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 | 0.43 | Neutral | 0.969 | Probably Damaging | 0.581 | Possibly Damaging | 5.33 | Benign | 0.59 | Tolerated | 3.77 | 5 | 0.1321 | 0.3820 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| 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 | -0.24 | Neutral | 0.677 | Possibly Damaging | 0.168 | Benign | 5.30 | Benign | 0.21 | Tolerated | 3.77 | 5 | 0.1584 | 0.3620 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| 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 | -0.24 | Neutral | 0.677 | Possibly Damaging | 0.168 | Benign | 5.30 | Benign | 0.21 | Tolerated | 3.77 | 5 | 0.1584 | 0.3620 | -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 | -0.24 | Neutral | 0.677 | Possibly Damaging | 0.168 | Benign | 5.30 | Benign | 0.21 | Tolerated | 3.77 | 5 | 0.1584 | 0.3620 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| 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 | -1.81 | Neutral | 0.177 | Benign | 0.075 | Benign | 3.86 | Benign | 0.00 | Affected | 3.77 | 5 | 0.0811 | 0.4028 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| 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 | -1.81 | Neutral | 0.177 | Benign | 0.075 | Benign | 3.86 | Benign | 0.00 | Affected | 3.77 | 5 | 0.0811 | 0.4028 | 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 | -1.81 | Neutral | 0.177 | Benign | 0.075 | Benign | 3.86 | Benign | 0.00 | Affected | 3.77 | 5 | 0.0811 | 0.4028 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||
| c.325A>C | S109R 2D AIThe SynGAP1 missense variant S109R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM, whereas pathogenic calls come from SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments highlight that AlphaMissense‑Optimized predicts pathogenicity, whereas the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts benign impact; Foldetta data are unavailable. Overall, the balance of evidence leans toward a benign effect for S109R, 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 | 0.622677 | Disordered | 0.669335 | Binding | 0.328 | 0.864 | 0.750 | -4.830 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.225 | Likely Benign | -1.80 | Neutral | 0.002 | Benign | 0.001 | Benign | 3.48 | Benign | 0.00 | Affected | 0.0884 | 0.2700 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| 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 | -1.96 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1190 | 0.4502 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| 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 | -1.96 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1190 | 0.4502 | -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 | -1.96 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1190 | 0.4502 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.327T>A | S109R 2D AIThe SynGAP1 missense variant S109R 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, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) remains benign; Foldetta stability analysis is unavailable. Overall, the majority of predictions lean toward a benign impact, and this is not contradicted by any ClinVar status. Thus, the variant is most likely benign based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.669335 | Binding | 0.328 | 0.864 | 0.750 | -4.830 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.198 | Likely Benign | -1.80 | Neutral | 0.002 | Benign | 0.001 | Benign | 3.48 | Benign | 0.00 | Affected | 0.0884 | 0.2700 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.327T>G | S109R 2D AIThe SynGAP1 missense variant S109R has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict pathogenicity are SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give mixed results: AlphaMissense‑Optimized reports a pathogenic effect, whereas the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome; Foldetta stability analysis is unavailable. Overall, the majority of predictions lean toward a benign impact, with one high‑accuracy tool suggesting pathogenicity, and there is no ClinVar status to contradict these findings. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.669335 | Binding | 0.328 | 0.864 | 0.750 | -4.830 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.198 | Likely Benign | -1.80 | Neutral | 0.002 | Benign | 0.001 | Benign | 3.48 | Benign | 0.00 | Affected | 0.0884 | 0.2700 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| 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 | -1.00 | Neutral | 0.586 | Possibly Damaging | 0.223 | Benign | 2.72 | Benign | 0.16 | Tolerated | 0.1053 | 0.4012 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| 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 | -1.00 | Neutral | 0.586 | Possibly Damaging | 0.223 | Benign | 2.72 | Benign | 0.16 | Tolerated | 0.1053 | 0.4012 | 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 | -1.00 | Neutral | 0.586 | Possibly Damaging | 0.223 | Benign | 2.72 | Benign | 0.16 | Tolerated | 0.1053 | 0.4012 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3322A>C | S1108R 2D AISynGAP1 missense variant S1108R is not reported in ClinVar (status: None) and is absent from gnomAD (no entry). Prediction tools that classify the variant as benign include REVEL, polyPhen‑2 HumVar, ESM1b, and FATHMM. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN is inconclusive, as it yields a 2‑vs‑2 split. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, has no available result for this variant. Overall, the computational evidence is mixed, with an equal number of benign and pathogenic calls and no high‑confidence consensus. Thus, the variant is most likely pathogenic based on the current predictions, and this assessment does not contradict the ClinVar status, which is unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -5.878 | Likely Benign | 0.912 | Likely Pathogenic | Ambiguous | 0.130 | Likely Benign | -2.75 | Deleterious | 0.611 | Possibly Damaging | 0.329 | Benign | 2.54 | Benign | 0.04 | Affected | 0.0864 | 0.3492 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3324C>A | S1108R 2D AISynGAP1 missense variant S1108R has no ClinVar record and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, ESM1b, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a 2‑to‑2 split and therefore unavailable; Foldetta, which would combine FoldX‑MD and Rosetta outputs, has no reported result. Consequently, the evidence is evenly divided, leaving the variant’s functional impact uncertain. The predictions do not contradict any ClinVar status, as none is available. Overall, the variant is most likely of uncertain significance rather than definitively benign or pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -5.878 | Likely Benign | 0.912 | Likely Pathogenic | Ambiguous | 0.109 | Likely Benign | -2.75 | Deleterious | 0.611 | Possibly Damaging | 0.329 | Benign | 2.54 | Benign | 0.04 | Affected | 0.0864 | 0.3492 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3324C>G | S1108R 2D AIThe SynGAP1 missense variant S1108R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, and FATHMM, while those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign). Foldetta, which would assess protein‑folding stability, has no available result for this variant. Overall, the computational evidence is balanced, providing no clear bias toward benign or pathogenic. Thus, the variant’s likely impact remains uncertain, and there is no contradiction with the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -5.878 | Likely Benign | 0.912 | Likely Pathogenic | Ambiguous | 0.108 | Likely Benign | -2.75 | Deleterious | 0.611 | Possibly Damaging | 0.329 | Benign | 2.54 | Benign | 0.04 | Affected | 0.0864 | 0.3492 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3328A>C | S1110R 2D AIThe SynGAP1 missense variant S1110R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the balance of evidence (six benign versus three pathogenic predictions) indicates that the variant is most likely benign. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.912647 | Disordered | 0.934156 | Binding | 0.346 | 0.892 | 0.875 | -5.075 | Likely Benign | 0.773 | Likely Pathogenic | Likely Benign | 0.065 | Likely Benign | -2.46 | Neutral | 0.144 | Benign | 0.042 | Benign | 2.31 | Pathogenic | 0.01 | Affected | 0.1057 | 0.3571 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3330C>A | S1110R 2D AIThe SynGAP1 missense variant S1110R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence (six benign vs. three pathogenic predictions) points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.912647 | Disordered | 0.934156 | Binding | 0.346 | 0.892 | 0.875 | -5.075 | Likely Benign | 0.773 | Likely Pathogenic | Likely Benign | 0.043 | Likely Benign | -2.46 | Neutral | 0.144 | Benign | 0.042 | Benign | 2.31 | Pathogenic | 0.01 | Affected | 0.1057 | 0.3571 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3330C>G | S1110R 2D AIThe SynGAP1 missense variant S1110R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence (six benign vs. three pathogenic predictions) points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.912647 | Disordered | 0.934156 | Binding | 0.346 | 0.892 | 0.875 | -5.075 | Likely Benign | 0.773 | Likely Pathogenic | Likely Benign | 0.043 | Likely Benign | -2.46 | Neutral | 0.144 | Benign | 0.042 | Benign | 2.31 | Pathogenic | 0.01 | Affected | 0.1057 | 0.3571 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3340A>C | S1114R 2D AIThe SynGAP1 missense variant S1114R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a likely benign outcome. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence supports a benign classification, and this conclusion does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | -5.718 | Likely Benign | 0.696 | Likely Pathogenic | Likely Benign | 0.037 | Likely Benign | -1.52 | Neutral | 0.157 | Benign | 0.153 | Benign | 2.68 | Benign | 0.03 | Affected | 0.0999 | 0.3649 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3342C>A | S1114R 2D AIThe SynGAP1 missense variant S1114R is not reported in ClinVar and has no entry in gnomAD. Prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. Only two tools predict pathogenicity: SIFT and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of predictions, including the high‑accuracy tools, suggest the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | -5.718 | Likely Benign | 0.696 | Likely Pathogenic | Likely Benign | 0.035 | Likely Benign | -1.52 | Neutral | 0.157 | Benign | 0.153 | Benign | 2.68 | Benign | 0.03 | Affected | 0.0999 | 0.3649 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3342C>G | S1114R 2D AIThe SynGAP1 missense variant S1114R is not reported in ClinVar and has no entry in gnomAD. Prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. Only two tools predict pathogenicity: SIFT and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of predictions, including the high‑accuracy tools, suggest the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | -5.718 | Likely Benign | 0.696 | Likely Pathogenic | Likely Benign | 0.035 | Likely Benign | -1.52 | Neutral | 0.157 | Benign | 0.153 | Benign | 2.68 | Benign | 0.03 | Affected | 0.0999 | 0.3649 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3352A>C | S1118R 2D AIThe SynGAP1 missense variant S1118R 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. 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, 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 preponderance of evidence indicates that S1118R 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 | 0.876521 | Disordered | 0.828802 | Binding | 0.310 | 0.919 | 0.750 | -2.670 | Likely Benign | 0.553 | Ambiguous | Likely Benign | 0.175 | Likely Benign | -0.74 | Neutral | 0.034 | Benign | 0.023 | Benign | 5.17 | Benign | 0.05 | Affected | 4.32 | 2 | 0.1314 | 0.3431 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.3354C>A | S1118R 2D AIThe SynGAP1 missense variant S1118R (ClinVar ID 2656489.0) is listed as ClinVar status Uncertain and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only SIFT predicts a pathogenic effect, 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 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 | 0.876521 | Disordered | 0.828802 | Binding | 0.310 | 0.919 | 0.750 | Uncertain | 1 | -2.670 | Likely Benign | 0.553 | Ambiguous | Likely Benign | 0.166 | Likely Benign | -0.74 | Neutral | 0.034 | Benign | 0.023 | Benign | 5.17 | Benign | 0.05 | Affected | 4.32 | 2 | 0.1314 | 0.3431 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||
| c.3354C>G | S1118R 2D AIThe SynGAP1 missense variant S1118R is listed in gnomAD (ID 6‑33443906‑C‑G) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.828802 | Binding | 0.310 | 0.919 | 0.750 | 6-33443906-C-G | -2.670 | Likely Benign | 0.553 | Ambiguous | Likely Benign | 0.165 | Likely Benign | -0.74 | Neutral | 0.034 | Benign | 0.023 | Benign | 5.17 | Benign | 0.05 | Affected | 4.32 | 2 | 0.1314 | 0.3431 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| c.3361A>C | S1121R 2D AIThe SynGAP1 missense variant S1121R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The SGM‑Consensus, 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, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact for S1121R, and this conclusion is consistent with the lack of ClinVar reporting. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.810024 | Binding | 0.365 | 0.935 | 0.875 | -6.945 | Likely Benign | 0.597 | Likely Pathogenic | Likely Benign | 0.142 | Likely Benign | -0.34 | Neutral | 0.016 | Benign | 0.015 | Benign | 5.45 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1346 | 0.3431 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.3363C>A | S1121R 2D AIThe SynGAP1 missense variant S1121R is not reported in ClinVar and is absent from gnomAD. 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 show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from 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 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 | 0.894241 | Disordered | 0.810024 | Binding | 0.365 | 0.935 | 0.875 | -6.945 | Likely Benign | 0.597 | Likely Pathogenic | Likely Benign | 0.100 | Likely Benign | -0.34 | Neutral | 0.016 | Benign | 0.015 | Benign | 5.45 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1346 | 0.3431 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.3363C>G | S1121R 2D AIThe SynGAP1 missense variant S1121R is catalogued in gnomAD (ID 6‑33443915‑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 report benign. Only SIFT and AlphaMissense‑Default predict pathogenicity, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; 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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.810024 | Binding | 0.365 | 0.935 | 0.875 | 6-33443915-C-G | -6.945 | Likely Benign | 0.597 | Likely Pathogenic | Likely Benign | 0.101 | Likely Benign | -0.34 | Neutral | 0.016 | Benign | 0.015 | Benign | 5.45 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1346 | 0.3431 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| c.349A>C | S117R 2D AIThe SynGAP1 missense variant S117R has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, whereas the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the majority of predictions lean toward a benign impact, and this 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 | 0.661982 | Disordered | 0.672422 | Binding | 0.357 | 0.877 | 0.625 | -4.187 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.276 | Likely Benign | -1.81 | Neutral | 0.845 | Possibly Damaging | 0.326 | Benign | 3.70 | Benign | 0.01 | Affected | 3.61 | 5 | 0.1040 | 0.3770 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.34A>C | S12R 2D AIThe SynGAP1 missense variant S12R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority of the four high‑accuracy tools) 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 | 0.480142 | Structured | 0.490599 | Uncertain | 0.355 | 0.916 | 0.500 | -4.033 | Likely Benign | 0.500 | Ambiguous | Likely Benign | 0.116 | Likely Benign | -0.30 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.09 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0944 | 0.3678 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.3508A>C | S1170R 2D AIThe SynGAP1 missense variant S1170R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the majority of conventional predictors lean toward pathogenicity, but the high‑accuracy consensus is split. Thus, the variant is most likely pathogenic based on the preponderance of predictions, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.622677 | Disordered | 0.719138 | Binding | 0.417 | 0.767 | 0.500 | -1.451 | Likely Benign | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.475 | Likely Benign | -1.89 | Neutral | 0.998 | Probably Damaging | 0.966 | Probably Damaging | 5.39 | Benign | 0.04 | Affected | 0.0770 | 0.3444 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3510T>A | S1170R 2D AIThe SynGAP1 missense variant S1170R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, whereas tools that predict a pathogenic effect 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 a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of individual predictors lean toward pathogenicity, with the SGM‑Consensus providing a counter‑signal; the evidence is therefore inconclusive. The variant is most likely pathogenic according to the prevailing predictions, and this does not contradict ClinVar status, which has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.622677 | Disordered | 0.719138 | Binding | 0.417 | 0.767 | 0.500 | -1.451 | Likely Benign | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.452 | Likely Benign | -1.89 | Neutral | 0.998 | Probably Damaging | 0.966 | Probably Damaging | 5.39 | Benign | 0.04 | Affected | 0.0770 | 0.3444 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3510T>G | S1170R 2D AIThe SynGAP1 missense variant S1170R is not 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 FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized model classifies the variant as pathogenic, whereas the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of conventional predictors lean toward pathogenicity, and the most accurate tools also favor a pathogenic classification, with no conflict from ClinVar or gnomAD data. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.622677 | Disordered | 0.719138 | Binding | 0.417 | 0.767 | 0.500 | -1.451 | Likely Benign | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.452 | Likely Benign | -1.89 | Neutral | 0.998 | Probably Damaging | 0.966 | Probably Damaging | 5.39 | Benign | 0.04 | Affected | 0.0770 | 0.3444 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.351C>A | S117R 2D AIThe SynGAP1 missense variant S117R has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification (3 benign vs. 1 pathogenic votes). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, whereas the SGM‑Consensus (majority vote) remains benign; Foldetta results are unavailable. Overall, the majority of tools (six benign vs. four pathogenic) and the consensus evidence lean 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 | 0.661982 | Disordered | 0.672422 | Binding | 0.357 | 0.877 | 0.625 | -4.187 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.144 | Likely Benign | -1.81 | Neutral | 0.845 | Possibly Damaging | 0.326 | Benign | 3.70 | Benign | 0.01 | Affected | 3.61 | 5 | 0.1040 | 0.3770 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.351C>G | S117R 2D AIThe SynGAP1 missense variant S117R is listed in ClinVar with no submitted interpretation and is present in gnomAD (ID 6‑33432216‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this is consistent with the absence of a pathogenic 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 | 0.661982 | Disordered | 0.672422 | Binding | 0.357 | 0.877 | 0.625 | 6-33432216-C-G | 1 | 6.20e-7 | -4.187 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.144 | Likely Benign | -1.81 | Neutral | 0.845 | Possibly Damaging | 0.326 | Benign | 3.70 | Benign | 0.01 | Affected | 3.61 | 5 | 0.1040 | 0.3770 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||
| c.3568A>C | S1190R 2D AIThe SynGAP1 missense variant S1190R is not reported in ClinVar and is absent from gnomAD. Prediction tools show a split assessment: benign calls come from REVEL, PROVEAN, ESM1b, and FATHMM, while pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Grouping by consensus, four tools predict benign and five predict pathogenic. High‑accuracy methods give further contrast: AlphaMissense‑Optimized labels the variant as pathogenic, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely benign; Foldetta results are unavailable. Overall, the balance of evidence leans toward a pathogenic interpretation, but the presence of strong benign predictions and the lack of a ClinVar classification mean the variant remains uncertain. No contradiction exists with ClinVar status, as no ClinVar entry is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.575842 | Disordered | 0.455760 | Uncertain | 0.742 | 0.624 | 0.625 | -5.258 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.441 | Likely Benign | -1.66 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.26 | Benign | 0.05 | Affected | 0.0939 | 0.2997 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3570C>A | S1190R 2D AIThe SynGAP1 missense variant S1190R 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, and FATHMM, while those that predict a pathogenic effect 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, SGM‑Consensus as Likely Benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result. Overall, the majority of individual predictors lean toward pathogenicity, but the SGM‑Consensus and several benign predictions introduce uncertainty. Based on the current predictions, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status because ClinVar has not classified the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.575842 | Disordered | 0.455760 | Uncertain | 0.742 | 0.624 | 0.625 | -5.258 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.377 | Likely Benign | -1.66 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.26 | Benign | 0.05 | Affected | 0.0939 | 0.2997 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3570C>G | S1190R 2D AISynGAP1 missense variant S1190R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, PROVEAN, ESM1b, and FATHMM. Those that predict pathogenicity 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, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the majority of tools and the AlphaMissense‑Optimized score point toward pathogenicity, while the SGM‑Consensus suggests benign. Thus, the variant is most likely pathogenic based on the current predictions, and this assessment does not contradict ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.575842 | Disordered | 0.455760 | Uncertain | 0.742 | 0.624 | 0.625 | -5.258 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.377 | Likely Benign | -1.66 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.26 | Benign | 0.05 | Affected | 0.0939 | 0.2997 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3691A>C | S1231R 2D AIThe SynGAP1 missense variant S1231R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM‑Consensus as “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable. Overall, the balance of evidence favors a benign interpretation; this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.490133 | Structured | 0.519419 | Binding | 0.876 | 0.544 | 0.250 | -6.862 | Likely Benign | 0.847 | Likely Pathogenic | Ambiguous | 0.108 | Likely Benign | -0.59 | Neutral | 0.801 | Possibly Damaging | 0.417 | Benign | 2.68 | Benign | 0.11 | Tolerated | 0.0709 | 0.2960 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3693C>A | S1231R 2D AIThe SynGAP1 missense variant S1231R is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, providing no clear direction. High‑accuracy assessments show the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign, while AlphaMissense‑Optimized remains uncertain; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.490133 | Structured | 0.519419 | Binding | 0.876 | 0.544 | 0.250 | -6.862 | Likely Benign | 0.847 | Likely Pathogenic | Ambiguous | 0.132 | Likely Benign | -0.59 | Neutral | 0.801 | Possibly Damaging | 0.417 | Benign | 2.68 | Benign | 0.11 | Tolerated | 0.0709 | 0.2960 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3693C>G | S1231R 2D AIThe SynGAP1 missense variant S1231R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.490133 | Structured | 0.519419 | Binding | 0.876 | 0.544 | 0.250 | -6.862 | Likely Benign | 0.847 | Likely Pathogenic | Ambiguous | 0.132 | Likely Benign | -0.59 | Neutral | 0.801 | Possibly Damaging | 0.417 | Benign | 2.68 | Benign | 0.11 | Tolerated | 0.0709 | 0.2960 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.36C>A | S12R 2D AIThe SynGAP1 missense variant S12R is present in gnomAD (ID 6‑33420300‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score all report benign or likely benign. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors benign. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.490599 | Uncertain | 0.355 | 0.916 | 0.500 | 6-33420300-C-A | -4.033 | Likely Benign | 0.500 | Ambiguous | Likely Benign | 0.097 | Likely Benign | -0.30 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.09 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0944 | 0.3678 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| c.36C>G | S12R 2D AIThe SynGAP1 missense variant S12R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33420300‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors a benign classification; Foldetta’s protein‑folding stability analysis is 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 | 0.480142 | Structured | 0.490599 | Uncertain | 0.355 | 0.916 | 0.500 | Uncertain | 1 | 6-33420300-C-G | 4 | 2.59e-6 | -4.033 | Likely Benign | 0.500 | Ambiguous | Likely Benign | 0.097 | Likely Benign | -0.30 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.09 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0944 | 0.3678 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||
| c.3730A>C | S1244R 2D AIThe SynGAP1 missense variant S1244R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as likely pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote) confirms a likely pathogenic status. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the preponderance of evidence 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 | Coiled-coil | 0.648219 | Disordered | 0.411055 | Uncertain | 0.833 | 0.549 | 0.500 | -10.986 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.309 | Likely Benign | -3.49 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.09 | Pathogenic | 0.04 | Affected | 0.0778 | 0.3098 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3732T>A | S1244R 2D AIThe SynGAP1 missense variant S1244R is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM‑Consensus as Likely Pathogenic; Foldetta results are unavailable. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.648219 | Disordered | 0.411055 | Uncertain | 0.833 | 0.549 | 0.500 | -10.986 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.274 | Likely Benign | -3.49 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.09 | Pathogenic | 0.04 | Affected | 0.0778 | 0.3098 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3732T>G | S1244R 2D AIThe SynGAP1 missense variant S1244R is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM‑Consensus as Likely Pathogenic; Foldetta results are unavailable. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.648219 | Disordered | 0.411055 | Uncertain | 0.833 | 0.549 | 0.500 | -10.986 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.274 | Likely Benign | -3.49 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.09 | Pathogenic | 0.04 | Affected | 0.0778 | 0.3098 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3781A>C | S1261R 2D AIThe SynGAP1 missense variant S1261R is not 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 remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus 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 multiple independent predictors points to a pathogenic effect for S1261R, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.501700 | Disordered | 0.671500 | Binding | 0.889 | 0.574 | 0.250 | -4.363 | Likely Benign | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.152 | Likely Benign | -2.97 | Deleterious | 0.996 | Probably Damaging | 0.898 | Possibly Damaging | 2.21 | Pathogenic | 0.04 | Affected | 0.0661 | 0.2642 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3783C>A | S1261R 2D AIThe SynGAP1 missense variant S1261R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence from multiple in silico tools points to a pathogenic 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 Pathogenic | Coiled-coil | 0.501700 | Disordered | 0.671500 | Binding | 0.889 | 0.574 | 0.250 | -4.363 | Likely Benign | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.190 | Likely Benign | -2.97 | Deleterious | 0.996 | Probably Damaging | 0.898 | Possibly Damaging | 2.21 | Pathogenic | 0.04 | Affected | 0.0661 | 0.2642 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3783C>G | S1261R 2D AIThe SynGAP1 missense variant S1261R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence indicates that S1261R is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.501700 | Disordered | 0.671500 | Binding | 0.889 | 0.574 | 0.250 | -4.363 | Likely Benign | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.190 | Likely Benign | -2.97 | Deleterious | 0.996 | Probably Damaging | 0.898 | Possibly Damaging | 2.21 | Pathogenic | 0.04 | Affected | 0.0661 | 0.2642 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.400A>C | S134R 2D AIThe SynGAP1 missense variant S134R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM‑Consensus as Likely Pathogenic; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.447574 | Structured | 0.695837 | Binding | 0.333 | 0.898 | 0.250 | -9.053 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.292 | Likely Benign | -2.54 | Deleterious | 0.380 | Benign | 0.147 | Benign | 3.84 | Benign | 0.00 | Affected | 0.0719 | 0.3528 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.402C>A | S134R 2D AIThe SynGAP1 missense variant S134R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict pathogenicity are PROVEAN, SIFT, ESM1b, 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 also predicts Pathogenic, while the SGM‑Consensus remains Likely Pathogenic; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.447574 | Structured | 0.695837 | Binding | 0.333 | 0.898 | 0.250 | -9.053 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.146 | Likely Benign | -2.54 | Deleterious | 0.380 | Benign | 0.147 | Benign | 3.84 | Benign | 0.00 | Affected | 0.0719 | 0.3528 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.402C>G | S134R 2D AIThe SynGAP1 missense variant S134R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict pathogenicity are PROVEAN, SIFT, ESM1b, 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 also predicts Pathogenic, while the SGM‑Consensus remains Likely Pathogenic; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.447574 | Structured | 0.695837 | Binding | 0.333 | 0.898 | 0.250 | -9.053 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.146 | Likely Benign | -2.54 | Deleterious | 0.380 | Benign | 0.147 | Benign | 3.84 | Benign | 0.00 | Affected | 0.0719 | 0.3528 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.415A>C | S139R 2D AIThe SynGAP1 missense variant S139R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that agree on a pathogenic effect are AlphaMissense‑Default and AlphaMissense‑Optimized; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts benign. Foldetta results are unavailable. Overall, the majority of conventional predictors and the SGM Consensus favor a benign interpretation, whereas AlphaMissense‑Optimized suggests pathogenicity. No ClinVar annotation exists to contradict these predictions. Thus, based on the available computational evidence, the variant is most likely benign, though the AlphaMissense‑Optimized prediction introduces some uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.553315 | Disordered | 0.600637 | Binding | 0.353 | 0.900 | 0.250 | -7.547 | In-Between | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.112 | Likely Benign | -2.07 | Neutral | 0.380 | Benign | 0.136 | Benign | 4.16 | Benign | 0.12 | Tolerated | 0.1004 | 0.2971 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.417C>A | S139R 2D AIThe SynGAP1 missense variant S139R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that predict a pathogenic effect are AlphaMissense‑Default and AlphaMissense‑Optimized; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence—including the consensus of high‑accuracy tools—suggests a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.553315 | Disordered | 0.600637 | Binding | 0.353 | 0.900 | 0.250 | -7.547 | In-Between | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.110 | Likely Benign | -2.07 | Neutral | 0.380 | Benign | 0.136 | Benign | 4.16 | Benign | 0.12 | Tolerated | 0.1004 | 0.2971 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.417C>G | S139R 2D AIThe SynGAP1 missense variant S139R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that predict a pathogenic effect are AlphaMissense‑Default and AlphaMissense‑Optimized; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.553315 | Disordered | 0.600637 | Binding | 0.353 | 0.900 | 0.250 | -7.547 | In-Between | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.110 | Likely Benign | -2.07 | Neutral | 0.380 | Benign | 0.136 | Benign | 4.16 | Benign | 0.12 | Tolerated | 0.1004 | 0.2971 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.460A>C | S154R 2D AIThe SynGAP1 missense variant S154R is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs two benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑accuracy predictors (five pathogenic vs four benign) indicate a pathogenic impact. This conclusion is not contradicted by ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -9.119 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.097 | Likely Benign | -1.73 | Neutral | 0.990 | Probably Damaging | 0.723 | Possibly Damaging | 4.10 | Benign | 0.14 | Tolerated | 0.0997 | 0.3298 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.462C>A | S154R 2D AIThe SynGAP1 missense variant S154R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, more tools (five) predict pathogenicity than benign (four), and the high‑accuracy AlphaMissense‑Optimized also indicates pathogenicity. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -9.119 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.072 | Likely Benign | -1.73 | Neutral | 0.990 | Probably Damaging | 0.723 | Possibly Damaging | 4.10 | Benign | 0.14 | Tolerated | 0.0997 | 0.3298 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.462C>G | S154R 2D AIThe SynGAP1 missense variant S154R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, more tools (five) predict pathogenicity than benign (four), and the high‑accuracy AlphaMissense‑Optimized also indicates pathogenicity. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -9.119 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.072 | Likely Benign | -1.73 | Neutral | 0.990 | Probably Damaging | 0.723 | Possibly Damaging | 4.10 | Benign | 0.14 | Tolerated | 0.0997 | 0.3298 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.463A>C | S155R 2D AIThe SynGAP1 missense variant S155R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the S155R 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 | 0.497853 | Structured | 0.515359 | Binding | 0.292 | 0.787 | 0.500 | -11.939 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.250 | Likely Benign | -2.74 | Deleterious | 0.995 | Probably Damaging | 0.979 | Probably Damaging | 3.88 | Benign | 0.00 | Affected | 0.0712 | 0.3528 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.465C>A | S155R 2D AIThe SynGAP1 missense variant S155R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM‑Consensus indicates a likely pathogenic status, and a Foldetta stability analysis is not available. Taken together, the majority of evidence points to a pathogenic impact for S155R. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.497853 | Structured | 0.515359 | Binding | 0.292 | 0.787 | 0.500 | -11.939 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.160 | Likely Benign | -2.74 | Deleterious | 0.995 | Probably Damaging | 0.979 | Probably Damaging | 3.88 | Benign | 0.00 | Affected | 0.0712 | 0.3528 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.465C>G | S155R 2D AIThe SynGAP1 missense variant S155R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM‑Consensus indicates a likely pathogenic status, and a Foldetta stability analysis is not available. Taken together, the majority of evidence points to a pathogenic impact for S155R. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.497853 | Structured | 0.515359 | Binding | 0.292 | 0.787 | 0.500 | -11.939 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.160 | Likely Benign | -2.74 | Deleterious | 0.995 | Probably Damaging | 0.979 | Probably Damaging | 3.88 | Benign | 0.00 | Affected | 0.0712 | 0.3528 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.493A>C | S165R 2D AIThe SynGAP1 missense variant S165R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs four benign) indicate that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.509123 | Binding | 0.324 | 0.644 | 0.250 | -9.527 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.293 | Likely Benign | -1.89 | Neutral | 0.567 | Possibly Damaging | 0.249 | Benign | 4.01 | Benign | 0.00 | Affected | 0.1003 | 0.3969 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.495T>A | S165R 2D AIThe SynGAP1 missense variant S165R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM. Tools that agree on a pathogenic effect include polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 vs 2). High‑accuracy AlphaMissense‑Optimized predicts pathogenic, while Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs. four benign) indicate a pathogenic effect. There is no ClinVar annotation to contradict this assessment, so the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.509123 | Binding | 0.324 | 0.644 | 0.250 | -9.527 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.177 | Likely Benign | -1.89 | Neutral | 0.567 | Possibly Damaging | 0.249 | Benign | 4.01 | Benign | 0.00 | Affected | 0.1003 | 0.3969 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.495T>G | S165R 2D AIThe SynGAP1 missense variant S165R is not reported 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, and FATHMM. Tools that agree on a pathogenic effect include polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools specifically show AlphaMissense‑Optimized as pathogenic, while SGM Consensus and Foldetta are unavailable. Based on the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.509123 | Binding | 0.324 | 0.644 | 0.250 | -9.527 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.177 | Likely Benign | -1.89 | Neutral | 0.567 | Possibly Damaging | 0.249 | Benign | 4.01 | Benign | 0.00 | Affected | 0.1003 | 0.3969 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.4A>C | S2R 2D AIThe SynGAP1 missense variant S2R is not reported 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, 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 both general and high‑accuracy predictors indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.543646 | Binding | 0.382 | 0.922 | 0.750 | -3.684 | Likely Benign | 0.426 | Ambiguous | Likely Benign | 0.062 | Likely Benign | -0.44 | Neutral | 0.117 | Benign | 0.008 | Benign | 4.05 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0996 | 0.4503 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.526A>C | S176R 2D AIThe SynGAP1 missense variant S176R is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM, whereas polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains likely benign; Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, and this assessment does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | Uncertain | 1 | -6.492 | Likely Benign | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.247 | Likely Benign | 0.94 | Neutral | 0.718 | Possibly Damaging | 0.168 | Benign | 4.16 | Benign | 0.87 | Tolerated | 0.0697 | 0.3160 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.528C>A | S176R 2D AIThe SynGAP1 missense variant S176R has no ClinVar record and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (majority vote) all classify the change as benign or likely benign. In contrast, polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized predict a pathogenic impact. High‑accuracy assessments are mixed: AlphaMissense‑Optimized reports a pathogenic outcome, whereas the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect; Foldetta data are unavailable. Overall, the majority of predictions support a benign interpretation, and there is no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | -6.492 | Likely Benign | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.230 | Likely Benign | 0.94 | Neutral | 0.718 | Possibly Damaging | 0.168 | Benign | 4.16 | Benign | 0.87 | Tolerated | 0.0697 | 0.3160 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.528C>G | S176R 2D AIThe SynGAP1 missense variant S176R has no ClinVar record and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (majority vote) all classify the change as benign or likely benign. In contrast, polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized predict a pathogenic impact. High‑accuracy assessments are mixed: AlphaMissense‑Optimized reports a pathogenic outcome, whereas the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect; Foldetta data are unavailable. Overall, the majority of predictions support a benign interpretation, and there is no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | -6.492 | Likely Benign | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.230 | Likely Benign | 0.94 | Neutral | 0.718 | Possibly Damaging | 0.168 | Benign | 4.16 | Benign | 0.87 | Tolerated | 0.0697 | 0.3160 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.562A>C | S188R 2D AIThe SynGAP1 missense variant S188R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the S188R variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.490133 | Structured | 0.428502 | Uncertain | 0.298 | 0.603 | 0.500 | -11.567 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.269 | Likely Benign | -3.82 | Deleterious | 0.985 | Probably Damaging | 0.767 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 0.0916 | 0.4236 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.564T>A | S188R 2D AIThe SynGAP1 missense variant S188R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. Foldetta, a protein‑folding stability method, did not provide a result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the S188R variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.490133 | Structured | 0.428502 | Uncertain | 0.298 | 0.603 | 0.500 | -11.567 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.264 | Likely Benign | -3.82 | Deleterious | 0.985 | Probably Damaging | 0.767 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 0.0916 | 0.4236 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.564T>G | S188R 2D AIThe SynGAP1 missense variant S188R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. Foldetta, a protein‑folding stability method, did not provide a result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.490133 | Structured | 0.428502 | Uncertain | 0.298 | 0.603 | 0.500 | -11.567 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.263 | Likely Benign | -3.82 | Deleterious | 0.985 | Probably Damaging | 0.767 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 0.0916 | 0.4236 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.568A>C | S190R 2D AIThe SynGAP1 missense variant S190R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority of the four high‑accuracy tools) also predicts 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 the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -10.137 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.156 | Likely Benign | -2.92 | Deleterious | 0.917 | Possibly Damaging | 0.446 | Benign | 4.07 | Benign | 0.04 | Affected | 0.0809 | 0.4059 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.570C>A | S190R 2D AIThe SynGAP1 missense variant S190R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority of the four high‑accuracy tools) also predicts 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 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 | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -10.137 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.146 | Likely Benign | -2.92 | Deleterious | 0.917 | Possibly Damaging | 0.446 | Benign | 4.07 | Benign | 0.04 | Affected | 0.0809 | 0.4059 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.570C>G | S190R 2D AIThe SynGAP1 missense variant S190R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, and the SGM‑Consensus (majority vote) also indicates Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from both general and high‑accuracy prediction tools indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar annotation exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -10.137 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.146 | Likely Benign | -2.92 | Deleterious | 0.917 | Possibly Damaging | 0.446 | Benign | 4.07 | Benign | 0.04 | Affected | 0.0809 | 0.4059 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.571A>C | S191R 2D AIThe SynGAP1 missense variant S191R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM‑Consensus as Likely Pathogenic; the Foldetta protein‑folding stability analysis is unavailable. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -10.046 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.324 | Likely Benign | -3.82 | Deleterious | 0.838 | Possibly Damaging | 0.367 | Benign | 3.78 | Benign | 0.01 | Affected | 0.0973 | 0.4344 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.573T>A | S191R 2D AIThe SynGAP1 missense variant S191R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM‑Consensus as Likely Pathogenic; the Foldetta protein‑folding stability analysis is unavailable. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -10.046 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.191 | Likely Benign | -3.82 | Deleterious | 0.838 | Possibly Damaging | 0.367 | Benign | 3.78 | Benign | 0.01 | Affected | 0.0973 | 0.4344 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.573T>G | S191R 2D AIThe SynGAP1 missense variant S191R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM‑Consensus as Likely Pathogenic; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of computational evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -10.046 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.191 | Likely Benign | -3.82 | Deleterious | 0.838 | Possibly Damaging | 0.367 | Benign | 3.78 | Benign | 0.01 | Affected | 0.0973 | 0.4344 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.631A>C | S211R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, and FATHMM, whereas a pathogenic signal is reported by SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign. Overall, the majority of tools predict a pathogenic effect, and the high‑accuracy predictions reinforce this conclusion. The variant is most likely pathogenic based on the available predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -14.126 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.49 | Likely Benign | 1.0 | 0.20 | Likely Benign | 0.35 | Likely Benign | 0.97 | Ambiguous | 0.132 | Likely Benign | -4.00 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.95 | Benign | 0.02 | Affected | 0.1003 | 0.3592 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.633C>A | S211R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, FATHMM, and Foldetta. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled “Likely Pathogenic.” The premPS score is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions and the two high‑accuracy pathogenic calls suggest that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -14.126 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.49 | Likely Benign | 1.0 | 0.20 | Likely Benign | 0.35 | Likely Benign | 0.97 | Ambiguous | 0.144 | Likely Benign | -4.00 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.95 | Benign | 0.02 | Affected | 0.1003 | 0.3592 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.633C>G | S211R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211R is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, Rosetta, FATHMM, and the protein‑stability integrator Foldetta, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic, and premPS is uncertain. High‑accuracy assessments give conflicting signals: AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus also predicts Likely Pathogenic, but Foldetta, which combines FoldX‑MD and Rosetta outputs, predicts Benign. Overall, the majority of tools and the consensus score point to a pathogenic effect, and this conclusion does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -14.126 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.49 | Likely Benign | 1.0 | 0.20 | Likely Benign | 0.35 | Likely Benign | 0.97 | Ambiguous | 0.144 | Likely Benign | -4.00 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.95 | Benign | 0.02 | Affected | 0.1003 | 0.3592 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.6C>A | S2R 2D AIThe SynGAP1 missense variant S2R is present in gnomAD (ID 6‑33420270‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score all report benign or likely benign. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors benign. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.543646 | Binding | 0.382 | 0.922 | 0.750 | 6-33420270-C-A | 1 | 6.52e-7 | -3.684 | Likely Benign | 0.426 | Ambiguous | Likely Benign | 0.070 | Likely Benign | -0.44 | Neutral | 0.117 | Benign | 0.008 | Benign | 4.05 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0996 | 0.4503 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||
| c.6C>G | S2R 2D AIThe SynGAP1 missense variant S2R is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the preponderance of evidence from multiple prediction tools and high‑accuracy methods indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.543646 | Binding | 0.382 | 0.922 | 0.750 | -3.684 | Likely Benign | 0.426 | Ambiguous | Likely Benign | 0.065 | Likely Benign | -0.44 | Neutral | 0.117 | Benign | 0.008 | Benign | 4.05 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0996 | 0.4503 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.769A>C | S257R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257R has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include FoldX, premPS, SIFT, and FATHMM, whereas a majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; Rosetta and Foldetta are uncertain. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect for S257R. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -11.746 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | -0.18 | Likely Benign | 0.0 | -1.33 | Ambiguous | -0.76 | Ambiguous | 0.29 | Likely Benign | 0.754 | Likely Pathogenic | -3.38 | Deleterious | 0.998 | Probably Damaging | 0.986 | Probably Damaging | 5.81 | Benign | 0.13 | Tolerated | 0.0762 | 0.3068 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.771C>A | S257R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257R is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools show a split: benign calls come from FoldX, premPS, SIFT, and FATHMM, whereas pathogenic calls are made by REVEL, PROVEAN, both polyPhen‑2 versions, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools with uncertain outcomes include Rosetta and Foldetta. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta’s stability analysis is inconclusive. Overall, the majority of reliable predictors indicate a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar classification. Therefore, the variant is most likely pathogenic, and this assessment is consistent with its lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -11.746 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | -0.18 | Likely Benign | 0.0 | -1.33 | Ambiguous | -0.76 | Ambiguous | 0.29 | Likely Benign | 0.707 | Likely Pathogenic | -3.38 | Deleterious | 0.998 | Probably Damaging | 0.986 | Probably Damaging | 5.81 | Benign | 0.13 | Tolerated | 0.0762 | 0.3068 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.771C>G | S257R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, premPS, SIFT, and FATHMM, whereas those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated tools (7 pathogenic vs. 4 benign) indicate a pathogenic impact. Thus, the variant is most likely pathogenic, and this prediction does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -11.746 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | -0.18 | Likely Benign | 0.0 | -1.33 | Ambiguous | -0.76 | Ambiguous | 0.29 | Likely Benign | 0.707 | Likely Pathogenic | -3.38 | Deleterious | 0.998 | Probably Damaging | 0.986 | Probably Damaging | 5.81 | Benign | 0.13 | Tolerated | 0.0762 | 0.3068 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1064G>A | G355E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G355E is catalogued in gnomAD (6‑33437969‑G‑A) but has no ClinVar entry. Prediction tools that agree on a benign effect include only REVEL, whereas the remaining evaluated algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic impact. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is uncertain. Overall, the preponderance of evidence from standard pathogenicity predictors points to a deleterious effect, and this conclusion is not contradicted by any ClinVar classification (none is available). Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.155435 | Structured | 0.388832 | Uncertain | 0.810 | 0.354 | 0.125 | 6-33437969-G-A | 2 | 1.24e-6 | -9.395 | Likely Pathogenic | 0.891 | Likely Pathogenic | Ambiguous | 0.72 | Ambiguous | 0.6 | 0.63 | Ambiguous | 0.68 | Ambiguous | 0.54 | Ambiguous | 0.349 | Likely Benign | -6.69 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.80 | Pathogenic | 0.04 | Affected | 3.38 | 24 | 0.1590 | 0.4271 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||
| c.1115G>A | G372E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G372E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are REVEL, Rosetta, Foldetta, FATHMM, and AlphaMissense‑Default; FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while Foldetta predicts pathogenic. The SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split and is treated as unavailable. Overall, the majority of evidence (seven benign vs. five pathogenic) supports a benign classification. This conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.433034 | Structured | 0.430335 | Uncertain | 0.322 | 0.774 | 0.375 | -6.682 | Likely Benign | 0.604 | Likely Pathogenic | Likely Benign | 1.58 | Ambiguous | 0.4 | 2.91 | Destabilizing | 2.25 | Destabilizing | 0.34 | Likely Benign | 0.566 | Likely Pathogenic | -0.81 | Neutral | 0.001 | Benign | 0.001 | Benign | -0.74 | Pathogenic | 0.08 | Tolerated | 0.1606 | 0.4103 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||
| c.1118G>A | G373E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G373E is listed in ClinVar with an Uncertain significance and is not present in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, Foldetta, SIFT, and AlphaMissense‑Default. Predictions from Rosetta and ESM1b are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as pathogenic. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar status of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.529623 | Disordered | 0.429267 | Uncertain | 0.295 | 0.799 | 0.625 | Uncertain | 1 | -7.281 | In-Between | 0.569 | Likely Pathogenic | Likely Benign | 4.13 | Destabilizing | 3.2 | 0.52 | Ambiguous | 2.33 | Destabilizing | -0.02 | Likely Benign | 0.420 | Likely Benign | -0.69 | Neutral | 0.001 | Benign | 0.000 | Benign | 3.90 | Benign | 0.01 | Affected | 0.1572 | 0.4309 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||
| c.1124G>A | G375E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G375E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, FATHMM, and AlphaMissense‑Default; ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) favors pathogenic, and Foldetta also predicts pathogenic. Overall, the majority of tools, including the high‑accuracy ones, indicate a pathogenic impact. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.604312 | Disordered | 0.428340 | Uncertain | 0.301 | 0.836 | 0.625 | -7.780 | In-Between | 0.600 | Likely Pathogenic | Likely Benign | 2.89 | Destabilizing | 1.4 | 9.47 | Destabilizing | 6.18 | Destabilizing | 0.45 | Likely Benign | 0.545 | Likely Pathogenic | -1.07 | Neutral | 0.845 | Possibly Damaging | 0.244 | Benign | 1.32 | Pathogenic | 0.09 | Tolerated | 0.1619 | 0.4299 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||
| c.1139G>A | G380E 2D AIThe SynGAP1 missense variant G380E has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, FoldX, Foldetta, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give mixed results: AlphaMissense‑Optimized classifies the variant as benign, Foldetta predicts a pathogenic impact on protein stability, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of tools (7 benign vs. 6 pathogenic) lean toward a benign interpretation, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. 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. | C2 | 0.724957 | Disordered | 0.432982 | Uncertain | 0.316 | 0.939 | 0.750 | -9.334 | Likely Pathogenic | 0.617 | Likely Pathogenic | Likely Benign | 6.25 | Destabilizing | 5.1 | -0.28 | Likely Benign | 2.99 | Destabilizing | 0.24 | Likely Benign | 0.582 | Likely Pathogenic | -0.86 | Neutral | 0.056 | Benign | 0.010 | Benign | 2.53 | Benign | 0.03 | Affected | 0.1585 | 0.3741 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||
| c.1142G>A | G381E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G381E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, FoldX, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Two tools give uncertain results: Rosetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as pathogenic. With seven pathogenic versus four benign predictions and two high‑accuracy tools supporting pathogenicity, the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.724957 | Disordered | 0.431692 | Uncertain | 0.301 | 0.951 | 0.750 | -9.360 | Likely Pathogenic | 0.540 | Ambiguous | Likely Benign | 5.52 | Destabilizing | 1.1 | 0.53 | Ambiguous | 3.03 | Destabilizing | 0.24 | Likely Benign | 0.588 | Likely Pathogenic | -0.71 | Neutral | 0.985 | Probably Damaging | 0.720 | Possibly Damaging | 1.32 | Pathogenic | 0.11 | Tolerated | 0.1554 | 0.3735 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||
| c.1145G>A | G382E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G382E is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438050‑G‑A). Prediction tools that agree on a benign effect include premPS, PROVEAN, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) predicts pathogenic. Overall, the majority of evidence points to a pathogenic impact for G382E, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.728858 | Disordered | 0.429690 | Uncertain | 0.315 | 0.951 | 0.750 | 6-33438050-G-A | -9.570 | Likely Pathogenic | 0.564 | Ambiguous | Likely Benign | 4.86 | Destabilizing | 1.7 | 6.64 | Destabilizing | 5.75 | Destabilizing | 0.48 | Likely Benign | 0.594 | Likely Pathogenic | -0.96 | Neutral | 0.994 | Probably Damaging | 0.986 | Probably Damaging | 1.32 | Pathogenic | 0.03 | Affected | 4.32 | 9 | 0.1775 | 0.3932 | -2 | 0 | -3.1 | 72.06 | |||||||||||||||||||||||||||
| c.1148G>A | G383E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G383E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Tools that predict a pathogenic effect are FoldX, Rosetta, SIFT, ESM1b, AlphaMissense‑Default, and the protein‑folding stability method Foldetta. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (pathogenic), FATHMM (benign), and PROVEAN (benign), is inconclusive (tie). Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a pathogenic effect. Overall, the majority of predictions (seven pathogenic vs. six benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.728858 | Disordered | 0.429104 | Uncertain | 0.296 | 0.949 | 0.750 | -9.535 | Likely Pathogenic | 0.570 | Likely Pathogenic | Likely Benign | 4.09 | Destabilizing | 2.4 | 2.62 | Destabilizing | 3.36 | Destabilizing | 0.39 | Likely Benign | 0.308 | Likely Benign | -0.78 | Neutral | 0.000 | Benign | 0.002 | Benign | 4.10 | Benign | 0.01 | Affected | 0.1582 | 0.3741 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||
| c.1157G>A | G386E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G386E is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438062‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are FoldX, Foldetta, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. Uncertain predictions come from Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive. Overall, the majority of tools predict a pathogenic impact, suggesting the variant is most likely pathogenic, which does not contradict the ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.733139 | Disordered | 0.424156 | Uncertain | 0.334 | 0.898 | 0.750 | Uncertain | 1 | 6-33438062-G-A | -9.286 | Likely Pathogenic | 0.686 | Likely Pathogenic | Likely Benign | 3.69 | Destabilizing | 2.9 | 0.79 | Ambiguous | 2.24 | Destabilizing | 0.54 | Ambiguous | 0.447 | Likely Benign | -0.83 | Neutral | 0.860 | Possibly Damaging | 0.354 | Benign | 3.93 | Benign | 0.01 | Affected | 4.32 | 3 | 0.1543 | 0.3354 | -2 | 0 | -3.1 | 72.06 | |||||||||||||||||||||||||
| c.1169G>A | G390E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G390E is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, FoldX, Rosetta, Foldetta, SIFT, FATHMM, and AlphaMissense‑Default. A high‑accuracy assessment shows AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of predictions support a pathogenic effect, and this aligns with the ClinVar designation of uncertain significance rather than contradicting it. 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. | C2 | 0.626927 | Disordered | 0.413274 | Uncertain | 0.304 | 0.763 | 0.875 | Uncertain | 1 | -7.913 | In-Between | 0.646 | Likely Pathogenic | Likely Benign | 2.61 | Destabilizing | 0.9 | 4.28 | Destabilizing | 3.45 | Destabilizing | 0.47 | Likely Benign | 0.575 | Likely Pathogenic | -0.87 | Neutral | 0.276 | Benign | 0.045 | Benign | 1.32 | Pathogenic | 0.05 | Affected | 4.32 | 8 | 0.1595 | 0.4309 | 0 | -2 | -3.1 | 72.06 | 241.5 | -108.4 | 0.6 | 0.5 | -0.1 | 0.1 | Uncertain | Gly390 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364 and res. Ala399-Ile411). The Ω loop is assumed to directly interact with the membrane, and it is observed to move arbitrarily throughout the WT solvent simulations. This loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play significant roles in protein functions that require flexibility, and so they are rich in glycine residues, prolines, and to a lesser extent, small hydrophilic residues to ensure maximum flexibility. Thus, the variant’s Glu390 may not be as well tolerated in the Ω loop. Additionally, the carboxylate group of Glu390 occasionally forms H-bonds with other loop residues in the variant simulations. The interaction between the acidic carboxylate side chain and the acidic membrane lipids may further influence the SynGAP-membrane complex. However, since the effects on the Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | ||||||||||||||||||
| c.1184G>A | G395E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G395E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome, while FoldX and Rosetta give uncertain results. 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, the SGM‑Consensus (majority vote) predicts benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Taken together, the majority of evidence points to a benign effect. There is no ClinVar entry to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.513880 | Disordered | 0.396199 | Uncertain | 0.474 | 0.601 | 0.500 | -6.350 | Likely Benign | 0.594 | Likely Pathogenic | Likely Benign | 1.60 | Ambiguous | 0.6 | -0.88 | Ambiguous | 0.36 | Likely Benign | 0.30 | Likely Benign | 0.310 | Likely Benign | -1.81 | Neutral | 0.037 | Benign | 0.010 | Benign | 4.25 | Benign | 0.12 | Tolerated | 0.1328 | 0.4089 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||
| c.1532G>A | G511E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G511E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No prediction or stability result is missing or inconclusive. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | -12.263 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 2.17 | Destabilizing | 0.2 | 2.62 | Destabilizing | 2.40 | Destabilizing | 1.15 | Destabilizing | 0.479 | Likely Benign | -7.69 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.24 | Benign | 0.02 | Affected | 0.1882 | 0.4240 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||
| c.158G>A | G53E 2D AIThe SynGAP1 missense variant G53E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are not available. 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 | 0.268042 | Structured | 0.460894 | Uncertain | 0.386 | 0.666 | 0.000 | -2.061 | Likely Benign | 0.853 | Likely Pathogenic | Ambiguous | 0.198 | Likely Benign | -0.25 | Neutral | 0.994 | Probably Damaging | 0.986 | Probably Damaging | 4.29 | Benign | 0.00 | Affected | 0.1413 | 0.4378 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.1826G>A | G609E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G609E has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools (Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | -10.470 | Likely Pathogenic | 0.421 | Ambiguous | Likely Benign | 2.95 | Destabilizing | 0.4 | -1.65 | Ambiguous | 0.65 | Ambiguous | 0.61 | Ambiguous | 0.531 | Likely Pathogenic | -2.28 | Neutral | 0.916 | Possibly Damaging | 0.588 | Possibly Damaging | -1.41 | Pathogenic | 0.17 | Tolerated | 0.1709 | 0.4491 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||
| c.2249G>A | G750E 2D AISynGAP1 missense variant G750E is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.618285 | Disordered | 0.646832 | Binding | 0.348 | 0.866 | 0.625 | Uncertain | 1 | -2.618 | Likely Benign | 0.413 | Ambiguous | Likely Benign | 0.146 | Likely Benign | -2.27 | Neutral | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 2.49 | Pathogenic | 0.01 | Affected | 3.99 | 5 | 0.1326 | 0.3768 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||
| c.2549G>A | G850E 2D AIThe SynGAP1 missense variant G850E 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. When predictions are grouped by consensus, the benign group contains seven tools, whereas the pathogenic group contains two. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports a benign effect, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Foldetta results are unavailable. Overall, the majority of evidence supports a benign classification, and this is consistent with the lack of ClinVar annotation. 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 | 0.648219 | Disordered | 0.540897 | Binding | 0.312 | 0.820 | 0.500 | -4.052 | Likely Benign | 0.247 | Likely Benign | Likely Benign | 0.217 | Likely Benign | -0.60 | Neutral | 0.770 | Possibly Damaging | 0.327 | Benign | 4.28 | Benign | 0.02 | Affected | 0.1612 | 0.4232 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.2600G>A | G867E 2D AIThe SynGAP1 missense variant G867E is catalogued in gnomAD (6‑33443152‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions are reported by polyPhen‑2 HumDiv and polyPhen‑2 HumVar, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.657954 | Binding | 0.285 | 0.801 | 0.250 | 6-33443152-G-A | 3 | 1.86e-6 | -5.204 | Likely Benign | 0.492 | Ambiguous | Likely Benign | 0.105 | Likely Benign | -1.57 | Neutral | 0.994 | Probably Damaging | 0.943 | Probably Damaging | 2.74 | Benign | 0.07 | Tolerated | 3.82 | 4 | 0.1305 | 0.3880 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| c.2645G>A | G882E 2D AIThe SynGAP1 missense variant G882E is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split; Foldetta results are unavailable. Overall, more tools (six) predict benign than pathogenic (three), and no ClinVar evidence contradicts this assessment. Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.690604 | Disordered | 0.632888 | Binding | 0.306 | 0.878 | 0.250 | -4.246 | Likely Benign | 0.613 | Likely Pathogenic | Likely Benign | 0.079 | Likely Benign | -1.16 | Neutral | 0.004 | Benign | 0.005 | Benign | 2.04 | Pathogenic | 0.01 | Affected | 0.1263 | 0.3244 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.2666G>A | G889E 2D AIThe SynGAP1 missense variant G889E is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, FATHMM, 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 combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions lean toward 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. | 0.690604 | Disordered | 0.552581 | Binding | 0.331 | 0.928 | 0.625 | -5.352 | Likely Benign | 0.572 | Likely Pathogenic | Likely Benign | 0.083 | Likely Benign | -1.96 | Neutral | 0.611 | Possibly Damaging | 0.187 | Benign | 2.41 | Pathogenic | 0.02 | Affected | 0.1442 | 0.3719 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.2681G>A | G894E 2D AIThe SynGAP1 missense variant G894E is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443233‑G‑A). 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 reported as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and no Foldetta (FoldX‑MD/Rosetta) result is available. Overall, the majority of predictions support a benign impact, and this is consistent with the ClinVar “Uncertain” classification; thus the variant is most likely benign and does not contradict the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.425700 | Uncertain | 0.310 | 0.925 | 0.750 | Uncertain | 1 | 6-33443233-G-A | 6 | 3.72e-6 | -5.377 | Likely Benign | 0.859 | Likely Pathogenic | Ambiguous | 0.180 | Likely Benign | -2.07 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.68 | Benign | 0.01 | Affected | 4.32 | 4 | 0.1489 | 0.3686 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||
| c.275G>A | G92E 2D AIThe SynGAP1 missense variant G92E is not reported 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 | 0.575842 | Disordered | 0.537848 | Binding | 0.337 | 0.874 | 0.625 | -3.240 | Likely Benign | 0.651 | Likely Pathogenic | Likely Benign | 0.156 | Likely Benign | -2.27 | Neutral | 0.999 | Probably Damaging | 0.972 | Probably Damaging | 4.07 | Benign | 0.00 | Affected | 0.1521 | 0.4426 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.2813G>A | G938E 2D AIThe SynGAP1 missense variant G938E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The variant’s predicted benign status does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.949795 | Binding | 0.318 | 0.883 | 0.625 | -5.394 | Likely Benign | 0.577 | Likely Pathogenic | Likely Benign | 0.112 | Likely Benign | -1.40 | Neutral | 0.997 | Probably Damaging | 0.979 | Probably Damaging | 2.75 | Benign | 0.28 | Tolerated | 0.1370 | 0.3720 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.2837G>A | G946E 2D AIThe SynGAP1 missense variant G946E is listed in ClinVar (ID 1299783.0) as benign and is present in gnomAD (6‑33443389‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while polyPhen‑2 HumDiv, SIFT, and ESM1b predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar designation and showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985417 | Disordered | 0.845792 | Binding | 0.357 | 0.920 | 0.750 | Benign | 3 | 6-33443389-G-A | 13 | 8.05e-6 | -8.793 | Likely Pathogenic | 0.257 | Likely Benign | Likely Benign | 0.341 | Likely Benign | -0.51 | Neutral | 0.818 | Possibly Damaging | 0.355 | Benign | 4.58 | Benign | 0.00 | Affected | 4.32 | 4 | 0.1691 | 0.4859 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||
| c.2840G>A | G947E 2D AIThe SynGAP1 missense variant G947E is reported in ClinVar as “Not submitted” and is present in gnomAD (variant ID 6-33443392-G-A). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only ESM1b predicts a pathogenic outcome, creating a single discordant signal. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that G947E 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 | 0.988695 | Disordered | 0.850554 | Binding | 0.358 | 0.919 | 0.750 | 6-33443392-G-A | 1 | 6.20e-7 | -9.574 | Likely Pathogenic | 0.243 | Likely Benign | Likely Benign | 0.302 | Likely Benign | 0.08 | Neutral | 0.126 | Benign | 0.096 | Benign | 4.92 | Benign | 0.10 | Tolerated | 4.32 | 4 | 0.1555 | 0.4259 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| c.2906G>A | G969E 2D AIThe SynGAP1 missense variant G969E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.950334 | Disordered | 0.956572 | Binding | 0.405 | 0.898 | 0.750 | -4.721 | Likely Benign | 0.167 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -0.10 | Neutral | 0.611 | Possibly Damaging | 0.171 | Benign | 4.28 | Benign | 0.01 | Affected | 0.1663 | 0.5399 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.2918G>A | G973E 2D AIThe SynGAP1 missense variant G973E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.959498 | Binding | 0.390 | 0.897 | 0.625 | -3.712 | Likely Benign | 0.210 | Likely Benign | Likely Benign | 0.079 | Likely Benign | -0.72 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.19 | Benign | 0.01 | Affected | 0.1463 | 0.4258 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.2972G>A | G991E 2D AIThe SynGAP1 missense variant G991E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic outcome. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized independently predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence—including the high‑accuracy tools—points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.745909 | Disordered | 0.911393 | Binding | 0.286 | 0.920 | 0.750 | -4.729 | Likely Benign | 0.341 | Ambiguous | Likely Benign | 0.065 | Likely Benign | -1.30 | Neutral | 0.846 | Possibly Damaging | 0.697 | Possibly Damaging | 4.13 | Benign | 0.01 | Affected | 0.1480 | 0.4277 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3032G>A | G1011E 2D AIThe SynGAP1 missense variant G1011E is listed in ClinVar (ID 4746137) with an “Uncertain” status and is not reported in gnomAD. Consensus from multiple in‑silico predictors shows a split: benign calls come from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls come from polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. High‑accuracy tools reinforce the benign trend: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of reliable predictors indicate 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 | 0.834292 | Disordered | 0.898380 | Binding | 0.332 | 0.869 | 0.625 | Uncertain | 1 | -3.870 | Likely Benign | 0.617 | Likely Pathogenic | Likely Benign | 0.091 | Likely Benign | -1.10 | Neutral | 0.642 | Possibly Damaging | 0.252 | Benign | 2.78 | Benign | 0.01 | Affected | 0.1692 | 0.4521 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||
| c.3143G>A | G1048E 2D AIThe SynGAP1 missense variant G1048E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only REVEL predicts a pathogenic outcome, while ESM1b is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | -7.028 | In-Between | 0.331 | Likely Benign | Likely Benign | 0.529 | Likely Pathogenic | -0.62 | Neutral | 0.018 | Benign | 0.030 | Benign | 2.54 | Benign | 0.10 | Tolerated | 0.1444 | 0.4063 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3149G>A | G1050E 2D AIThe SynGAP1 missense variant G1050E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only ESM1b predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect. There is no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.987317 | Disordered | 0.906802 | Binding | 0.370 | 0.928 | 0.875 | -8.175 | Likely Pathogenic | 0.266 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -0.28 | Neutral | 0.411 | Benign | 0.171 | Benign | 2.50 | Benign | 0.08 | Tolerated | 0.1418 | 0.4258 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.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 | -0.64 | Neutral | 0.901 | Possibly Damaging | 0.537 | Possibly Damaging | 3.90 | Benign | 0.12 | Tolerated | 0.1405 | 0.3873 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| 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 | -0.03 | Neutral | 0.901 | Possibly Damaging | 0.456 | Possibly Damaging | 3.30 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.1525 | 0.4459 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| c.3176G>A | G1059E 2D AIThe SynGAP1 missense variant G1059E is reported in gnomAD (variant ID 6‑33443728‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only two tools—SIFT and ESM1b—predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | 6-33443728-G-A | 1 | 6.22e-7 | -10.459 | Likely Pathogenic | 0.297 | Likely Benign | Likely Benign | 0.390 | Likely Benign | -0.71 | Neutral | 0.126 | Benign | 0.066 | Benign | 2.53 | Benign | 0.00 | Affected | 4.32 | 2 | 0.1464 | 0.4069 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| c.3185G>A | G1062E 2D AIThe SynGAP1 missense variant G1062E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.976962 | Disordered | 0.936972 | Binding | 0.368 | 0.917 | 0.875 | -8.185 | Likely Pathogenic | 0.272 | Likely Benign | Likely Benign | 0.383 | Likely Benign | -1.02 | Neutral | 0.126 | Benign | 0.041 | Benign | 4.10 | Benign | 0.01 | Affected | 0.1490 | 0.4069 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.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 | -2.85 | Deleterious | 0.992 | Probably Damaging | 0.834 | Possibly Damaging | 2.59 | Benign | 0.01 | Affected | 0.1460 | 0.4387 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.32G>A | G11E 2D AIThe SynGAP1 missense variant G11E is reported in gnomAD (variant ID 6-33420296‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus itself is likely benign. Foldetta results are not available, so they do not influence the assessment. Overall, the preponderance of evidence points to a benign variant, 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 | 0.444081 | Structured | 0.501027 | Binding | 0.348 | 0.915 | 0.375 | 6-33420296-G-A | 5 | 3.24e-6 | -4.206 | Likely Benign | 0.219 | Likely Benign | Likely Benign | 0.109 | Likely Benign | 0.09 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.95 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1444 | 0.4628 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| c.3347G>A | G1116E 2D AIThe SynGAP1 missense variant G1116E is reported in gnomAD (variant ID 6-33443899‑G‑A) but has no ClinVar entry. 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, while AlphaMissense‑Default remains uncertain. No tool predicts pathogenicity. The high‑accuracy consensus (SGM‑Consensus) also indicates a likely benign outcome, and AlphaMissense‑Optimized corroborates this. Foldetta, a protein‑folding stability predictor, was not available for this variant. Overall, the collective evidence strongly supports 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 | 0.889439 | Disordered | 0.873279 | Binding | 0.320 | 0.909 | 0.750 | 6-33443899-G-A | -6.375 | Likely Benign | 0.375 | Ambiguous | Likely Benign | 0.345 | Likely Benign | -0.33 | Neutral | 0.043 | Benign | 0.022 | Benign | 4.06 | Benign | 0.07 | Tolerated | 4.32 | 2 | 0.1467 | 0.4069 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||
| c.3356G>A | G1119E 2D AIThe SynGAP1 missense variant G1119E is reported in gnomAD (variant ID 6-33443908‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only ESM1b predicts a pathogenic outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that G1119E is most likely benign, 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 | 0.827927 | Disordered | 0.818538 | Binding | 0.339 | 0.928 | 0.875 | 6-33443908-G-A | 1 | 6.61e-7 | -9.151 | Likely Pathogenic | 0.338 | Likely Benign | Likely Benign | 0.284 | Likely Benign | -0.41 | Neutral | 0.005 | Benign | 0.013 | Benign | 3.93 | Benign | 0.12 | Tolerated | 4.32 | 2 | 0.1654 | 0.4259 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| c.335G>A | G112E 2D AIThe SynGAP1 missense variant G112E is not 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, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split; Foldetta predictions are not available. Overall, the majority of evidence (five benign vs. three pathogenic) supports 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. | 0.728858 | Disordered | 0.640153 | Binding | 0.332 | 0.867 | 0.750 | -3.470 | Likely Benign | 0.818 | Likely Pathogenic | Ambiguous | 0.134 | Likely Benign | -3.30 | Deleterious | 0.421 | Benign | 0.146 | Benign | 3.96 | Benign | 0.00 | Affected | 0.1330 | 0.3814 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3371G>A | G1124E 2D AIThe SynGAP1 missense variant G1124E is not 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 show AlphaMissense‑Optimized as benign; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors a benign outcome (2 benign vs. 1 pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.837511 | Disordered | 0.833401 | Binding | 0.341 | 0.931 | 0.875 | -10.403 | Likely Pathogenic | 0.345 | Ambiguous | Likely Benign | 0.301 | Likely Benign | -0.84 | Neutral | 0.126 | Benign | 0.066 | Benign | 4.78 | Benign | 0.02 | Affected | 0.1405 | 0.4063 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3374G>A | G1125E 2D AIThe SynGAP1 missense variant G1125E is not reported in ClinVar (ClinVar status: not reported) but is present in gnomAD (gnomAD ID 6‑33443926‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, AlphaMissense‑Optimized, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; AlphaMissense‑Default remains uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome (2 benign vs. 1 pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.835839 | Binding | 0.339 | 0.923 | 0.875 | 6-33443926-G-A | 11 | 7.34e-6 | -9.849 | Likely Pathogenic | 0.353 | Ambiguous | Likely Benign | 0.264 | Likely Benign | -0.32 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 4.58 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.1430 | 0.4063 | -2 | 0 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||
| c.3380G>A | G1127E 2D AIThe SynGAP1 missense variant G1127E is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the remaining tools (ESM1b and AlphaMissense‑Default) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a tie between benign and uncertain calls. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the evidence strongly 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. | 0.899122 | Disordered | 0.852422 | Binding | 0.344 | 0.915 | 0.875 | -7.359 | In-Between | 0.422 | Ambiguous | Likely Benign | 0.314 | Likely Benign | -0.56 | Neutral | 0.224 | Benign | 0.091 | Benign | 4.88 | Benign | 0.15 | Tolerated | 0.1395 | 0.4244 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3383G>A | G1128E 2D AIThe SynGAP1 missense variant G1128E is present in gnomAD (6‑33443935‑G‑A) and has no ClinVar entry. In silico predictors that agree on a benign effect include REVEL, PROVEAN, PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as likely benign. High‑accuracy tools reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is a high‑accuracy majority vote. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its stability impact remains unknown. Overall, the computational evidence overwhelmingly supports a benign classification, and this is consistent with the absence of a pathogenic ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.865136 | Binding | 0.309 | 0.911 | 0.875 | 6-33443935-G-A | 1 | 6.70e-7 | -5.580 | Likely Benign | 0.452 | Ambiguous | Likely Benign | 0.235 | Likely Benign | -0.24 | Neutral | 0.002 | Benign | 0.008 | Benign | 4.43 | Benign | 1.00 | Tolerated | 4.32 | 4 | 0.1610 | 0.4497 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| c.338G>A | G113E 2D AIThe SynGAP1 missense variant G113E is not reported in ClinVar (ClinVar ID: None) but is present in gnomAD (ID 6‑33432203‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) also as 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 reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.639486 | Binding | 0.350 | 0.870 | 0.750 | 6-33432203-G-A | 1 | 6.20e-7 | -3.169 | Likely Benign | 0.669 | Likely Pathogenic | Likely Benign | 0.092 | Likely Benign | -0.34 | Neutral | 0.028 | Benign | 0.006 | Benign | 4.21 | Benign | 0.05 | Affected | 3.61 | 5 | 0.1464 | 0.4035 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| c.680G>A | G227E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G227E is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6-33435531-G-A). Functional prediction tools largely agree on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all report pathogenicity, while only polyPhen‑2 (HumVar) and FATHMM predict a benign outcome; premPS remains inconclusive. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Taken together, the overwhelming majority of evidence points to a pathogenic effect. This conclusion is consistent with the ClinVar “Uncertain” classification, which does not contradict the predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.106997 | Structured | 0.329995 | Uncertain | 0.800 | 0.329 | 0.250 | Conflicting | 2 | 6-33435531-G-A | 3 | 1.86e-6 | -9.186 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.56 | Destabilizing | 0.4 | 5.36 | Destabilizing | 3.96 | Destabilizing | 0.94 | Ambiguous | 0.792 | Likely Pathogenic | -6.49 | Deleterious | 0.906 | Possibly Damaging | 0.360 | Benign | 5.72 | Benign | 0.01 | Affected | 3.43 | 12 | 0.1414 | 0.4049 | 0 | -2 | -3.1 | 72.06 | 237.7 | -112.1 | 0.1 | 0.3 | 0.0 | 0.3 | X | X | Uncertain | The introduced residue Glu227 is located in a β hairpin loop connecting two anti-parallel β sheet strands (res. Cys219-Thr224 and Thr228-Ala232). In the variant simulations, the carboxylate group of Glu227 frequently forms a salt bridge with the amino group of the neighboring residue Lys229. Despite this interaction, the integrity of the secondary structure element is not compromised. However, the β hairpins are potential nucleation sites during the initial stages of protein folding. Additionally, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||||||
| c.77G>A | G26E 2D AIThe SynGAP1 missense variant G26E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.438291 | Uncertain | 0.351 | 0.878 | 0.375 | -3.966 | Likely Benign | 0.481 | Ambiguous | Likely Benign | 0.199 | Likely Benign | -2.08 | Neutral | 0.994 | Probably Damaging | 0.986 | Probably Damaging | 3.90 | Benign | 0.00 | Affected | 0.1623 | 0.4238 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.908G>A | G303E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G303E is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33437813‑G‑A). Across the available in‑silico predictors, benign calls are made by REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by SIFT and ESM1b; the remaining tools (FoldX, Foldetta, premPS, AlphaMissense‑Default) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, and Foldetta remains uncertain. Taken together, the majority of evidence points to a benign effect; this conclusion is not contradicted by any ClinVar annotation, as no pathogenic classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.450668 | Structured | 0.271087 | Uncertain | 0.630 | 0.254 | 0.250 | 6-33437813-G-A | 3 | 1.86e-6 | -9.339 | Likely Pathogenic | 0.549 | Ambiguous | Likely Benign | 1.87 | Ambiguous | 0.5 | 0.37 | Likely Benign | 1.12 | Ambiguous | 0.89 | Ambiguous | 0.063 | Likely Benign | -1.56 | Neutral | 0.001 | Benign | 0.005 | Benign | 4.04 | Benign | 0.05 | Affected | 3.55 | 18 | 0.1155 | 0.4172 | -2 | 0 | -3.1 | 72.06 | |||||||||||||||||||||||||
| c.1235T>G | L412W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L412W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.122885 | Structured | 0.331108 | Uncertain | 0.937 | 0.196 | 0.000 | -13.436 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 8.44 | Destabilizing | 0.4 | 9.91 | Destabilizing | 9.18 | Destabilizing | 1.65 | Destabilizing | 0.503 | Likely Pathogenic | -5.53 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.19 | Benign | 0.00 | Affected | 0.0586 | 0.2664 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||
| c.1304T>G | L435W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L435W is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM. The majority of other in silico predictors (REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the change as pathogenic, and the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, while Foldetta’s stability analysis is inconclusive. Overall, the computational evidence strongly favors a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | Uncertain | 1 | -14.889 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 2.11 | Destabilizing | 0.1 | 0.69 | Ambiguous | 1.40 | Ambiguous | 1.66 | Destabilizing | 0.572 | Likely Pathogenic | -5.63 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.15 | Benign | 0.00 | Affected | 3.37 | 29 | 0.0536 | 0.2496 | -2 | -2 | -4.7 | 73.05 | 242.2 | -25.2 | 0.0 | 0.0 | 0.3 | 0.1 | X | Potentially Pathogenic | The iso-butyl side chain of Leu435, located in an α helix (res. Met414-Glu436), packs against other hydrophobic residues in an interhelix space (e.g., Val699, Val447, Leu489, Leu439) in the WT simulations. In the variant simulations, the indole ring of Trp435 fits into the same niche despite its considerably bulkier size. Additionally, the side chain forms an H-bond with the backbone carbonyl of Leu696 in an α helix (res. Asp684-Gln702). Although no apparent negative changes are observed during the variant simulation, the size difference between the swapped residues could affect the protein folding process. | ||||||||||||||||
| c.1607T>G | L536W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L536W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a deleterious effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; all of these classify the variant as pathogenic. Tools that are inconclusive (FoldX, Rosetta, Foldetta) do not provide evidence for or against pathogenicity. High‑accuracy assessments further support a damaging impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, while Foldetta’s stability analysis is uncertain. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.137348 | Structured | 0.042188 | Uncertain | 0.931 | 0.341 | 0.000 | -14.169 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 1.07 | Ambiguous | 0.6 | 1.31 | Ambiguous | 1.19 | Ambiguous | 1.33 | Destabilizing | 0.897 | Likely Pathogenic | -5.92 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.50 | Pathogenic | 0.00 | Affected | 0.0843 | 0.2577 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||
| c.1646T>G | L549W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L549W is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta and Foldetta, whereas the remaining tools—REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM Consensus, and premPS—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as benign. Overall, the preponderance of evidence points to a pathogenic effect for L549W. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.007921 | Uncertain | 0.955 | 0.281 | 0.000 | -14.277 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.76 | Ambiguous | 0.4 | -0.19 | Likely Benign | 0.29 | Likely Benign | 1.06 | Destabilizing | 0.763 | Likely Pathogenic | -5.23 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.30 | Pathogenic | 0.04 | Affected | 0.0699 | 0.1632 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||
| c.1991T>G | L664W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L664W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: benign calls are made only by REVEL and FATHMM, whereas the remaining 13 predictors—including FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the substitution as pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a pathogenic effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.089318 | Uncertain | 0.937 | 0.339 | 0.000 | -17.438 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 7.81 | Destabilizing | 0.5 | 3.17 | Destabilizing | 5.49 | Destabilizing | 1.57 | Destabilizing | 0.479 | Likely Benign | -5.99 | Deleterious | 1.000 | Probably Damaging | 0.984 | Probably Damaging | 2.84 | Benign | 0.00 | Affected | 0.0543 | 0.2272 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||
| c.2054T>G | L685W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L685W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, while the majority of tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. FoldX, Rosetta, and Foldetta provide uncertain results and are not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.162061 | Uncertain | 0.913 | 0.280 | 0.000 | -15.885 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.53 | Ambiguous | 0.2 | 1.14 | Ambiguous | 1.34 | Ambiguous | 1.14 | Destabilizing | 0.509 | Likely Pathogenic | -5.99 | Deleterious | 1.000 | Probably Damaging | 0.984 | Probably Damaging | 3.23 | Benign | 0.00 | Affected | 0.0700 | 0.2328 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||
| c.2642T>G | L881W 2D AIThe SynGAP1 missense variant L881W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for 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 | 0.703578 | Disordered | 0.629350 | Binding | 0.299 | 0.874 | 0.250 | -6.646 | Likely Benign | 0.231 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -0.96 | Neutral | 0.014 | Benign | 0.008 | Benign | 2.44 | Pathogenic | 0.00 | Affected | 0.0662 | 0.3288 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||||||||||||
| c.305T>G | L102W 2D AIThe SynGAP1 missense variant L102W 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 L102W, 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 | 0.795062 | Disordered | 0.696014 | Binding | 0.357 | 0.885 | 0.625 | -5.833 | Likely Benign | 0.202 | Likely Benign | Likely Benign | 0.125 | Likely Benign | -1.42 | Neutral | 0.996 | Probably Damaging | 0.984 | Probably Damaging | 4.09 | Benign | 0.00 | Affected | 0.0821 | 0.3078 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||||||||||||
| 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 | -1.96 | Neutral | 0.994 | Probably Damaging | 0.884 | Possibly Damaging | 2.46 | Pathogenic | 0.00 | Affected | 0.0742 | 0.3763 | -2 | -2 | -4.7 | 73.05 | ||||||||||||||||||||||||||||||||||||||||
| 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 | -1.40 | Neutral | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.38 | Pathogenic | 0.02 | Affected | 0.0749 | 0.3740 | -2 | -2 | -4.7 | 73.05 | ||||||||||||||||||||||||||||||||||||||||
| 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 | -2.00 | Neutral | 0.999 | Probably Damaging | 0.968 | Probably Damaging | 2.58 | Benign | 0.03 | Affected | 0.0787 | 0.4033 | -2 | -2 | -4.7 | 73.05 | ||||||||||||||||||||||||||||||||||||||||
| c.3431T>G | L1144W 2D AIThe SynGAP1 missense variant L1144W is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33444466‑T‑G). Prediction tools that agree on a benign effect include ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split; Foldetta results are unavailable. Overall, the majority of predictions (six pathogenic vs. three benign) indicate a pathogenic impact. This conclusion is not contradicted by ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.950334 | Disordered | 0.726803 | Binding | 0.277 | 0.840 | 1.000 | 6-33444466-T-G | 1 | 6.20e-7 | -5.745 | Likely Benign | 0.707 | Likely Pathogenic | Likely Benign | 0.575 | Likely Pathogenic | -2.87 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 5.36 | Benign | 0.01 | Affected | 4.32 | 4 | 0.0703 | 0.3166 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||||||||
| c.3905T>G | L1302W 2D AIThe SynGAP1 missense variant L1302W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM; ESM1b is uncertain and not counted. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs. three benign) lean toward pathogenicity, and this is consistent with the SGM Consensus result. Therefore, the variant is most likely pathogenic based on current computational evidence, and this 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. | 0.784345 | Disordered | 0.889642 | Binding | 0.429 | 0.842 | 0.875 | -7.133 | In-Between | 0.297 | Likely Benign | Likely Benign | 0.290 | Likely Benign | -4.20 | Deleterious | 0.996 | Probably Damaging | 0.946 | Probably Damaging | 1.49 | Pathogenic | 0.00 | Affected | 0.0671 | 0.2530 | -2 | -2 | -4.7 | 73.05 | ||||||||||||||||||||||||||||||||||||||||
| c.557T>G | L186W 2D AIThe SynGAP1 missense variant L186W has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence from both general and high‑accuracy tools indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.458154 | Structured | 0.428613 | Uncertain | 0.397 | 0.617 | 0.500 | -16.177 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.274 | Likely Benign | -4.78 | Deleterious | 0.996 | Probably Damaging | 0.819 | Possibly Damaging | 3.46 | Benign | 0.00 | Affected | 0.0539 | 0.3138 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||||||||||||
| c.587T>G | L196W 2D AIThe SynGAP1 missense variant L196W has no ClinVar entry (ClinVar status: not reported) and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for this variant, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.284882 | Structured | 0.429452 | Uncertain | 0.489 | 0.521 | 0.125 | -12.148 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.293 | Likely Benign | -4.91 | Deleterious | 0.992 | Probably Damaging | 0.869 | Possibly Damaging | 3.58 | Benign | 0.00 | Affected | 0.0551 | 0.2718 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||||||||||||
| c.599T>G | L200W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L200W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools (SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and Foldetta) predict a pathogenic impact. Two tools (AlphaMissense‑Optimized and Rosetta) provide inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as Pathogenic, the latter integrating stability predictions from FoldX‑MD and Rosetta. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.428168 | Uncertain | 0.687 | 0.453 | 0.125 | -11.550 | Likely Pathogenic | 0.824 | Likely Pathogenic | Ambiguous | 2.90 | Destabilizing | 1.0 | 1.95 | Ambiguous | 2.43 | Destabilizing | 1.20 | Destabilizing | 0.200 | Likely Benign | -2.93 | Deleterious | 0.999 | Probably Damaging | 0.970 | Probably Damaging | 3.98 | Benign | 0.02 | Affected | 0.0627 | 0.2893 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||
| c.110C>A | S37Y 2D  AIThe SynGAP1 missense variant S37Y is listed in gnomAD (ID 6‑33423519‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. 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 is missing. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.433492 | Uncertain | 0.317 | 0.806 | 0.500 | 6-33423519-C-A | 1 | 6.20e-7 | -4.447 | Likely Benign | 0.370 | Ambiguous | Likely Benign | 0.132 | Likely Benign | -1.61 | Neutral | 0.880 | Possibly Damaging | 0.888 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1247 | 0.5256 | -2 | -3 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||
| c.1121C>A | S374Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S374Y is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, whereas polyPhen‑2 HumDiv and SIFT predict a pathogenic impact. Uncertain calls come from FoldX, Rosetta, Foldetta, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive, and Foldetta likewise yields an uncertain stability change. Overall, the majority of available predictions favor a benign effect, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.642678 | Disordered | 0.428948 | Uncertain | 0.333 | 0.812 | 0.625 | Uncertain | 1 | -7.774 | In-Between | 0.344 | Ambiguous | Likely Benign | 0.71 | Ambiguous | 1.2 | 0.66 | Ambiguous | 0.69 | Ambiguous | -0.02 | Likely Benign | 0.310 | Likely Benign | -1.18 | Neutral | 0.875 | Possibly Damaging | 0.271 | Benign | 5.41 | Benign | 0.01 | Affected | 4.32 | 13 | 0.1175 | 0.6705 | -3 | -2 | -0.5 | 76.10 | 237.3 | -76.9 | 0.5 | 0.4 | 0.5 | 0.3 | Uncertain | Ser374 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus, large and relatively hydrophobic residues like tyrosine are rarely tolerated. Additionally, the hydroxyl group of Tyr374 frequently forms various hydrogen bonds with other loop residues in the variant simulations. Although no negative structural effects are observed in the variant simulations, Tyr374 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effect on Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | ||||||||||||||||||
| c.11C>A | S4Y 2D AIThe SynGAP1 missense variant S4Y is reported in gnomAD (ID 6‑33420275‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are unavailable. Taken together, the majority of evidence points to a benign impact. There is no ClinVar classification to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.547364 | Binding | 0.390 | 0.924 | 0.750 | 6-33420275-C-A | -5.156 | Likely Benign | 0.209 | Likely Benign | Likely Benign | 0.099 | Likely Benign | -0.34 | Neutral | 0.880 | Possibly Damaging | 0.608 | Possibly Damaging | 4.12 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0748 | 0.6181 | -2 | -3 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||
| c.1412C>A | S471Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, premPS, and AlphaMissense‑Optimized; pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The high‑accuracy AlphaMissense‑Optimized scores the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it as likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, returns an uncertain stability change. No evidence from ClinVar contradicts these computational assessments. Overall, the preponderance of pathogenic predictions and the SGM Consensus suggest the variant is most likely pathogenic, consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | -11.257 | Likely Pathogenic | 0.493 | Ambiguous | Likely Benign | -0.33 | Likely Benign | 0.1 | -1.31 | Ambiguous | -0.82 | Ambiguous | 0.19 | Likely Benign | 0.446 | Likely Benign | -4.79 | Deleterious | 0.980 | Probably Damaging | 0.584 | Possibly Damaging | -1.27 | Pathogenic | 0.03 | Affected | 0.0607 | 0.4417 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.1559C>A | S520Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Rosetta and Foldetta, whereas the majority of algorithms predict pathogenicity: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools give inconclusive results: FoldX (Uncertain) and premPS (Uncertain). High‑accuracy assessments further support a mixed signal: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus indicates likely pathogenic, and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | -13.124 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | -0.93 | Ambiguous | 0.4 | 0.16 | Likely Benign | -0.39 | Likely Benign | 0.59 | Ambiguous | 0.814 | Likely Pathogenic | -5.57 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.36 | Pathogenic | 0.00 | Affected | 0.0743 | 0.4563 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.1601C>A | S534Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534Y has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, FATHMM, premPS, AlphaMissense‑Optimized, and Foldetta, while those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen2_HumDiv, polyPhen2_HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as benign. Overall, the majority of tools (seven versus six) lean toward a pathogenic effect, and the high‑accuracy consensus is split, leaving the variant’s impact uncertain. Based on the aggregate predictions, the variant is most likely pathogenic, which does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | -11.540 | Likely Pathogenic | 0.575 | Likely Pathogenic | Likely Benign | -0.01 | Likely Benign | 0.1 | 0.66 | Ambiguous | 0.33 | Likely Benign | 0.46 | Likely Benign | 0.314 | Likely Benign | -5.02 | Deleterious | 0.998 | Probably Damaging | 0.998 | Probably Damaging | 3.27 | Benign | 0.00 | Affected | 0.0629 | 0.5073 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.1670C>A | S557Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S557Y is not reported in ClinVar and has no gnomAD entry. Prediction tools largely agree on a deleterious effect: all except premPS (which predicts benign) return pathogenic or likely pathogenic. The high‑accuracy methods reinforce this: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels it likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No tool indicates a benign outcome. Consequently, the variant is most likely pathogenic according to the available computational evidence, and this assessment does not conflict with ClinVar status, which currently contains no entry for S557Y. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.028107 | Structured | 0.010261 | Uncertain | 0.924 | 0.215 | 0.000 | -13.792 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 18.89 | Destabilizing | 1.1 | 3.48 | Destabilizing | 11.19 | Destabilizing | -0.20 | Likely Benign | 0.965 | Likely Pathogenic | -5.45 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.77 | Pathogenic | 0.00 | Affected | 0.1157 | 0.6087 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.1910C>A | S637Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S637Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, FoldX, premPS, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the majority of individual predictors (seven versus five) lean toward pathogenicity, and the consensus‑based SGM‑Consensus also supports a likely pathogenic classification. Therefore, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.076542 | Structured | 0.083482 | Uncertain | 0.920 | 0.253 | 0.000 | -12.633 | Likely Pathogenic | 0.770 | Likely Pathogenic | Likely Benign | 0.13 | Likely Benign | 0.1 | 1.52 | Ambiguous | 0.83 | Ambiguous | 0.50 | Likely Benign | 0.209 | Likely Benign | -3.78 | Deleterious | 0.985 | Probably Damaging | 0.681 | Possibly Damaging | 3.35 | Benign | 0.00 | Affected | 0.0968 | 0.4071 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.1976C>A | S659Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S659Y is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default; FoldX is uncertain and therefore not considered evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of individual predictors lean toward a benign impact, and there is no ClinVar entry to contradict this assessment. Thus, based on the available predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.154597 | Uncertain | 0.954 | 0.283 | 0.000 | -10.832 | Likely Pathogenic | 0.600 | Likely Pathogenic | Likely Benign | -0.64 | Ambiguous | 0.1 | 0.00 | Likely Benign | -0.32 | Likely Benign | 0.29 | Likely Benign | 0.173 | Likely Benign | -4.24 | Deleterious | 0.084 | Benign | 0.014 | Benign | 3.38 | Benign | 0.04 | Affected | 0.0993 | 0.5962 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.2003C>A | S668Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S668Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include premPS and FATHMM, whereas the remaining 12 tools (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict it to be pathogenic or likely pathogenic. High‑accuracy methods give consistent results: AlphaMissense‑Optimized scores it as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No predictions are missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.247041 | Structured | 0.084935 | Uncertain | 0.922 | 0.370 | 0.000 | -14.833 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 18.34 | Destabilizing | 6.2 | 12.69 | Destabilizing | 15.52 | Destabilizing | 0.06 | Likely Benign | 0.641 | Likely Pathogenic | -5.95 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.18 | Benign | 0.00 | Affected | 0.0647 | 0.5693 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.2069C>A | S690Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S690Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM, whereas the majority of other in silico predictors (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the variant as pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus confirms a Likely Pathogenic status, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Based on the preponderance of pathogenic predictions and the absence of benign consensus, the variant is most likely pathogenic, with no contradiction to ClinVar status (which has no entry for this variant). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.055536 | Structured | 0.247926 | Uncertain | 0.944 | 0.253 | 0.000 | -14.051 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 11.45 | Destabilizing | 3.1 | 3.02 | Destabilizing | 7.24 | Destabilizing | 0.16 | Likely Benign | 0.381 | Likely Benign | -5.76 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.39 | Benign | 0.00 | Affected | 0.0512 | 0.4643 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.20C>A | S7Y 2D AIThe SynGAP1 missense variant S7Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The predictions do not contradict any ClinVar annotation, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.590140 | Disordered | 0.548467 | Binding | 0.386 | 0.922 | 0.750 | -5.240 | Likely Benign | 0.230 | Likely Benign | Likely Benign | 0.193 | Likely Benign | -0.36 | Neutral | 0.561 | Possibly Damaging | 0.047 | Benign | 4.06 | Benign | 0.00 | Affected | 0.0708 | 0.5053 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.227C>A | S76Y 2D AIThe SynGAP1 missense variant S76Y is listed in ClinVar (ID 4801334) with an uncertain significance status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence points to a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.444487 | Uncertain | 0.279 | 0.826 | 0.500 | Uncertain | 1 | -4.243 | Likely Benign | 0.209 | Likely Benign | Likely Benign | 0.119 | Likely Benign | -2.35 | Neutral | 0.972 | Probably Damaging | 0.831 | Possibly Damaging | 3.71 | Benign | 0.00 | Affected | 0.0540 | 0.4753 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||
| c.2297C>A | S766Y 2D AIThe SynGAP1 missense variant S766Y is reported in gnomAD (ID 6‑33442455‑C‑A) but has no ClinVar entry. Functional prediction tools show mixed results: benign calls come from REVEL, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts benign, but the SGM‑Consensus (majority vote) predicts pathogenic, and no Foldetta stability data are available. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.405110 | Structured | 0.923125 | Binding | 0.338 | 0.874 | 0.250 | 6-33442455-C-A | -8.636 | Likely Pathogenic | 0.641 | Likely Pathogenic | Likely Benign | 0.222 | Likely Benign | -2.67 | Deleterious | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 4.09 | Benign | 0.00 | Affected | 3.64 | 6 | 0.0794 | 0.5609 | -2 | -3 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||
| c.2312C>A | S771Y 2D AIThe SynGAP1 missense variant S771Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools, ESM1b and AlphaMissense‑Default, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it contains two benign and two uncertain calls, and Foldetta data are unavailable. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.436924 | Structured | 0.922503 | Binding | 0.306 | 0.883 | 0.250 | -7.041 | In-Between | 0.397 | Ambiguous | Likely Benign | 0.176 | Likely Benign | -2.13 | Neutral | 0.990 | Probably Damaging | 0.892 | Possibly Damaging | 4.02 | Benign | 0.05 | Affected | 0.0707 | 0.5155 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||||||
| c.2339C>A | S780Y 2D AIThe SynGAP1 missense variant S780Y 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, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default; ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact. This conclusion is 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. | 0.599170 | Disordered | 0.812415 | Binding | 0.283 | 0.883 | 0.500 | -7.682 | In-Between | 0.656 | Likely Pathogenic | Likely Benign | 0.091 | Likely Benign | -1.71 | Neutral | 0.995 | Probably Damaging | 0.925 | Probably Damaging | 2.61 | Benign | 0.11 | Tolerated | 0.0810 | 0.6428 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||||||
| c.2363C>A | S788Y 2D AIThe SynGAP1 missense variant S788Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments show that the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic effect, AlphaMissense‑Optimized is uncertain (treated as unavailable), and Foldetta results are not provided. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.956248 | Disordered | 0.573557 | Binding | 0.349 | 0.895 | 0.750 | -8.745 | Likely Pathogenic | 0.795 | Likely Pathogenic | Ambiguous | 0.251 | Likely Benign | -4.56 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 1.50 | Pathogenic | 0.00 | Affected | 0.0844 | 0.5551 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||||
| c.2447C>A | S816Y 2D AIThe SynGAP1 missense variant S816Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default, all of which classify the substitution as deleterious. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized yields an uncertain result, while Foldetta data are unavailable. Based on the preponderance of pathogenic predictions and the SGM‑Consensus, the variant is most likely pathogenic; this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -8.369 | Likely Pathogenic | 0.880 | Likely Pathogenic | Ambiguous | 0.222 | Likely Benign | -2.83 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.60 | Benign | 0.03 | Affected | 0.0668 | 0.4741 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2525C>A | S842Y 2D AIThe SynGAP1 missense variant S842Y is listed in ClinVar as Pathogenic (ClinVar ID 624244.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized returns a pathogenic score, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled 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 the variant is most likely pathogenic, in agreement with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.604312 | Disordered | 0.617281 | Binding | 0.274 | 0.861 | 0.250 | Likely Pathogenic | 1 | -16.124 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.191 | Likely Benign | -4.28 | Deleterious | 0.944 | Possibly Damaging | 0.676 | Possibly Damaging | 1.97 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.0576 | 0.5403 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||
| c.260C>A | S87Y 2D AIThe SynGAP1 missense variant S87Y is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM. Tools that agree on a pathogenic effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑accuracy predictors (six out of nine) indicate a pathogenic impact, whereas three predict benign. Therefore, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.690604 | Disordered | 0.550904 | Binding | 0.302 | 0.878 | 0.500 | -10.410 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.052 | Likely Benign | -2.20 | Neutral | 0.880 | Possibly Damaging | 0.608 | Possibly Damaging | 3.75 | Benign | 0.00 | Affected | 0.0522 | 0.4798 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||||||
| c.2675C>A | S892Y 2D AIThe SynGAP1 missense variant S892Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are 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 further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote) also predicts 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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.473390 | Uncertain | 0.319 | 0.926 | 0.875 | -4.696 | Likely Benign | 0.645 | Likely Pathogenic | Likely Benign | 0.113 | Likely Benign | -2.29 | Neutral | 0.998 | Probably Damaging | 0.959 | Probably Damaging | 2.55 | Benign | 0.00 | Affected | 0.0814 | 0.5051 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2693C>A | S898Y 2D AISynGAP1 missense variant S898Y 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, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Overall, the majority of tools and the consensus prediction indicate 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 | 0.690604 | Disordered | 0.426070 | Uncertain | 0.305 | 0.922 | 0.500 | -5.927 | Likely Benign | 0.712 | Likely Pathogenic | Likely Benign | 0.182 | Likely Benign | -2.69 | Deleterious | 0.998 | Probably Damaging | 0.959 | Probably Damaging | 2.44 | Pathogenic | 0.00 | Affected | 0.1244 | 0.6838 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2777C>A | S926Y 2D AIThe SynGAP1 missense variant S926Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic outcome. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports it as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic effect for S926Y, 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 | 0.461924 | Structured | 0.981753 | Binding | 0.295 | 0.854 | 0.250 | -6.602 | Likely Benign | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.444 | Likely Benign | -4.53 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.50 | Pathogenic | 0.00 | Affected | 0.0602 | 0.4932 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2864C>A | S955Y 2D AIThe SynGAP1 missense variant S955Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) support a benign classification. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984871 | Disordered | 0.945325 | Binding | 0.350 | 0.924 | 0.750 | -6.212 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -1.62 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | 0.1321 | 0.4932 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2867C>A | S956Y 2D AIThe SynGAP1 missense variant S956Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the lack of ClinVar annotation. Thus, the variant is most likely benign, with no contradiction from ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984871 | Disordered | 0.957345 | Binding | 0.364 | 0.917 | 0.750 | -4.920 | Likely Benign | 0.233 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -0.90 | Neutral | 0.411 | Benign | 0.097 | Benign | 1.93 | Pathogenic | 0.22 | Tolerated | 0.1449 | 0.4932 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2966C>A | S989Y 2D AIThe SynGAP1 missense variant S989Y is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy predictions therefore indicate a benign outcome: AlphaMissense‑Optimized is benign, the SGM Consensus is benign, and Foldetta data are unavailable. Consequently, the variant is most likely benign based on the current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.795062 | Disordered | 0.908835 | Binding | 0.296 | 0.911 | 0.750 | -4.774 | Likely Benign | 0.471 | Ambiguous | Likely Benign | 0.103 | Likely Benign | -3.32 | Deleterious | 0.986 | Probably Damaging | 0.876 | Possibly Damaging | 2.60 | Benign | 0.00 | Affected | 0.0611 | 0.4815 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||||||
| c.2969C>A | S990Y 2D AIThe SynGAP1 missense variant S990Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Taken together, the majority of evidence points to a benign impact. The predictions do not contradict the ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.816150 | Disordered | 0.902387 | Binding | 0.301 | 0.919 | 0.750 | -4.272 | Likely Benign | 0.314 | Likely Benign | Likely Benign | 0.131 | Likely Benign | -2.52 | Deleterious | 0.832 | Possibly Damaging | 0.500 | Possibly Damaging | 2.74 | Benign | 0.00 | Affected | 0.0893 | 0.5832 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2996C>A | S999Y 2D AIThe SynGAP1 missense variant S999Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S999Y, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.950682 | Binding | 0.262 | 0.897 | 0.625 | -6.446 | Likely Benign | 0.346 | Ambiguous | Likely Benign | 0.069 | Likely Benign | -1.74 | Neutral | 0.934 | Possibly Damaging | 0.559 | Possibly Damaging | 2.64 | Benign | 0.00 | Affected | 0.0881 | 0.6249 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.3038C>A | S1013Y 2D AIThe SynGAP1 missense variant S1013Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.899570 | Binding | 0.308 | 0.846 | 0.625 | -4.882 | Likely Benign | 0.338 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -1.78 | Neutral | 0.290 | Benign | 0.124 | Benign | 2.66 | Benign | 0.03 | Affected | 0.0954 | 0.5629 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.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 | -1.01 | Neutral | 0.021 | Benign | 0.008 | Benign | 2.69 | Benign | 0.04 | Affected | 3.77 | 5 | 0.0708 | 0.5262 | -2 | -3 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||
| 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 | -2.43 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 3.81 | Benign | 0.00 | Affected | 0.0977 | 0.5684 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| 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 | -2.41 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.56 | Benign | 0.02 | Affected | 3.77 | 5 | 0.0671 | 0.5845 | -2 | -3 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||
| 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 | -2.07 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.45 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.1007 | 0.5877 | -2 | -3 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||
| c.3395C>A | S1132Y 2D AIThe SynGAP1 missense variant S1132Y is listed in ClinVar as a benign alteration (ClinVar ID 845357.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, 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 supports a benign classification, which aligns with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.845506 | Binding | 0.289 | 0.894 | 0.750 | Likely Benign | 1 | -5.894 | Likely Benign | 0.392 | Ambiguous | Likely Benign | 0.401 | Likely Benign | -1.76 | Neutral | 0.500 | Possibly Damaging | 0.208 | Benign | 5.40 | Benign | 0.09 | Tolerated | 4.32 | 4 | 0.0889 | 0.5233 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||
| c.3413C>A | S1138Y 2D AISynGAP1 missense variant S1138Y is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33444448‑C‑A). Prediction tools that agree on benign impact include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. AlphaMissense‑Default remains uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is ambiguous but leans toward benign (2 benign vs 1 pathogenic, 1 uncertain). High‑accuracy methods further support a benign interpretation: AlphaMissense‑Optimized predicts benign, while Foldetta results are unavailable. Overall, the balance of evidence, especially from high‑accuracy tools, suggests 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. | 0.891961 | Disordered | 0.738250 | Binding | 0.346 | 0.869 | 1.000 | Uncertain | 2 | 6-33444448-C-A | 3 | 1.86e-6 | -6.610 | Likely Benign | 0.449 | Ambiguous | Likely Benign | 0.391 | Likely Benign | -2.51 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 5.41 | Benign | 0.05 | Affected | 4.32 | 4 | 0.1034 | 0.5449 | -2 | -3 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||
| c.3425C>A | S1142Y 2D AIThe SynGAP1 missense variant S1142Y is not 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 pathogenic vs. 2 benign). Foldetta results are unavailable. Overall, the majority of conventional predictors lean toward pathogenicity, but the single high‑accuracy benign prediction and the inconclusive consensus temper this view. 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. | 0.919029 | Disordered | 0.719935 | Binding | 0.276 | 0.844 | 1.000 | -6.146 | Likely Benign | 0.569 | Likely Pathogenic | Likely Benign | 0.200 | Likely Benign | -3.39 | Deleterious | 0.971 | Probably Damaging | 0.876 | Possibly Damaging | 2.64 | Benign | 0.00 | Affected | 0.0849 | 0.5429 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||||||
| c.3452C>A | S1151Y 2D AIThe SynGAP1 missense variant S1151Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. AlphaMissense‑Optimized also 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 high‑confidence tools and the consensus prediction favor 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 | 0.741537 | Disordered | 0.805072 | Binding | 0.394 | 0.839 | 0.625 | -4.456 | Likely Benign | 0.642 | Likely Pathogenic | Likely Benign | 0.166 | Likely Benign | -0.87 | Neutral | 0.995 | Probably Damaging | 0.925 | Probably Damaging | 2.68 | Benign | 0.05 | Affected | 0.0778 | 0.5287 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.3476C>A | S1159Y 2D AIThe SynGAP1 missense variant S1159Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the majority of evidence (six benign predictions versus five pathogenic, plus a benign consensus) points to a likely benign impact for S1159Y. 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 | 0.626927 | Disordered | 0.867068 | Binding | 0.343 | 0.846 | 0.375 | -5.665 | Likely Benign | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.195 | Likely Benign | -1.57 | Neutral | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 2.65 | Benign | 0.07 | Tolerated | 0.0567 | 0.4923 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.3635C>A | S1212Y 2D AIThe SynGAP1 missense variant S1212Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus confirms a likely pathogenic status. Foldetta results are unavailable, so they do not influence the overall assessment. Based on the convergence of multiple prediction algorithms, 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 | Coiled-coil | 0.566480 | Disordered | 0.548409 | Binding | 0.852 | 0.565 | 0.500 | -12.186 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.304 | Likely Benign | -4.55 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.03 | Pathogenic | 0.00 | Affected | 0.0546 | 0.4291 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||||
| c.3674C>A | S1225Y 2D AIThe SynGAP1 missense variant S1225Y is not 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), SIFT, and ESM1b; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also leans toward benign (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 points to a benign impact, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.513880 | Disordered | 0.441915 | Uncertain | 0.891 | 0.544 | 0.500 | -8.360 | Likely Pathogenic | 0.359 | Ambiguous | Likely Benign | 0.419 | Likely Benign | -2.27 | Neutral | 0.975 | Probably Damaging | 0.767 | Possibly Damaging | 5.34 | Benign | 0.04 | Affected | 0.0547 | 0.4691 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.3770C>A | S1257Y 2D AIThe SynGAP1 missense variant S1257Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b; 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) leans pathogenic (2 pathogenic vs 1 benign). Foldetta results are unavailable. Overall, the majority of evaluated predictors (five pathogenic vs. three benign) indicate a pathogenic 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. | Coiled-coil | 0.541878 | Disordered | 0.482380 | Uncertain | 0.889 | 0.572 | 0.375 | -8.632 | Likely Pathogenic | 0.399 | Ambiguous | Likely Benign | 0.120 | Likely Benign | -2.65 | Deleterious | 0.989 | Probably Damaging | 0.883 | Possibly Damaging | 2.55 | Benign | 0.03 | Affected | 0.0480 | 0.4463 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.419C>A | S140Y 2D AIThe SynGAP1 missense variant S140Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the S140Y 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 | 0.476583 | Structured | 0.587898 | Binding | 0.321 | 0.896 | 0.625 | -13.071 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.252 | Likely Benign | -3.88 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 3.48 | Benign | 0.00 | Affected | 0.0597 | 0.5849 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.50C>A | S17Y 2D AIThe SynGAP1 missense variant S17Y is listed in gnomAD (ID 6‑33420314‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors benign. No Foldetta stability data are available, so it does not influence the conclusion. Overall, the majority of evidence indicates that S17Y is most likely benign, and this assessment does not contradict any ClinVar status, as none is reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.452228 | Uncertain | 0.341 | 0.910 | 0.375 | 6-33420314-C-A | -4.492 | Likely Benign | 0.551 | Ambiguous | Likely Benign | 0.050 | Likely Benign | -1.06 | Neutral | 0.742 | Possibly Damaging | 0.047 | Benign | 3.99 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0818 | 0.6366 | -2 | -3 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||
| c.545C>A | S182Y 2D AIThe SynGAP1 missense variant S182Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while benign calls are made only by REVEL and FATHMM. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized indicates a pathogenic effect, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic. A protein‑folding stability analysis with Foldetta is unavailable, so it does not influence the overall assessment. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.501700 | Disordered | 0.436016 | Uncertain | 0.368 | 0.619 | 0.625 | -15.951 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.274 | Likely Benign | -4.40 | Deleterious | 0.940 | Possibly Damaging | 0.564 | Possibly Damaging | 3.64 | Benign | 0.00 | Affected | 0.0656 | 0.5158 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.554C>A | S185Y 2D AIThe SynGAP1 missense variant S185Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts Pathogenic, and the SGM‑Consensus also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.545602 | Disordered | 0.430485 | Uncertain | 0.365 | 0.623 | 0.500 | -13.633 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.316 | Likely Benign | -4.93 | Deleterious | 0.718 | Possibly Damaging | 0.178 | Benign | 3.56 | Benign | 0.00 | Affected | 0.0736 | 0.5439 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.611C>A | S204Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S204Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus (SGM Consensus) is inconclusive because it receives an equal split between pathogenic and benign calls. AlphaMissense‑Optimized, a high‑accuracy model, predicts benign, whereas Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts pathogenic. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.268042 | Structured | 0.420667 | Uncertain | 0.816 | 0.405 | 0.125 | -10.518 | Likely Pathogenic | 0.782 | Likely Pathogenic | Likely Benign | 8.99 | Destabilizing | 3.8 | 5.20 | Destabilizing | 7.10 | Destabilizing | -0.03 | Likely Benign | 0.170 | Likely Benign | -0.96 | Neutral | 0.978 | Probably Damaging | 0.694 | Possibly Damaging | 4.14 | Benign | 0.03 | Affected | 0.0452 | 0.5625 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||
| c.635C>A | S212Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S212Y is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include FoldX, FATHMM, and premPS. In contrast, a majority of tools predict a pathogenic impact: REVEL, SGM‑Consensus, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, is inconclusive for this variant. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; Foldetta remains uncertain. Overall, the preponderance of evidence from multiple in silico predictors indicates that S212Y is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.381517 | Uncertain | 0.846 | 0.278 | 0.125 | -14.812 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.43 | Likely Benign | 0.5 | 2.32 | Destabilizing | 1.38 | Ambiguous | 0.22 | Likely Benign | 0.819 | Likely Pathogenic | -5.15 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 5.76 | Benign | 0.00 | Affected | 0.0555 | 0.6120 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.704C>A | S235Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FATHMM and Rosetta, whereas the majority of other in silico predictors (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the variant as pathogenic. Two tools give inconclusive results: Foldetta (protein‑folding stability) and premPS. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for S235Y, and this conclusion is not contradicted by any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | -15.842 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 3.53 | Destabilizing | 1.8 | 0.43 | Likely Benign | 1.98 | Ambiguous | 0.66 | Ambiguous | 0.887 | Likely Pathogenic | -5.14 | Deleterious | 0.971 | Probably Damaging | 0.641 | Possibly Damaging | 5.45 | Benign | 0.00 | Affected | 0.0733 | 0.5269 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.83C>A | S28Y 2D AIThe SynGAP1 missense variant S28Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect. There is no conflict with 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 | 0.545602 | Disordered | 0.438157 | Uncertain | 0.354 | 0.884 | 0.125 | -4.521 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -0.94 | Neutral | 0.009 | Benign | 0.001 | Benign | 4.13 | Benign | 0.05 | Affected | 0.0895 | 0.5067 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.887C>A | S296Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S296Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and premPS, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Foldetta give uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic, and Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact. The variant is most likely pathogenic based on 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 Pathogenic | C2 | 0.444081 | Structured | 0.282669 | Uncertain | 0.887 | 0.284 | 0.250 | -12.148 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 1.46 | Ambiguous | 0.2 | 0.48 | Likely Benign | 0.97 | Ambiguous | 0.15 | Likely Benign | 0.486 | Likely Benign | -4.34 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.93 | Pathogenic | 0.05 | Affected | 0.0800 | 0.5610 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.899C>A | S300Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300Y has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Foldetta, premPS, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Two tools (AlphaMissense‑Default and Rosetta) are uncertain and do not influence the consensus. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of evidence points toward a pathogenic effect, and this assessment does not contradict any ClinVar status (none is available). Thus, based on current predictions, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.356642 | Structured | 0.256848 | Uncertain | 0.742 | 0.280 | 0.375 | -10.464 | Likely Pathogenic | 0.422 | Ambiguous | Likely Benign | -0.08 | Likely Benign | 0.4 | 0.55 | Ambiguous | 0.24 | Likely Benign | 0.28 | Likely Benign | 0.116 | Likely Benign | -2.52 | Deleterious | 0.975 | Probably Damaging | 0.686 | Possibly Damaging | 1.52 | Pathogenic | 0.01 | Affected | 0.0678 | 0.5395 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.905C>A | S302Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S302Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic effect are SIFT, polyPhen‑2 HumDiv, and ESM1b. Two tools give uncertain results: AlphaMissense‑Default and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta also predicts benign stability. No prediction or folding result is missing or inconclusive. 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. | C2 | 0.414856 | Structured | 0.263489 | Uncertain | 0.616 | 0.258 | 0.375 | -9.674 | Likely Pathogenic | 0.355 | Ambiguous | Likely Benign | -0.02 | Likely Benign | 0.1 | 0.56 | Ambiguous | 0.27 | Likely Benign | -0.17 | Likely Benign | 0.070 | Likely Benign | -1.03 | Neutral | 0.801 | Possibly Damaging | 0.383 | Benign | 4.07 | Benign | 0.01 | Affected | 0.0882 | 0.5990 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||
| c.1191C>G | C397W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C397W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign calls come from premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus, whereas pathogenic calls are made by REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, but Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts pathogenic. Overall, the majority of tools lean toward a benign effect, and this is consistent with the lack of ClinVar evidence. Therefore, the variant is most likely benign, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.395774 | Uncertain | 0.778 | 0.551 | 0.250 | -6.857 | Likely Benign | 0.614 | Likely Pathogenic | Likely Benign | 2.40 | Destabilizing | 2.3 | 4.46 | Destabilizing | 3.43 | Destabilizing | 0.19 | Likely Benign | 0.545 | Likely Pathogenic | -1.87 | Neutral | 0.987 | Probably Damaging | 0.814 | Possibly Damaging | 4.64 | Benign | 0.02 | Affected | 0.1637 | 0.5092 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.1296T>G | C432W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C432W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments reinforce this: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus indicates a likely pathogenic status, and Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result, providing no counter‑evidence. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic effect. This conclusion is consistent with the absence of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.362533 | Uncertain | 0.960 | 0.285 | 0.000 | -13.936 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 1.17 | Ambiguous | 0.4 | 0.72 | Ambiguous | 0.95 | Ambiguous | 0.58 | Ambiguous | 0.433 | Likely Benign | -10.50 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 3.43 | Benign | 0.00 | Affected | 0.1217 | 0.3246 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.147C>G | C49W 2D AIThe SynGAP1 missense variant C49W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic and the SGM‑Consensus 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 C49W 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 | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -12.247 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.291 | Likely Benign | -3.56 | Deleterious | 0.880 | Possibly Damaging | 0.914 | Probably Damaging | 3.83 | Benign | 0.00 | Affected | 0.1380 | 0.3172 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||||||||||||
| c.1572C>G | C524W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C524W is not reported in ClinVar and is absent from gnomAD. Prediction tools uniformly indicate a deleterious effect: benign predictions are absent, while pathogenic predictions are made by REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.024729 | Uncertain | 0.916 | 0.385 | 0.125 | -12.351 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.03 | Destabilizing | 1.2 | 9.88 | Destabilizing | 6.46 | Destabilizing | 0.93 | Ambiguous | 0.675 | Likely Pathogenic | -10.94 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.41 | Pathogenic | 0.00 | Affected | 0.1953 | 0.3920 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.1593C>G | C531W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C531W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a deleterious effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, all of which classify the change as pathogenic. Tools with uncertain or mixed outputs are Rosetta (uncertain) and premPS (uncertain). High‑accuracy assessments further support a damaging impact: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also reports pathogenic. Based on the overwhelming agreement among pathogenic predictions and the corroborating high‑accuracy tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.017941 | Uncertain | 0.878 | 0.401 | 0.000 | -14.107 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 5.27 | Destabilizing | 3.4 | 0.63 | Ambiguous | 2.95 | Destabilizing | 0.70 | Ambiguous | 0.510 | Likely Pathogenic | -9.12 | Deleterious | 0.998 | Probably Damaging | 0.871 | Possibly Damaging | -1.25 | Pathogenic | 0.00 | Affected | 0.1234 | 0.3074 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.1638C>G | C546W 2D 3DClick to see structure in 3D Viewer AIClinVar has no entry for this SynGAP1 missense variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect include only SIFT, which scores the substitution as tolerated. The majority of other in silico predictors classify the change as pathogenic: REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) report a likely pathogenic outcome. Predictions that are inconclusive or unavailable are FoldX, Foldetta, and premPS. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus indicates likely pathogenic, while Foldetta’s stability analysis is uncertain. Overall, the consensus of the available evidence points to a pathogenic effect for the variant, and this conclusion does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.027463 | Structured | 0.009041 | Uncertain | 0.960 | 0.288 | 0.000 | -14.685 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | -0.79 | Ambiguous | 1.2 | 3.60 | Destabilizing | 1.41 | Ambiguous | 0.56 | Ambiguous | 0.703 | Likely Pathogenic | -9.09 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.24 | Pathogenic | 0.08 | Tolerated | 0.1855 | 0.2904 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.1641T>G | C547W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C547W is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic, while premPS remains uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenic. Taken together, the overwhelming consensus from both general and high‑accuracy predictors is that C547W is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.007912 | Uncertain | 0.971 | 0.275 | 0.000 | -15.788 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 11.03 | Destabilizing | 0.3 | 2.63 | Destabilizing | 6.83 | Destabilizing | 0.54 | Ambiguous | 0.764 | Likely Pathogenic | -10.64 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.34 | Pathogenic | 0.01 | Affected | 0.1854 | 0.2750 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.1656C>G | C552W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C552W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only premPS, whereas the majority of in‑silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all classify the variant as pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability assessments. High‑accuracy methods specifically indicate pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.013265 | Structured | 0.005714 | Uncertain | 0.955 | 0.256 | 0.000 | -15.723 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | -1.19 | Ambiguous | 0.1 | -0.66 | Ambiguous | -0.93 | Ambiguous | 0.50 | Likely Benign | 0.830 | Likely Pathogenic | -9.51 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.26 | Pathogenic | 0.02 | Affected | 0.1397 | 0.2371 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.1677C>G | C559W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change C559W is not listed in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM; pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is Uncertain, SGM Consensus is Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is Benign. Overall, seven of the twelve evaluated tools predict pathogenicity versus six benign, giving a slight majority toward a deleterious effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.016021 | Structured | 0.010460 | Uncertain | 0.842 | 0.204 | 0.000 | -12.765 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | -0.19 | Likely Benign | 0.0 | 0.01 | Likely Benign | -0.09 | Likely Benign | 0.44 | Likely Benign | 0.274 | Likely Benign | -8.54 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.42 | Benign | 0.03 | Affected | 0.2492 | 0.2135 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.1728C>G | C576W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C576W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, while the majority of other in silico predictors (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic impact; premPS is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the preponderance of pathogenic predictions and the absence of benign consensus, the variant is most likely pathogenic, with no contradiction to ClinVar status (which has no entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.017684 | Uncertain | 0.913 | 0.245 | 0.000 | -14.796 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 13.87 | Destabilizing | 1.5 | 5.46 | Destabilizing | 9.67 | Destabilizing | 0.60 | Ambiguous | 0.473 | Likely Benign | -10.01 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.38 | Benign | 0.00 | Affected | 0.1894 | 0.3017 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.1797C>G | C599W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C599W is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only premPS; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009865 | Structured | 0.151725 | Uncertain | 0.960 | 0.151 | 0.000 | -17.500 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.85 | Destabilizing | 0.6 | 3.32 | Destabilizing | 3.59 | Destabilizing | 0.16 | Likely Benign | 0.715 | Likely Pathogenic | -10.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.52 | Pathogenic | 0.00 | Affected | 0.1500 | 0.2363 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.2463C>G | C821W 2D AIThe SynGAP1 missense variant C821W is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs two benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evaluated predictors (six pathogenic vs three benign) indicate a pathogenic impact. This prediction is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.745909 | Disordered | 0.672821 | Binding | 0.351 | 0.883 | 0.750 | -4.843 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.201 | Likely Benign | -3.30 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.64 | Benign | 0.01 | Affected | 0.1742 | 0.3268 | -8 | -2 | -3.4 | 83.07 | ||||||||||||||||||||||||||||||||||||||||
| c.657T>G | C219W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219W is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only FATHMM, whereas the majority of tools (SGM‑Consensus, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; Rosetta and premPS are inconclusive. High‑accuracy methods give consistent pathogenic results: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Taken together, the overwhelming evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | -16.565 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 10.10 | Destabilizing | 3.6 | 1.20 | Ambiguous | 5.65 | Destabilizing | 0.52 | Ambiguous | 0.706 | Likely Pathogenic | -9.23 | Deleterious | 0.997 | Probably Damaging | 0.808 | Possibly Damaging | 5.77 | Benign | 0.00 | Affected | 0.1131 | 0.3285 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.690C>G | C230W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are made by FATHMM and FoldX, whereas the majority of other in silico predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic effect. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus confirms a likely pathogenic outcome, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the preponderance of evidence points to a pathogenic impact for C230W, and this conclusion is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.268042 | Structured | 0.308076 | Uncertain | 0.870 | 0.308 | 0.000 | -11.022 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -0.21 | Likely Benign | 0.0 | -1.87 | Ambiguous | -1.04 | Ambiguous | 0.74 | Ambiguous | 0.739 | Likely Pathogenic | -8.79 | Deleterious | 0.983 | Probably Damaging | 0.841 | Possibly Damaging | 5.84 | Benign | 0.01 | Affected | 0.1589 | 0.3663 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.699T>G | C233W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233W is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic calls come from SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a benign outcome, while Rosetta and premPS are uncertain. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Taken together, the overwhelming majority of evidence indicates that C233W is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -17.899 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 14.72 | Destabilizing | 6.6 | 1.07 | Ambiguous | 7.90 | Destabilizing | 0.54 | Ambiguous | 0.772 | Likely Pathogenic | -9.79 | Deleterious | 0.983 | Probably Damaging | 0.715 | Possibly Damaging | 5.71 | Benign | 0.00 | Affected | 0.1727 | 0.5292 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.846T>G | C282W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change C282W is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to REVEL, which scores the variant as benign. All other evaluated predictors—FoldX, Foldetta, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. Uncertain results come only from premPS and Rosetta, which are treated as unavailable. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports a likely pathogenic status; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts pathogenic. **Thus, the variant is most likely pathogenic based on the collective predictions, and this conclusion is not contradicted by any ClinVar annotation.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.098513 | Structured | 0.348535 | Uncertain | 0.942 | 0.250 | 0.000 | -15.392 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 10.69 | Destabilizing | 1.7 | -1.05 | Ambiguous | 4.82 | Destabilizing | 0.70 | Ambiguous | 0.418 | Likely Benign | -10.11 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.63 | Pathogenic | 0.03 | Affected | 0.1457 | 0.2978 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.855C>G | C285W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant C285W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and Rosetta, whereas pathogenic predictions are made by SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy subset confirms this trend: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenicity, and Foldetta remains uncertain. No prediction tool is missing or inconclusive enough to alter the overall assessment. Consequently, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.144935 | Structured | 0.375400 | Uncertain | 0.946 | 0.250 | 0.000 | -9.017 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 3.35 | Destabilizing | 1.1 | -2.28 | Stabilizing | 0.54 | Ambiguous | 0.61 | Ambiguous | 0.327 | Likely Benign | -8.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.78 | Pathogenic | 0.11 | Tolerated | 0.1934 | 0.3697 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.1021G>C | G341R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G341R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, polyPhen‑2 HumVar, and Foldetta. Those that predict a pathogenic effect are SGM‑Consensus (Likely Pathogenic), polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and Rosetta. High‑accuracy assessments show that the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts a likely pathogenic outcome, while Foldetta predicts a benign effect; AlphaMissense‑Optimized remains inconclusive. Overall, the majority of predictions lean toward a benign impact, and this does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign, though the evidence is not definitive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.356642 | Structured | 0.431164 | Uncertain | 0.745 | 0.479 | 0.250 | -8.263 | Likely Pathogenic | 0.945 | Likely Pathogenic | Ambiguous | 0.28 | Likely Benign | 0.2 | -1.25 | Ambiguous | -0.49 | Likely Benign | 0.18 | Likely Benign | 0.379 | Likely Benign | -1.03 | Neutral | 0.801 | Possibly Damaging | 0.417 | Benign | 0.34 | Pathogenic | 0.17 | Tolerated | 0.0838 | 0.3618 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1030G>C | G344R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G344R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while the only inconclusive result is premPS, which is listed as uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic status; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports pathogenic. Consequently, the variant is most likely pathogenic, and this assessment is consistent with the absence of a ClinVar entry (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.264545 | Structured | 0.368110 | Uncertain | 0.913 | 0.485 | 0.250 | -12.609 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 14.84 | Destabilizing | 0.8 | 13.66 | Destabilizing | 14.25 | Destabilizing | 0.81 | Ambiguous | 0.801 | Likely Pathogenic | -7.17 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -0.49 | Pathogenic | 0.01 | Affected | 0.0844 | 0.4614 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1063G>A | G355R 2D AIThe SynGAP1 missense variant G355R 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, Rosetta, and Foldetta. Tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are AlphaMissense‑Optimized, FoldX, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evaluated tools predict a pathogenic impact, whereas a minority predict benign. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.155435 | Structured | 0.388832 | Uncertain | 0.810 | 0.354 | 0.125 | -11.022 | Likely Pathogenic | 0.922 | Likely Pathogenic | Ambiguous | 0.61 | Ambiguous | 1.4 | 0.10 | Likely Benign | 0.36 | Likely Benign | 0.60 | Ambiguous | 0.340 | Likely Benign | -6.74 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.80 | Pathogenic | 0.02 | Affected | 0.1041 | 0.4567 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1063G>C | G355R 2D AIThe SynGAP1 missense variant G355R 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, Rosetta, and Foldetta. Tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are AlphaMissense‑Optimized, FoldX, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evaluated tools predict a pathogenic impact, whereas a minority predict benign. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.155435 | Structured | 0.388832 | Uncertain | 0.810 | 0.354 | 0.125 | -11.022 | Likely Pathogenic | 0.922 | Likely Pathogenic | Ambiguous | 0.61 | Ambiguous | 1.4 | 0.10 | Likely Benign | 0.36 | Likely Benign | 0.60 | Ambiguous | 0.340 | Likely Benign | -6.74 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.80 | Pathogenic | 0.02 | Affected | 0.1041 | 0.4567 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1108G>C | G370R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G370R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are SGM‑Consensus, FoldX, ESM1b, FATHMM, AlphaMissense‑Default, and Foldetta; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Overall, the balance of evidence leans toward pathogenicity, with two of the three high‑accuracy tools supporting this view. The variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.461924 | Structured | 0.434325 | Uncertain | 0.359 | 0.720 | 0.500 | -8.375 | Likely Pathogenic | 0.731 | Likely Pathogenic | Likely Benign | 3.62 | Destabilizing | 3.7 | 1.72 | Ambiguous | 2.67 | Destabilizing | 0.22 | Likely Benign | 0.373 | Likely Benign | -0.80 | Neutral | 0.016 | Benign | 0.002 | Benign | 1.32 | Pathogenic | 0.55 | Tolerated | 0.0978 | 0.4313 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1114G>A | G372R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G372R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, Rosetta, Foldetta, SIFT, FATHMM, and AlphaMissense‑Default. Two tools, FoldX and ESM1b, returned uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta predicting pathogenic. Overall, the majority of predictions (seven pathogenic vs. five benign) and the consensus of high‑accuracy methods indicate a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.433034 | Structured | 0.430335 | Uncertain | 0.322 | 0.774 | 0.375 | -7.344 | In-Between | 0.617 | Likely Pathogenic | Likely Benign | 1.49 | Ambiguous | 0.3 | 2.87 | Destabilizing | 2.18 | Destabilizing | 0.20 | Likely Benign | 0.572 | Likely Pathogenic | -0.61 | Neutral | 0.001 | Benign | 0.001 | Benign | -0.74 | Pathogenic | 0.02 | Affected | 0.1323 | 0.4313 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1114G>C | G372R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G372R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, Rosetta, Foldetta, SIFT, FATHMM, and AlphaMissense‑Default. Two tools (FoldX and ESM1b) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as pathogenic. Overall, the majority of predictions (seven pathogenic vs five benign) indicate that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.433034 | Structured | 0.430335 | Uncertain | 0.322 | 0.774 | 0.375 | -7.344 | In-Between | 0.617 | Likely Pathogenic | Likely Benign | 1.49 | Ambiguous | 0.3 | 2.87 | Destabilizing | 2.18 | Destabilizing | 0.20 | Likely Benign | 0.572 | Likely Pathogenic | -0.61 | Neutral | 0.001 | Benign | 0.001 | Benign | -0.74 | Pathogenic | 0.02 | Affected | 0.1323 | 0.4313 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1117G>A | G373R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G373R is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438022‑G‑A). Prediction tools that classify the variant as benign include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Optimized, and premPS. Those that predict pathogenicity are REVEL, FoldX, Foldetta, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as pathogenic. No prediction or folding result is missing or inconclusive. Overall, the majority of tools (six versus five) and the consensus of high‑accuracy methods lean toward a benign effect. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.529623 | Disordered | 0.429267 | Uncertain | 0.295 | 0.799 | 0.625 | 6-33438022-G-A | 1 | 6.28e-7 | -7.878 | In-Between | 0.653 | Likely Pathogenic | Likely Benign | 4.28 | Destabilizing | 3.5 | 0.14 | Likely Benign | 2.21 | Destabilizing | 0.21 | Likely Benign | 0.510 | Likely Pathogenic | -0.64 | Neutral | 0.001 | Benign | 0.000 | Benign | 3.90 | Benign | 0.01 | Affected | 3.53 | 16 | 0.1089 | 0.4524 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||
| c.1117G>C | G373R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G373R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, FoldX, Foldetta, SIFT, and AlphaMissense‑Default; ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as pathogenic. Overall, the majority of tools (seven benign vs five pathogenic) lean toward a benign interpretation, and this does not contradict the ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.529623 | Disordered | 0.429267 | Uncertain | 0.295 | 0.799 | 0.625 | -7.878 | In-Between | 0.653 | Likely Pathogenic | Likely Benign | 4.28 | Destabilizing | 3.5 | 0.14 | Likely Benign | 2.21 | Destabilizing | 0.21 | Likely Benign | 0.522 | Likely Pathogenic | -0.64 | Neutral | 0.001 | Benign | 0.000 | Benign | 3.90 | Benign | 0.01 | Affected | 3.53 | 16 | 0.1089 | 0.4524 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||
| c.1123G>A | G375R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G375R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized, whereas tools that predict pathogenicity are FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of predictions (7 pathogenic vs. 5 benign) indicate a likely pathogenic effect, 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 Pathogenic | C2 | 0.604312 | Disordered | 0.428340 | Uncertain | 0.301 | 0.836 | 0.625 | -8.955 | Likely Pathogenic | 0.609 | Likely Pathogenic | Likely Benign | 2.97 | Destabilizing | 1.3 | 12.66 | Destabilizing | 7.82 | Destabilizing | 0.36 | Likely Benign | 0.497 | Likely Benign | -1.15 | Neutral | 0.845 | Possibly Damaging | 0.523 | Possibly Damaging | 1.32 | Pathogenic | 0.11 | Tolerated | 0.1335 | 0.4513 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1123G>C | G375R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G375R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions come from FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts benign, whereas Foldetta indicates a destabilizing, pathogenic change, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as likely pathogenic. Overall, the majority 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 | C2 | 0.604312 | Disordered | 0.428340 | Uncertain | 0.301 | 0.836 | 0.625 | -8.955 | Likely Pathogenic | 0.609 | Likely Pathogenic | Likely Benign | 2.97 | Destabilizing | 1.3 | 12.66 | Destabilizing | 7.82 | Destabilizing | 0.36 | Likely Benign | 0.497 | Likely Benign | -1.15 | Neutral | 0.845 | Possibly Damaging | 0.523 | Possibly Damaging | 1.32 | Pathogenic | 0.11 | Tolerated | 0.1335 | 0.4513 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1126G>C | G376R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G376R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include Rosetta, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are SGM‑Consensus, REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Foldetta reports an uncertain outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools (8 pathogenic vs. 5 benign) and the consensus from high‑accuracy methods lean toward a pathogenic interpretation. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.680603 | Disordered | 0.428979 | Uncertain | 0.326 | 0.869 | 0.625 | -8.500 | Likely Pathogenic | 0.658 | Likely Pathogenic | Likely Benign | 3.48 | Destabilizing | 1.3 | -0.46 | Likely Benign | 1.51 | Ambiguous | 0.30 | Likely Benign | 0.589 | Likely Pathogenic | -1.21 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.32 | Pathogenic | 0.09 | Tolerated | 0.1316 | 0.4027 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1132G>C | G378R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G378R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from premPS, PROVEAN, and SIFT, while pathogenic predictions arise from REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts benign, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also indicates pathogenicity. Overall, the preponderance of evidence points to a pathogenic impact for G378R. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.767246 | Disordered | 0.432858 | Uncertain | 0.341 | 0.915 | 0.625 | -8.863 | Likely Pathogenic | 0.745 | Likely Pathogenic | Likely Benign | 12.27 | Destabilizing | 6.3 | 13.17 | Destabilizing | 12.72 | Destabilizing | 0.12 | Likely Benign | 0.653 | Likely Pathogenic | -0.96 | Neutral | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.32 | Pathogenic | 0.06 | Tolerated | 0.1343 | 0.4356 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1136C>G | S379W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S379W is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438041‑C‑G). Prediction tools that indicate a benign effect include premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact comprise REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus as benign. Because the majority of conventional tools favor pathogenicity while the high‑accuracy subset is split, the overall evidence leans toward a pathogenic effect. This conclusion does not contradict the ClinVar uncertain status, which remains unresolved. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.728858 | Disordered | 0.433206 | Uncertain | 0.327 | 0.931 | 0.625 | Uncertain | 1 | 6-33438041-C-G | -8.898 | Likely Pathogenic | 0.388 | Ambiguous | Likely Benign | 4.32 | Destabilizing | 3.4 | 3.56 | Destabilizing | 3.94 | Destabilizing | 0.16 | Likely Benign | 0.520 | Likely Pathogenic | -1.02 | Neutral | 0.998 | Probably Damaging | 0.844 | Possibly Damaging | 3.82 | Benign | 0.01 | Affected | 4.32 | 11 | 0.1196 | 0.6070 | -2 | -3 | -0.1 | 99.14 | 271.3 | -75.7 | 1.4 | 1.0 | 0.6 | 0.5 | Uncertain | Ser379 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus hydrophobic residues like tryptophan are rarely tolerated. Although no major negative structural effects are observed in the variant simulations, Trp379 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effect on Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn | |||||||||||||||||
| c.1138G>A | G380R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G380R missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized, while those that agree on a pathogenic effect are REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, Foldetta predicts a pathogenic outcome, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of evidence (10 pathogenic vs. 4 benign) points to a pathogenic impact. The variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.724957 | Disordered | 0.432982 | Uncertain | 0.316 | 0.939 | 0.750 | -9.205 | Likely Pathogenic | 0.635 | Likely Pathogenic | Likely Benign | 5.94 | Destabilizing | 2.6 | 0.90 | Ambiguous | 3.42 | Destabilizing | 0.11 | Likely Benign | 0.640 | Likely Pathogenic | -0.86 | Neutral | 0.940 | Possibly Damaging | 0.459 | Possibly Damaging | 2.53 | Benign | 0.01 | Affected | 0.1319 | 0.3956 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1138G>C | G380R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G380R missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized, while those that agree on a pathogenic effect are REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, Foldetta predicts pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of tools (10 pathogenic vs 4 benign) and the Foldetta result support a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.724957 | Disordered | 0.432982 | Uncertain | 0.316 | 0.939 | 0.750 | -9.205 | Likely Pathogenic | 0.635 | Likely Pathogenic | Likely Benign | 5.94 | Destabilizing | 2.6 | 0.90 | Ambiguous | 3.42 | Destabilizing | 0.11 | Likely Benign | 0.619 | Likely Pathogenic | -0.86 | Neutral | 0.940 | Possibly Damaging | 0.459 | Possibly Damaging | 2.53 | Benign | 0.01 | Affected | 0.1319 | 0.3956 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1141G>A | G381R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G381R is listed in ClinVar with an uncertain significance (ClinVar ID 4801336) and is present in gnomAD (variant ID 6‑33438046‑G‑A). Prediction tools that classify the variant as benign include premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, FoldX, Rosetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely pathogenic. High‑accuracy assessments further show AlphaMissense‑Optimized as benign, while both the SGM‑Consensus and Foldetta (combining FoldX‑MD and Rosetta outputs) predict pathogenicity. Overall, the preponderance of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.724957 | Disordered | 0.431692 | Uncertain | 0.301 | 0.951 | 0.750 | Uncertain | 1 | 6-33438046-G-A | -8.990 | Likely Pathogenic | 0.652 | Likely Pathogenic | Likely Benign | 5.60 | Destabilizing | 0.9 | 2.80 | Destabilizing | 4.20 | Destabilizing | 0.20 | Likely Benign | 0.589 | Likely Pathogenic | -0.82 | Neutral | 0.985 | Probably Damaging | 0.795 | Possibly Damaging | 1.32 | Pathogenic | 0.08 | Tolerated | 4.32 | 9 | 0.1339 | 0.3945 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||
| c.1141G>C | G381R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G381R is catalogued in gnomAD (ID 6‑33438046‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from SGM‑Consensus, REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized reports a benign outcome, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta) both predict pathogenicity. Overall, the majority of evidence indicates a pathogenic impact for G381R, and this conclusion is not contradicted by ClinVar status, which currently lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.724957 | Disordered | 0.431692 | Uncertain | 0.301 | 0.951 | 0.750 | 6-33438046-G-C | 2 | 1.25e-6 | -8.990 | Likely Pathogenic | 0.652 | Likely Pathogenic | Likely Benign | 5.60 | Destabilizing | 0.9 | 2.80 | Destabilizing | 4.20 | Destabilizing | 0.20 | Likely Benign | 0.589 | Likely Pathogenic | -0.82 | Neutral | 0.985 | Probably Damaging | 0.795 | Possibly Damaging | 1.32 | Pathogenic | 0.08 | Tolerated | 4.32 | 9 | 0.1339 | 0.3945 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||
| c.1144G>A | G382R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G382R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include premPS, PROVEAN, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts a benign change, whereas the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta stability outputs) both predict pathogenicity. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.728858 | Disordered | 0.429690 | Uncertain | 0.315 | 0.951 | 0.750 | -8.997 | Likely Pathogenic | 0.654 | Likely Pathogenic | Likely Benign | 4.53 | Destabilizing | 1.6 | 8.03 | Destabilizing | 6.28 | Destabilizing | 0.23 | Likely Benign | 0.595 | Likely Pathogenic | -0.95 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 1.32 | Pathogenic | 0.02 | Affected | 0.1295 | 0.4346 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1144G>C | G382R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G382R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include premPS, PROVEAN, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts a benign change, whereas the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta stability outputs) both predict pathogenicity. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.728858 | Disordered | 0.429690 | Uncertain | 0.315 | 0.951 | 0.750 | -8.997 | Likely Pathogenic | 0.654 | Likely Pathogenic | Likely Benign | 4.53 | Destabilizing | 1.6 | 8.03 | Destabilizing | 6.28 | Destabilizing | 0.23 | Likely Benign | 0.570 | Likely Pathogenic | -0.95 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 1.32 | Pathogenic | 0.02 | Affected | 0.1295 | 0.4346 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1147G>A | G383R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G383R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that agree on a pathogenic effect are FoldX, Rosetta, Foldetta, polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, Foldetta predicts a pathogenic outcome, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs. two benign). Overall, the majority of predictions lean toward pathogenicity, and this does not contradict the ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.728858 | Disordered | 0.429104 | Uncertain | 0.296 | 0.949 | 0.750 | -9.067 | Likely Pathogenic | 0.660 | Likely Pathogenic | Likely Benign | 4.03 | Destabilizing | 2.3 | 3.36 | Destabilizing | 3.70 | Destabilizing | 0.29 | Likely Benign | 0.449 | Likely Benign | -0.84 | Neutral | 0.498 | Possibly Damaging | 0.119 | Benign | 4.10 | Benign | 0.00 | Affected | 0.1295 | 0.3741 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1147G>C | G383R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G383R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that agree on a pathogenic effect are FoldX, Rosetta, Foldetta, polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, Foldetta predicts a pathogenic outcome, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs. two benign). Overall, the majority of predictions lean toward pathogenicity, and this does not contradict the ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.728858 | Disordered | 0.429104 | Uncertain | 0.296 | 0.949 | 0.750 | -9.067 | Likely Pathogenic | 0.660 | Likely Pathogenic | Likely Benign | 4.03 | Destabilizing | 2.3 | 3.36 | Destabilizing | 3.70 | Destabilizing | 0.29 | Likely Benign | 0.440 | Likely Benign | -0.84 | Neutral | 0.498 | Possibly Damaging | 0.119 | Benign | 4.10 | Benign | 0.00 | Affected | 0.1295 | 0.3741 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1150G>C | G384R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G384R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, PROVEAN, and AlphaMissense‑Optimized, whereas pathogenic calls are made by FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, 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 further support a deleterious effect: AlphaMissense‑Optimized predicts benign, but SGM‑Consensus and Foldetta both predict pathogenic, with Foldetta integrating FoldX‑MD and Rosetta stability outputs. Overall, the majority 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 | C2 | 0.728858 | Disordered | 0.427831 | Uncertain | 0.323 | 0.934 | 0.750 | -9.186 | Likely Pathogenic | 0.719 | Likely Pathogenic | Likely Benign | 2.16 | Destabilizing | 0.4 | 5.06 | Destabilizing | 3.61 | Destabilizing | 0.25 | Likely Benign | 0.475 | Likely Benign | -0.96 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 1.32 | Pathogenic | 0.02 | Affected | 0.1250 | 0.4156 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1154C>G | S385W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S385W is listed in ClinVar as Benign (ClinVar ID 218691.0) and is present in gnomAD (ID 6‑33438059‑C‑G). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, 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 ESM1b. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM Consensus as Benign, and Foldetta as Uncertain. Taken together, the majority of evidence points to a benign impact, which aligns with the ClinVar classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.733139 | Disordered | 0.425480 | Uncertain | 0.341 | 0.925 | 0.750 | Benign | 1 | 6-33438059-C-G | -9.353 | Likely Pathogenic | 0.362 | Ambiguous | Likely Benign | 0.53 | Ambiguous | 0.2 | 0.69 | Ambiguous | 0.61 | Ambiguous | 0.00 | Likely Benign | 0.373 | Likely Benign | -0.84 | Neutral | 0.986 | Probably Damaging | 0.968 | Probably Damaging | 4.63 | Benign | 0.00 | Affected | 4.32 | 3 | 0.1272 | 0.6670 | -2 | -3 | -0.1 | 99.14 | 260.4 | -71.2 | 0.5 | 1.3 | 0.7 | 0.4 | Uncertain | Ser385 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus hydrophobic residues like tryptophan are rarely tolerated. Although no major negative structural effects are observed in the variant simulations, Trp385 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effects on Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||
| c.1156G>A | G386R 2D 3DClick to see structure in 3D Viewer AIClinVar reports no entry for this SynGAP1 G386R variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are FoldX, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default, while Rosetta is uncertain. High‑accuracy methods give a benign call from AlphaMissense‑Optimized, a pathogenic result from Foldetta, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive. Overall, the evidence is mixed; the variant is most likely benign, and this assessment does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.733139 | Disordered | 0.424156 | Uncertain | 0.334 | 0.898 | 0.750 | -9.024 | Likely Pathogenic | 0.709 | Likely Pathogenic | Likely Benign | 3.62 | Destabilizing | 2.9 | 1.07 | Ambiguous | 2.35 | Destabilizing | 0.29 | Likely Benign | 0.453 | Likely Benign | -0.82 | Neutral | 0.753 | Possibly Damaging | 0.220 | Benign | 4.03 | Benign | 0.01 | Affected | 0.1329 | 0.4032 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1156G>C | G386R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G386R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Computational predictors that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise FoldX, polyPhen‑2 (HumDiv), SIFT, ESM1b, AlphaMissense‑Default, and Foldetta; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the balance of evidence favors a pathogenic classification. This conclusion is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.733139 | Disordered | 0.424156 | Uncertain | 0.334 | 0.898 | 0.750 | -9.024 | Likely Pathogenic | 0.709 | Likely Pathogenic | Likely Benign | 3.62 | Destabilizing | 2.9 | 1.07 | Ambiguous | 2.35 | Destabilizing | 0.29 | Likely Benign | 0.453 | Likely Benign | -0.82 | Neutral | 0.753 | Possibly Damaging | 0.220 | Benign | 4.03 | Benign | 0.01 | Affected | 0.1329 | 0.4032 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1159G>C | G387R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G387R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include premPS, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Tools that predict pathogenicity are SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign effect, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions are missing or inconclusive. Overall, the majority of evidence (10 pathogenic vs. 4 benign) indicates the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.642678 | Disordered | 0.422910 | Uncertain | 0.293 | 0.861 | 0.750 | -8.728 | Likely Pathogenic | 0.683 | Likely Pathogenic | Likely Benign | 4.13 | Destabilizing | 2.9 | 2.57 | Destabilizing | 3.35 | Destabilizing | 0.15 | Likely Benign | 0.516 | Likely Pathogenic | -0.54 | Neutral | 0.003 | Benign | 0.004 | Benign | 1.32 | Pathogenic | 0.01 | Affected | 0.1309 | 0.4356 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1162G>C | G388R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G388R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, and AlphaMissense‑Optimized, whereas the remaining eleven tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) uniformly predict a pathogenic impact. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized indicates benign, but the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both predict pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overall consensus of the majority of tools and the high‑accuracy predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.736850 | Disordered | 0.420316 | Uncertain | 0.319 | 0.827 | 0.750 | -9.142 | Likely Pathogenic | 0.694 | Likely Pathogenic | Likely Benign | 6.54 | Destabilizing | 8.5 | 4.79 | Destabilizing | 5.67 | Destabilizing | 0.31 | Likely Benign | 0.606 | Likely Pathogenic | -0.74 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 1.32 | Pathogenic | 0.02 | Affected | 0.1296 | 0.4417 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1168G>A | G390R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G390R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta) both predict pathogenicity. Overall, the majority of tools and the high‑accuracy methods indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.626927 | Disordered | 0.413274 | Uncertain | 0.304 | 0.763 | 0.875 | -9.242 | Likely Pathogenic | 0.686 | Likely Pathogenic | Likely Benign | 2.43 | Destabilizing | 0.9 | 4.85 | Destabilizing | 3.64 | Destabilizing | 0.16 | Likely Benign | 0.605 | Likely Pathogenic | -0.92 | Neutral | 0.480 | Possibly Damaging | 0.163 | Benign | 1.32 | Pathogenic | 0.08 | Tolerated | 0.1190 | 0.4524 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1168G>C | G390R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G390R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta) both predict pathogenicity. Overall, the majority of tools and the high‑accuracy methods indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.626927 | Disordered | 0.413274 | Uncertain | 0.304 | 0.763 | 0.875 | -9.242 | Likely Pathogenic | 0.686 | Likely Pathogenic | Likely Benign | 2.43 | Destabilizing | 0.9 | 4.85 | Destabilizing | 3.64 | Destabilizing | 0.16 | Likely Benign | 0.605 | Likely Pathogenic | -0.92 | Neutral | 0.480 | Possibly Damaging | 0.163 | Benign | 1.32 | Pathogenic | 0.08 | Tolerated | 0.1190 | 0.4524 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1171G>C | G391R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G391R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that classify the variant as benign include premPS, PROVEAN, and SIFT, whereas those that predict pathogenicity comprise REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further show AlphaMissense‑Optimized labeling the variant as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not conflict with the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.637480 | Disordered | 0.409509 | Uncertain | 0.279 | 0.741 | 0.750 | -9.115 | Likely Pathogenic | 0.709 | Likely Pathogenic | Likely Benign | 2.80 | Destabilizing | 1.3 | 3.86 | Destabilizing | 3.33 | Destabilizing | 0.32 | Likely Benign | 0.628 | Likely Pathogenic | -0.95 | Neutral | 0.999 | Probably Damaging | 0.960 | Probably Damaging | 1.32 | Pathogenic | 0.17 | Tolerated | 0.1313 | 0.4124 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1177G>C | G393R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G393R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include Rosetta and premPS, whereas the remaining tools—SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.538167 | Disordered | 0.402365 | Uncertain | 0.333 | 0.670 | 0.625 | -9.148 | Likely Pathogenic | 0.815 | Likely Pathogenic | Ambiguous | 3.88 | Destabilizing | 1.4 | -0.38 | Likely Benign | 1.75 | Ambiguous | 0.47 | Likely Benign | 0.596 | Likely Pathogenic | -2.99 | Deleterious | 0.991 | Probably Damaging | 0.881 | Possibly Damaging | 1.32 | Pathogenic | 0.02 | Affected | 0.1353 | 0.4464 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1183G>A | G395R 2D AIThe SynGAP1 missense variant G395R has no ClinVar record and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from SIFT, ESM1b, and AlphaMissense‑Default. Two tools, FoldX and Foldetta, yield uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta remains uncertain. Overall, the balance of evidence favors 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. | C2 | 0.513880 | Disordered | 0.396199 | Uncertain | 0.474 | 0.601 | 0.500 | -9.851 | Likely Pathogenic | 0.768 | Likely Pathogenic | Likely Benign | 1.26 | Ambiguous | 2.1 | -0.25 | Likely Benign | 0.51 | Ambiguous | 0.50 | Likely Benign | 0.430 | Likely Benign | -2.01 | Neutral | 0.037 | Benign | 0.027 | Benign | 4.23 | Benign | 0.02 | Affected | 0.0953 | 0.4313 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1183G>C | G395R 2D AIThe SynGAP1 missense variant G395R has no ClinVar record and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from SIFT, ESM1b, and AlphaMissense‑Default. Two tools, FoldX and Foldetta, yield uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta remains uncertain. Overall, the balance of evidence favors 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. | C2 | 0.513880 | Disordered | 0.396199 | Uncertain | 0.474 | 0.601 | 0.500 | -9.851 | Likely Pathogenic | 0.768 | Likely Pathogenic | Likely Benign | 1.26 | Ambiguous | 2.1 | -0.25 | Likely Benign | 0.51 | Ambiguous | 0.50 | Likely Benign | 0.430 | Likely Benign | -2.01 | Neutral | 0.037 | Benign | 0.027 | Benign | 4.23 | Benign | 0.02 | Affected | 0.0953 | 0.4313 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1186G>C | G396R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G396R missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign impact include REVEL, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the variant is more frequently predicted to be pathogenic (five tools) than benign (five tools), and the high‑accuracy consensus leans toward pathogenicity, though Foldetta does not provide a definitive verdict. Thus, the variant is most likely pathogenic based on the current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.394626 | Uncertain | 0.640 | 0.584 | 0.500 | -9.310 | Likely Pathogenic | 0.775 | Likely Pathogenic | Likely Benign | 1.68 | Ambiguous | 1.1 | 1.56 | Ambiguous | 1.62 | Ambiguous | 0.66 | Ambiguous | 0.319 | Likely Benign | -2.65 | Deleterious | 0.718 | Possibly Damaging | 0.216 | Benign | 4.42 | Benign | 0.24 | Tolerated | 0.0986 | 0.4007 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.127G>C | G43R 2D AIThe SynGAP1 missense variant G43R 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 G43R, 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 | 0.308712 | Structured | 0.431462 | Uncertain | 0.396 | 0.762 | 0.375 | -2.104 | Likely Benign | 0.266 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -1.26 | Neutral | 0.870 | Possibly Damaging | 0.500 | Possibly Damaging | 4.22 | Benign | 0.00 | Affected | 0.1025 | 0.3645 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.1327G>C | G443R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G443R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM all classify it as benign. Only two tools predict pathogenicity: polyPhen‑2 HumDiv and AlphaMissense‑Default. Predictions that are inconclusive—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—are treated as unavailable. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments are: AlphaMissense‑Optimized (uncertain), SGM Consensus (likely benign), and Foldetta (uncertain). Overall, the preponderance of evidence points to a benign impact for G443R, 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 | GAP | 0.250310 | Structured | 0.258623 | Uncertain | 0.935 | 0.206 | 0.000 | -6.954 | Likely Benign | 0.886 | Likely Pathogenic | Ambiguous | -0.88 | Ambiguous | 0.3 | -1.19 | Ambiguous | -1.04 | Ambiguous | 0.28 | Likely Benign | 0.132 | Likely Benign | -1.49 | Neutral | 0.832 | Possibly Damaging | 0.286 | Benign | 3.40 | Benign | 0.21 | Tolerated | 0.0934 | 0.3197 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1375G>C | G459R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G459R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM Consensus score (Likely Pathogenic) all indicate a pathogenic impact. Stability‑based methods (FoldX, Rosetta, premPS) are inconclusive, and Foldetta likewise reports an uncertain effect. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as Likely Pathogenic, and Foldetta as unavailable. Taken together, the consensus of the majority of tools points to a pathogenic effect for G459R. This prediction is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -12.958 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 1.84 | Ambiguous | 0.2 | 0.79 | Ambiguous | 1.32 | Ambiguous | 0.79 | Ambiguous | 0.486 | Likely Benign | -7.41 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | 0.0903 | 0.4248 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1504G>C | G502R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G502R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect; the only inconclusive result is from premPS, which is listed as uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a destabilizing, pathogenic effect. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.083462 | Structured | 0.340113 | Uncertain | 0.882 | 0.152 | 0.000 | -15.571 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 8.80 | Destabilizing | 0.3 | 10.07 | Destabilizing | 9.44 | Destabilizing | 0.88 | Ambiguous | 0.917 | Likely Pathogenic | -7.73 | Deleterious | 1.000 | Probably Damaging | 0.985 | Probably Damaging | -1.65 | Pathogenic | 0.00 | Affected | 0.1014 | 0.3317 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1531G>A | G511R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G511R is listed in ClinVar as Pathogenic (ClinVar ID 1774641.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Stability calculations from FoldX and Rosetta are uncertain, and premPS is unavailable. Overall, the majority of evidence points to a pathogenic impact, aligning with the ClinVar classification and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | Likely Pathogenic | 1 | -11.327 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 1.94 | Ambiguous | 0.3 | 1.32 | Ambiguous | 1.63 | Ambiguous | 0.94 | Ambiguous | 0.416 | Likely Benign | -7.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.26 | Benign | 0.06 | Tolerated | 3.37 | 35 | 0.1307 | 0.4104 | -3 | -2 | -4.1 | 99.14 | 279.4 | -159.9 | 0.0 | 0.0 | 0.7 | 0.1 | X | X | Potentially Pathogenic | Gly511 is located in an α-helix (res. Gly502-Tyr518), facing hydrophobic residues in an inter-helix space (e.g., Leu610, Ile514) in the WT simulations. In contrast, in the variant simulations, the bulkier and positively charged guanidinium side chain of Arg511 forms a salt bridge with the carboxylate group of Glu217 or hydrogen bonds with the backbone carbonyl group of Leu610. Although the residue swap introduces a third positively charged residue in close vicinity (Arg511, Lys507, Arg515), the protein structure seems to remain stable in the variant simulations. Importantly, according to ClinVar, the residue swap alters the last nucleotide of an exon and is predicted to destroy the splice donor site, resulting in aberrant splicing and pathogenic status. | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||
| c.1531G>C | G511R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G511R is listed in ClinVar (ID 452818.0) as Pathogenic and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain, which is treated as unavailable evidence. Overall, the majority of available predictions support a pathogenic impact, aligning with the ClinVar classification. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | Pathogenic | 1 | -11.327 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 1.94 | Ambiguous | 0.3 | 1.32 | Ambiguous | 1.63 | Ambiguous | 0.94 | Ambiguous | 0.415 | Likely Benign | -7.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.26 | Benign | 0.06 | Tolerated | 3.37 | 35 | 0.1307 | 0.4104 | -3 | -2 | -4.1 | 99.14 | 279.4 | -159.9 | 0.0 | 0.0 | 0.7 | 0.1 | X | X | Potentially Pathogenic | Gly511 is located in an α-helix (res. Gly502-Tyr518), facing hydrophobic residues in an inter-helix space (e.g., Leu610, Ile514) in the WT simulations. In contrast, in the variant simulations, the bulkier and positively charged guanidinium side chain of Arg511 forms a salt bridge with the carboxylate group of Glu217 or hydrogen bonds with the backbone carbonyl group of Leu610. Although the residue swap introduces a third positively charged residue in close vicinity (Arg511, Lys507, Arg515), the protein structure seems to remain stable in the variant simulations. Importantly, according to ClinVar, the residue swap alters the last nucleotide of an exon and is predicted to destroy the splice donor site, resulting in aberrant splicing and pathogenic status. | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||
| c.155C>G | S52W 2D AIThe SynGAP1 missense variant S52W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign). AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. Overall, more tools (five) predict pathogenicity than benign (three), and no high‑accuracy consensus or folding‑stability evidence contradicts this trend. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not conflict with the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.291804 | Structured | 0.457753 | Uncertain | 0.499 | 0.677 | 0.000 | -8.649 | Likely Pathogenic | 0.909 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | -1.85 | Neutral | 0.986 | Probably Damaging | 0.968 | Probably Damaging | 4.05 | Benign | 0.00 | Affected | 0.0580 | 0.6254 | -2 | -3 | -0.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.157G>A | G53R 2D AIThe SynGAP1 missense variant G53R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic + 2 benign), and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable. Overall, the majority of available predictions (5 pathogenic vs. 3 benign) lean toward a pathogenic impact. Because there is no ClinVar entry to contradict this assessment, 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. | 0.268042 | Structured | 0.460894 | Uncertain | 0.386 | 0.666 | 0.000 | -8.400 | Likely Pathogenic | 0.901 | Likely Pathogenic | Ambiguous | 0.181 | Likely Benign | -1.20 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 4.13 | Benign | 0.00 | Affected | 0.0953 | 0.4347 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.157G>C | G53R 2D AIThe SynGAP1 missense variant G53R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic + 2 benign), and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable. Overall, the majority of tools (5 pathogenic vs. 3 benign) predict 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 has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.268042 | Structured | 0.460894 | Uncertain | 0.386 | 0.666 | 0.000 | -8.400 | Likely Pathogenic | 0.901 | Likely Pathogenic | Ambiguous | 0.181 | Likely Benign | -1.20 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 4.13 | Benign | 0.00 | Affected | 0.0953 | 0.4347 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.1712C>G | S571W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S571W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that provide a clear verdict overwhelmingly classify the substitution as pathogenic: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict deleterious effects. No tool in the dataset returned a benign classification; the only non‑conclusive results come from FoldX, Rosetta, Foldetta, and premPS, which are listed as uncertain. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta’s stability analysis is inconclusive. Based on the aggregate predictions, the variant is most likely pathogenic, and this assessment is consistent with the absence of a ClinVar entry (no contradictory status). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.069024 | Structured | 0.045569 | Uncertain | 0.928 | 0.270 | 0.000 | -14.025 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | -1.13 | Ambiguous | 0.1 | -1.44 | Ambiguous | -1.29 | Ambiguous | 0.67 | Ambiguous | 0.867 | Likely Pathogenic | -6.64 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.32 | Pathogenic | 0.00 | Affected | 0.0648 | 0.3809 | -2 | -3 | -0.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1738G>C | G580R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G580R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict a pathogenic outcome. No tool predicts a benign effect. Several methods return uncertain results—Rosetta, Foldetta (combining FoldX‑MD and Rosetta outputs), and premPS—so these do not influence the overall assessment. High‑accuracy evaluations reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, while Foldetta remains uncertain. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.025952 | Uncertain | 0.853 | 0.236 | 0.000 | -11.459 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 2.20 | Destabilizing | 0.1 | 1.26 | Ambiguous | 1.73 | Ambiguous | 0.81 | Ambiguous | 0.623 | Likely Pathogenic | -7.33 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.26 | Pathogenic | 0.03 | Affected | 0.1009 | 0.3197 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1811C>G | S604W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S604W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Benign predictions are provided by Rosetta, premPS, and FATHMM. Stability‑based methods give mixed results: FoldX is uncertain, while Foldetta is also uncertain. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors pathogenic. Foldetta remains inconclusive. Overall, the consensus of the majority of tools indicates a pathogenic effect. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.010926 | Structured | 0.192527 | Uncertain | 0.911 | 0.195 | 0.000 | -19.117 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -1.23 | Ambiguous | 0.1 | -2.05 | Stabilizing | -1.64 | Ambiguous | -0.19 | Likely Benign | 0.645 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.07 | Benign | 0.00 | Affected | 0.0818 | 0.4602 | -2 | -3 | -0.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1825G>A | G609R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G609R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Predictions that remain uncertain are Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated tools (eight pathogenic vs. three benign) predict a pathogenic impact for G609R. This conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | -10.172 | Likely Pathogenic | 0.543 | Ambiguous | Likely Benign | 2.09 | Destabilizing | 0.1 | 0.37 | Likely Benign | 1.23 | Ambiguous | 0.60 | Ambiguous | 0.520 | Likely Pathogenic | -2.68 | Deleterious | 0.974 | Probably Damaging | 0.818 | Possibly Damaging | -1.41 | Pathogenic | 0.07 | Tolerated | 0.1158 | 0.4348 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1825G>C | G609R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G609R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Predictions that remain uncertain are Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated tools (eight pathogenic vs. three benign) predict a pathogenic impact for G609R. This conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | -10.172 | Likely Pathogenic | 0.543 | Ambiguous | Likely Benign | 2.09 | Destabilizing | 0.1 | 0.37 | Likely Benign | 1.23 | Ambiguous | 0.60 | Ambiguous | 0.520 | Likely Pathogenic | -2.68 | Deleterious | 0.974 | Probably Damaging | 0.818 | Possibly Damaging | -1.41 | Pathogenic | 0.07 | Tolerated | 0.1158 | 0.4348 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1939G>C | G647R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G647R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. In contrast, AlphaMissense‑Default and polyPhen‑2 HumDiv predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta) is inconclusive. No evidence from FoldX or Rosetta alone is available. Overall, the preponderance of evidence supports a benign classification, and this is consistent with the lack of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.048328 | Structured | 0.325524 | Uncertain | 0.936 | 0.356 | 0.000 | -6.590 | Likely Benign | 0.636 | Likely Pathogenic | Likely Benign | -0.51 | Ambiguous | 0.1 | -0.97 | Ambiguous | -0.74 | Ambiguous | 0.29 | Likely Benign | 0.097 | Likely Benign | -1.81 | Neutral | 0.787 | Possibly Damaging | 0.349 | Benign | 3.49 | Benign | 0.17 | Tolerated | 0.1020 | 0.3712 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1972G>C | G658R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G658R is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, SIFT, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default. Four tools (FoldX, Foldetta, premPS, ESM1b) return uncertain results. High‑accuracy methods give a mixed signal: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta is uncertain. Because the majority of conventional predictors lean benign and no ClinVar evidence contradicts this, the variant is most likely benign, though the conflicting high‑accuracy predictions leave some uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.029376 | Structured | 0.180299 | Uncertain | 0.942 | 0.251 | 0.000 | -7.725 | In-Between | 0.618 | Likely Pathogenic | Likely Benign | -1.17 | Ambiguous | 0.1 | -0.46 | Likely Benign | -0.82 | Ambiguous | 0.64 | Ambiguous | 0.120 | Likely Benign | -3.11 | Deleterious | 0.955 | Possibly Damaging | 0.591 | Possibly Damaging | 3.40 | Benign | 0.19 | Tolerated | 0.1157 | 0.3888 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.2041G>C | G681R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G681R is listed in gnomAD (6-33441300-G-C) but has no ClinVar entry. In silico predictors largely converge on a deleterious effect: benign calls are limited to FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—report pathogenicity. premPS is inconclusive. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates pathogenic folding instability. No prediction tool suggests a benign outcome, and the variant’s presence in gnomAD does not alter the consensus. Thus, the variant is most likely pathogenic, with no conflict with ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.301917 | Structured | 0.140647 | Uncertain | 0.694 | 0.320 | 0.000 | 6-33441300-G-C | 1 | 6.20e-7 | -12.170 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 2.25 | Destabilizing | 1.7 | 5.46 | Destabilizing | 3.86 | Destabilizing | 0.99 | Ambiguous | 0.556 | Likely Pathogenic | -7.98 | Deleterious | 0.999 | Probably Damaging | 0.928 | Probably Damaging | 3.42 | Benign | 0.00 | Affected | 3.43 | 14 | 0.1022 | 0.3879 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||
| c.2056G>C | G686R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G686R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, Foldetta, and FATHMM, whereas the remaining tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized) all predict a pathogenic impact; FoldX is listed as uncertain and is treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.109221 | Structured | 0.177104 | Uncertain | 0.919 | 0.268 | 0.000 | -14.801 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.79 | Ambiguous | 0.3 | 0.15 | Likely Benign | 0.47 | Likely Benign | 1.10 | Destabilizing | 0.503 | Likely Pathogenic | -7.21 | Deleterious | 0.974 | Probably Damaging | 0.449 | Possibly Damaging | 3.46 | Benign | 0.00 | Affected | 0.0951 | 0.3580 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.2134G>C | G712R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G712R is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors—PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, SIFT, ESM1b, PROVEAN, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, Rosetta, and the SGM Consensus—classify it as pathogenic. Two tools, FoldX and premPS, return uncertain results. High‑accuracy methods all support pathogenicity: AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta each predict a deleterious effect. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.278302 | Structured | 0.384858 | Uncertain | 0.947 | 0.365 | 0.000 | -11.776 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 1.75 | Ambiguous | 0.0 | 4.68 | Destabilizing | 3.22 | Destabilizing | 0.82 | Ambiguous | 0.458 | Likely Benign | -6.58 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.35 | Benign | 0.01 | Affected | 0.1229 | 0.4482 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.2248G>A | G750R 2D AIThe SynGAP1 missense variant G750R is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33441713‑G‑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, which aggregates 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 four 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 annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.618285 | Disordered | 0.646832 | Binding | 0.348 | 0.866 | 0.625 | 6-33441713-G-A | 17 | 1.05e-5 | -3.861 | Likely Benign | 0.619 | Likely Pathogenic | Likely Benign | 0.179 | Likely Benign | -2.09 | Neutral | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 3.99 | 5 | 0.0960 | 0.4015 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.2248G>C | G750R 2D AIThe SynGAP1 missense variant G750R is not 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 are mixed: AlphaMissense‑Optimized predicts benign, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2), and Foldetta data are unavailable. Overall, the majority of standard predictors (5 pathogenic vs 4 benign) lean toward pathogenicity, and no ClinVar annotation contradicts this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.618285 | Disordered | 0.646832 | Binding | 0.348 | 0.866 | 0.625 | -3.861 | Likely Benign | 0.619 | Likely Pathogenic | Likely Benign | 0.179 | Likely Benign | -2.09 | Neutral | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 3.99 | 5 | 0.0960 | 0.4015 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.2255C>G | S752W 2D AIThe SynGAP1 missense variant S752W is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, 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 benign, SGM‑Consensus as Likely Pathogenic, and the Foldetta stability analysis is unavailable. Overall, the majority of predictions lean toward pathogenicity, and this conclusion is not contradicted by ClinVar status (which is absent). Thus, the variant is most likely pathogenic based on the collective evidence, despite the single benign prediction from AlphaMissense‑Optimized. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.604312 | Disordered | 0.690594 | Binding | 0.365 | 0.877 | 0.625 | -6.771 | Likely Benign | 0.565 | Likely Pathogenic | Likely Benign | 0.341 | Likely Benign | -3.54 | Deleterious | 1.000 | Probably Damaging | 0.992 | Probably Damaging | 1.49 | Pathogenic | 0.00 | Affected | 0.0837 | 0.6241 | -2 | -3 | -0.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2269G>C | G757R 2D AIThe SynGAP1 missense variant G757R is not reported 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, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports likely benign; Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.830995 | Binding | 0.310 | 0.869 | 0.375 | -2.254 | Likely Benign | 0.534 | Ambiguous | Likely Benign | 0.158 | Likely Benign | -0.04 | Neutral | 0.801 | Possibly Damaging | 0.494 | Possibly Damaging | 2.79 | Benign | 0.05 | Affected | 0.0903 | 0.3481 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2326G>C | G776R 2D AIThe SynGAP1 missense variant G776R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which collectively suggest a likely benign outcome. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the Foldetta protein‑folding stability assessment is unavailable for this variant. Overall, the balance of evidence leans toward a benign interpretation, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.377384 | Structured | 0.886983 | Binding | 0.296 | 0.888 | 0.250 | -6.209 | Likely Benign | 0.886 | Likely Pathogenic | Ambiguous | 0.181 | Likely Benign | -2.28 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 4.22 | Benign | 0.01 | Affected | 0.0932 | 0.5115 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2398G>C | G800R 2D AIThe SynGAP1 missense variant G800R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, 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. Based on the collective predictions, 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 | SH3-binding motif | 0.852992 | Disordered | 0.588350 | Binding | 0.303 | 0.884 | 0.625 | -3.613 | Likely Benign | 0.405 | Ambiguous | Likely Benign | 0.147 | Likely Benign | -0.27 | Neutral | 0.003 | Benign | 0.004 | Benign | 2.84 | Benign | 0.17 | Tolerated | 0.0868 | 0.3835 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.2401G>C | G801R 2D AIThe SynGAP1 missense variant G801R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM‑Consensus also indicates a benign outcome; Foldetta data are not available. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.874069 | Disordered | 0.636323 | Binding | 0.320 | 0.892 | 0.625 | -4.226 | Likely Benign | 0.424 | Ambiguous | Likely Benign | 0.045 | Likely Benign | -0.18 | Neutral | 0.846 | Possibly Damaging | 0.624 | Possibly Damaging | 2.73 | Benign | 0.64 | Tolerated | 0.0850 | 0.3793 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.2404G>C | G802R 2D AIThe SynGAP1 missense variant G802R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Only SIFT predicts a pathogenic effect, and AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized reports benign, and the SGM‑Consensus (majority vote) likewise predicts likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence supports a benign classification for G802R, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.894241 | Disordered | 0.681966 | Binding | 0.294 | 0.898 | 0.625 | -4.756 | Likely Benign | 0.504 | Ambiguous | Likely Benign | 0.072 | Likely Benign | -1.05 | Neutral | 0.259 | Benign | 0.196 | Benign | 2.68 | Benign | 0.01 | Affected | 0.0995 | 0.4514 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.2474C>G | S825W 2D AIThe SynGAP1 missense variant S825W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity largely agree: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict a deleterious effect. Only REVEL classifies the variant as benign, representing the sole benign prediction. High‑accuracy methods further support a pathogenic interpretation: AlphaMissense‑Optimized returns a pathogenic score, and the SGM‑Consensus indicates “Likely Pathogenic.” Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the consensus of the majority of tools, including the high‑accuracy predictors, indicates that S825W is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.675549 | Disordered | 0.618614 | Binding | 0.384 | 0.886 | 0.750 | -8.396 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.316 | Likely Benign | -5.25 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.91 | Pathogenic | 0.00 | Affected | 0.0818 | 0.6083 | -2 | -3 | -0.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2542G>C | G848R 2D AIThe SynGAP1 missense variant G848R 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 for G848R, 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 | 0.724957 | Disordered | 0.563942 | Binding | 0.287 | 0.816 | 0.500 | -4.867 | Likely Benign | 0.761 | Likely Pathogenic | Likely Benign | 0.194 | Likely Benign | -1.05 | Neutral | 0.977 | Probably Damaging | 0.856 | Possibly Damaging | 2.59 | Benign | 0.03 | Affected | 0.0952 | 0.4251 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2548G>A | G850R 2D AIThe SynGAP1 missense variant G850R is listed in ClinVar with an uncertain significance (ClinVar ID 2042462.0) and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only SIFT predicts a pathogenic effect, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized labeling the variant as benign and the SGM‑Consensus indicating a likely benign outcome; Foldetta, a protein‑folding stability method, did not provide a result for this substitution. Overall, the preponderance of evidence points to a benign impact, which aligns with the ClinVar designation of uncertain significance rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.648219 | Disordered | 0.540897 | Binding | 0.312 | 0.820 | 0.500 | Uncertain | 1 | -5.082 | Likely Benign | 0.398 | Ambiguous | Likely Benign | 0.194 | Likely Benign | -0.07 | Neutral | 0.010 | Benign | 0.010 | Benign | 4.30 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1011 | 0.4476 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.2548G>C | G850R 2D AIThe SynGAP1 missense variant G850R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The high‑accuracy consensus (SGM‑Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN is “Likely Benign.” AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.648219 | Disordered | 0.540897 | Binding | 0.312 | 0.820 | 0.500 | -5.082 | Likely Benign | 0.398 | Ambiguous | Likely Benign | 0.194 | Likely Benign | -0.07 | Neutral | 0.010 | Benign | 0.010 | Benign | 4.30 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1011 | 0.4476 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.2554G>C | G852R 2D AIThe SynGAP1 missense variant G852R is not reported 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 G852R, 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 | 0.733139 | Disordered | 0.506063 | Binding | 0.276 | 0.816 | 0.625 | -5.507 | Likely Benign | 0.315 | Likely Benign | Likely Benign | 0.098 | Likely Benign | -1.31 | Neutral | 0.918 | Possibly Damaging | 0.697 | Possibly Damaging | 4.16 | Benign | 0.01 | Affected | 0.0978 | 0.4446 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2557G>C | G853R 2D AIThe SynGAP1 missense variant G853R is listed in ClinVar (ID 3373731) as Benign and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are 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 benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of predictions support a benign impact, aligning with the ClinVar classification; thus the variant is most likely benign and not contradicting the existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.657645 | Disordered | 0.496246 | Uncertain | 0.284 | 0.815 | 0.625 | Likely Benign | 1 | -4.749 | Likely Benign | 0.366 | Ambiguous | Likely Benign | 0.091 | Likely Benign | -1.27 | Neutral | 0.846 | Possibly Damaging | 0.624 | Possibly Damaging | 4.18 | Benign | 0.00 | Affected | 0.0918 | 0.4323 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.2582C>G | S861W 2D AIThe SynGAP1 missense variant S861W has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority of the four high‑accuracy tools) 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 evidence points to a pathogenic impact, and this assessment does not contradict any ClinVar status because none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.557691 | Disordered | 0.540903 | Binding | 0.285 | 0.797 | 0.250 | -8.538 | Likely Pathogenic | 0.585 | Likely Pathogenic | Likely Benign | 0.267 | Likely Benign | -3.13 | Deleterious | 0.999 | Probably Damaging | 0.975 | Probably Damaging | 3.89 | Benign | 0.01 | Affected | 0.0874 | 0.6247 | -2 | -3 | -0.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2599G>A | G867R 2D AIThe SynGAP1 missense variant G867R is not reported 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 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 | 0.517562 | Disordered | 0.657954 | Binding | 0.285 | 0.801 | 0.250 | -3.569 | Likely Benign | 0.755 | Likely Pathogenic | Likely Benign | 0.131 | Likely Benign | -1.76 | Neutral | 0.997 | Probably Damaging | 0.943 | Probably Damaging | 2.70 | Benign | 0.05 | Affected | 3.82 | 4 | 0.0886 | 0.4494 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.2599G>C | G867R 2D AIThe SynGAP1 missense variant G867R is catalogued in gnomAD (6‑33443151‑G‑C) 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 score, whereas pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized reports a benign effect, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign status. No Foldetta stability analysis is available for this residue. Overall, the majority of evidence points to a benign effect for G867R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.657954 | Binding | 0.285 | 0.801 | 0.250 | 6-33443151-G-C | 1 | 6.20e-7 | -3.569 | Likely Benign | 0.755 | Likely Pathogenic | Likely Benign | 0.131 | Likely Benign | -1.76 | Neutral | 0.997 | Probably Damaging | 0.943 | Probably Damaging | 2.70 | Benign | 0.05 | Affected | 3.82 | 4 | 0.0886 | 0.4494 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||
| c.2627C>G | S876W 2D AIThe SynGAP1 missense variant S876W is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID: 6‑33443179‑C‑G). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). The high‑accuracy AlphaMissense‑Optimized result is uncertain, and the SGM‑Consensus indicates a likely pathogenic classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the preponderance of pathogenic predictions and the SGM‑Consensus, the variant is most likely pathogenic; this assessment does not contradict ClinVar status, as no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.549308 | Disordered | 0.631130 | Binding | 0.280 | 0.872 | 0.250 | 6-33443179-C-G | 1 | 6.20e-7 | -9.305 | Likely Pathogenic | 0.829 | Likely Pathogenic | Ambiguous | 0.291 | Likely Benign | -3.72 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.54 | Benign | 0.01 | Affected | 3.77 | 5 | 0.0964 | 0.6700 | -3 | -2 | -0.1 | 99.14 | ||||||||||||||||||||||||||||||||||
| c.2644G>A | G882R 2D AIThe SynGAP1 missense variant G882R is not reported 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive because it yields a 2‑to‑2 split. Foldetta results are unavailable. Overall, the majority of predictions lean toward a benign impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.690604 | Disordered | 0.632888 | Binding | 0.306 | 0.878 | 0.250 | -4.715 | Likely Benign | 0.758 | Likely Pathogenic | Likely Benign | 0.051 | Likely Benign | -1.48 | Neutral | 0.001 | Benign | 0.003 | Benign | 2.04 | Pathogenic | 0.01 | Affected | 0.0905 | 0.4126 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.2644G>C | G882R 2D AIThe SynGAP1 missense variant G882R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta results are unavailable. Overall, the majority of predictions (six benign vs three pathogenic) support a benign classification. This consensus does not contradict any ClinVar status, as the variant is not yet catalogued there. 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. | 0.690604 | Disordered | 0.632888 | Binding | 0.306 | 0.878 | 0.250 | -4.715 | Likely Benign | 0.758 | Likely Pathogenic | Likely Benign | 0.051 | Likely Benign | -1.48 | Neutral | 0.001 | Benign | 0.003 | Benign | 2.04 | Pathogenic | 0.01 | Affected | 0.0905 | 0.4126 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.2665G>A | G889R 2D AIThe SynGAP1 missense variant G889R is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (ID 6‑33443217‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized; pathogenic predictions come from SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign effect, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic) and Foldetta results are unavailable. Overall, the majority of evidence (six benign vs three pathogenic) supports a benign impact. This conclusion does not contradict ClinVar, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.690604 | Disordered | 0.552581 | Binding | 0.331 | 0.928 | 0.625 | 6-33443217-G-A | 1 | 6.20e-7 | -3.357 | Likely Benign | 0.685 | Likely Pathogenic | Likely Benign | 0.070 | Likely Benign | -1.96 | Neutral | 0.027 | Benign | 0.009 | Benign | 2.38 | Pathogenic | 0.02 | Affected | 4.32 | 4 | 0.0925 | 0.4165 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.2665G>C | G889R 2D AIThe SynGAP1 missense variant G889R is not reported in ClinVar (ClinVar status: not present) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs. 2 benign), and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.690604 | Disordered | 0.552581 | Binding | 0.331 | 0.928 | 0.625 | -3.357 | Likely Benign | 0.685 | Likely Pathogenic | Likely Benign | 0.072 | Likely Benign | -1.96 | Neutral | 0.027 | Benign | 0.009 | Benign | 2.38 | Pathogenic | 0.02 | Affected | 4.32 | 4 | 0.0925 | 0.4165 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.2680G>A | G894R 2D AISynGAP1 missense variant G894R has no ClinVar record and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and Foldetta results are unavailable. Considering the consensus from high‑accuracy tools and the balance of individual predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for G894R. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.425700 | Uncertain | 0.310 | 0.925 | 0.750 | -5.222 | Likely Benign | 0.922 | Likely Pathogenic | Ambiguous | 0.216 | Likely Benign | -1.68 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.86 | Benign | 0.01 | Affected | 0.0982 | 0.4332 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2680G>C | G894R 2D AISynGAP1 missense variant G894R has no ClinVar record and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and Foldetta results are unavailable. Considering the consensus from high‑accuracy tools and the balance of individual predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for G894R. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.425700 | Uncertain | 0.310 | 0.925 | 0.750 | -5.222 | Likely Benign | 0.922 | Likely Pathogenic | Ambiguous | 0.216 | Likely Benign | -1.68 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.86 | Benign | 0.01 | Affected | 0.0982 | 0.4332 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2686G>C | G896R 2D AIThe SynGAP1 missense variant G896R is not 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, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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, and PROVEAN) is inconclusive due to a 2‑to‑2 split. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Consequently, the evidence is evenly split between benign and pathogenic predictions, with no decisive support from the high‑accuracy or folding‑stability analyses. The variant is therefore most likely of uncertain significance; it 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. | 0.675549 | Disordered | 0.412816 | Uncertain | 0.314 | 0.923 | 0.625 | -4.511 | Likely Benign | 0.897 | Likely Pathogenic | Ambiguous | 0.218 | Likely Benign | -2.45 | Neutral | 0.999 | Probably Damaging | 0.967 | Probably Damaging | 2.44 | Pathogenic | 0.14 | Tolerated | 0.0931 | 0.4228 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.2707G>C | G903R 2D AIThe SynGAP1 missense variant G903R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Tools that predict a pathogenic effect are SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; 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 standard predictors lean toward a benign impact, and no ClinVar annotation contradicts this assessment. Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.680603 | Disordered | 0.549818 | Binding | 0.291 | 0.917 | 0.375 | -3.503 | Likely Benign | 0.865 | Likely Pathogenic | Ambiguous | 0.119 | Likely Benign | -2.02 | Neutral | 0.241 | Benign | 0.244 | Benign | 2.33 | Pathogenic | 0.02 | Affected | 0.0872 | 0.4064 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.2728G>C | G910R 2D AIThe SynGAP1 missense variant G910R is not reported 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, 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. 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 | 0.762850 | Disordered | 0.707319 | Binding | 0.264 | 0.917 | 0.250 | -4.566 | Likely Benign | 0.945 | Likely Pathogenic | Ambiguous | 0.235 | Likely Benign | -1.78 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.86 | Benign | 0.02 | Affected | 0.0875 | 0.4198 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2743G>C | G915R 2D AIThe SynGAP1 missense variant G915R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for G915R, 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 | 0.657645 | Disordered | 0.808641 | Binding | 0.302 | 0.880 | 0.375 | -4.528 | Likely Benign | 0.656 | Likely Pathogenic | Likely Benign | 0.104 | Likely Benign | -2.31 | Neutral | 0.999 | Probably Damaging | 0.969 | Probably Damaging | 2.69 | Benign | 0.00 | Affected | 0.0805 | 0.4204 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.274G>A | G92R 2D AIThe SynGAP1 missense variant G92R is listed in gnomAD (6-33425882‑G‑A) but has no ClinVar entry. Functional 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, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM‑Consensus as “Likely Benign,” and Foldetta results are unavailable. Taken together, the preponderance of evidence from multiple independent predictors and the consensus score points to a benign classification. 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 | 0.575842 | Disordered | 0.537848 | Binding | 0.337 | 0.874 | 0.625 | 6-33425882-G-A | 1 | 6.20e-7 | -2.909 | Likely Benign | 0.876 | Likely Pathogenic | Ambiguous | 0.139 | Likely Benign | -2.38 | Neutral | 0.999 | Probably Damaging | 0.979 | Probably Damaging | 4.01 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1041 | 0.4605 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||
| c.274G>C | G92R 2D AIThe SynGAP1 missense variant G92R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the majority of high‑confidence tools and the consensus prediction lean toward a benign interpretation, with no conflict with ClinVar status. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.575842 | Disordered | 0.537848 | Binding | 0.337 | 0.874 | 0.625 | -2.909 | Likely Benign | 0.876 | Likely Pathogenic | Ambiguous | 0.139 | Likely Benign | -2.38 | Neutral | 0.999 | Probably Damaging | 0.979 | Probably Damaging | 4.01 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1041 | 0.4605 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.2812G>A | G938R 2D AIThe SynGAP1 missense variant G938R is listed in ClinVar (ID 1019898.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence (seven benign versus three pathogenic predictions) supports a benign classification. This consensus does not contradict the ClinVar “Uncertain” designation, which remains unresolved. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.949795 | Binding | 0.318 | 0.883 | 0.625 | Uncertain | 1 | -5.271 | Likely Benign | 0.732 | Likely Pathogenic | Likely Benign | 0.141 | Likely Benign | -1.11 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.74 | Benign | 0.36 | Tolerated | 3.77 | 5 | 0.0924 | 0.3614 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.2812G>C | G938R 2D AIThe SynGAP1 missense variant G938R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Benign” call. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.949795 | Binding | 0.318 | 0.883 | 0.625 | -5.271 | Likely Benign | 0.732 | Likely Pathogenic | Likely Benign | 0.141 | Likely Benign | -1.11 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.74 | Benign | 0.36 | Tolerated | 3.77 | 5 | 0.0924 | 0.3614 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.2818G>C | G940R 2D AIThe SynGAP1 missense variant G940R is listed in ClinVar (ID 1923639.0) as Benign and is present in gnomAD (6‑33443370‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and Foldetta (FoldX‑MD/Rosetta stability assessment) has no available result for this variant. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta data is unavailable. Overall, the majority of evidence points to a benign impact, which is consistent with the ClinVar classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.920635 | Binding | 0.383 | 0.902 | 0.625 | Benign | 1 | 6-33443370-G-C | 5 | 3.10e-6 | -6.169 | Likely Benign | 0.480 | Ambiguous | Likely Benign | 0.060 | Likely Benign | 0.02 | Neutral | 0.922 | Possibly Damaging | 0.543 | Possibly Damaging | 2.73 | Benign | 0.15 | Tolerated | 3.77 | 5 | 0.0922 | 0.4024 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||
| c.2827G>C | G943R 2D AIThe SynGAP1 missense variant G943R is reported in gnomAD (variant ID 6-33443379‑G‑C) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity; only ESM1b is uncertain. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions strongly supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.973328 | Disordered | 0.860437 | Binding | 0.372 | 0.910 | 0.750 | 6-33443379-G-C | 1 | 6.20e-7 | -7.159 | In-Between | 0.335 | Likely Benign | Likely Benign | 0.308 | Likely Benign | 1.00 | Neutral | 0.411 | Benign | 0.062 | Benign | 2.86 | Benign | 0.94 | Tolerated | 4.32 | 4 | 0.0976 | 0.4933 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||
| c.2830G>C | G944R 2D AIThe SynGAP1 missense variant G944R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for G944R, 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 | 0.852408 | Binding | 0.360 | 0.923 | 0.750 | -6.577 | Likely Benign | 0.359 | Ambiguous | Likely Benign | 0.459 | Likely Benign | -1.82 | Neutral | 0.639 | Possibly Damaging | 0.299 | Benign | 3.73 | Benign | 0.00 | Affected | 0.1030 | 0.4733 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2836G>A | G946R 2D AIThe SynGAP1 missense variant G946R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while ESM1b is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus itself is Likely Benign. Foldetta results are unavailable. Overall, the majority of computational evidence indicates that G946R 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 | 0.985417 | Disordered | 0.845792 | Binding | 0.357 | 0.920 | 0.750 | -7.127 | In-Between | 0.308 | Likely Benign | Likely Benign | 0.296 | Likely Benign | -0.69 | Neutral | 0.818 | Possibly Damaging | 0.435 | Benign | 4.65 | Benign | 0.00 | Affected | 0.1157 | 0.5133 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2836G>C | G946R 2D AIThe SynGAP1 missense variant G946R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while ESM1b is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus itself is Likely Benign. Foldetta results are unavailable. Overall, the majority of computational evidence indicates that G946R 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 | 0.985417 | Disordered | 0.845792 | Binding | 0.357 | 0.920 | 0.750 | -7.127 | In-Between | 0.308 | Likely Benign | Likely Benign | 0.296 | Likely Benign | -0.69 | Neutral | 0.818 | Possibly Damaging | 0.435 | Benign | 4.65 | Benign | 0.00 | Affected | 0.1157 | 0.5133 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2839G>A | G947R 2D AIThe SynGAP1 missense variant G947R is listed in gnomAD (6-33443391-G-A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Optimized) and pathogenic (SIFT). Two tools remain uncertain (ESM1b, AlphaMissense‑Default). High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign effect, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—does not reach a definitive conclusion (two benign, two uncertain). Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no reported result for this variant. Overall, the preponderance of evidence points to a benign impact, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988695 | Disordered | 0.850554 | Binding | 0.358 | 0.919 | 0.750 | 6-33443391-G-A | 6 | 3.72e-6 | -7.481 | In-Between | 0.343 | Ambiguous | Likely Benign | 0.273 | Likely Benign | -0.60 | Neutral | 0.411 | Benign | 0.140 | Benign | 4.94 | Benign | 0.04 | Affected | 4.32 | 4 | 0.1034 | 0.4733 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.2839G>C | G947R 2D AIThe SynGAP1 missense variant G947R is not 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. 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, and Foldetta stability analysis is unavailable. Overall, the balance of evidence favors a benign classification, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988695 | Disordered | 0.850554 | Binding | 0.358 | 0.919 | 0.750 | -7.481 | In-Between | 0.343 | Ambiguous | Likely Benign | 0.273 | Likely Benign | -0.60 | Neutral | 0.411 | Benign | 0.140 | Benign | 4.94 | Benign | 0.04 | Affected | 4.32 | 4 | 0.1034 | 0.4733 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.2842G>C | G948R 2D AIThe SynGAP1 missense variant G948R 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 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 | 0.988505 | Disordered | 0.862121 | Binding | 0.365 | 0.919 | 0.750 | -6.782 | Likely Benign | 0.315 | Likely Benign | Likely Benign | 0.266 | Likely Benign | -0.60 | Neutral | 0.818 | Possibly Damaging | 0.435 | Benign | 4.58 | Benign | 0.04 | Affected | 0.1069 | 0.4933 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2845G>C | G949R 2D AIThe SynGAP1 missense variant G949R 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, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic calls come from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; ESM1b is uncertain. High‑accuracy assessment further supports a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign outcome, and Foldetta data are unavailable. Overall, the preponderance of evidence indicates the variant is most likely benign, and this conclusion does not conflict with any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988861 | Disordered | 0.874971 | Binding | 0.365 | 0.923 | 0.750 | -7.650 | In-Between | 0.301 | Likely Benign | Likely Benign | 0.317 | Likely Benign | -0.14 | Neutral | 0.997 | Probably Damaging | 0.934 | Probably Damaging | 2.21 | Pathogenic | 0.01 | Affected | 0.1095 | 0.4569 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.2848G>C | G950R 2D AIThe SynGAP1 missense variant G950R is not reported 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 points to a benign impact for G950R, 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 | 0.987317 | Disordered | 0.888649 | Binding | 0.368 | 0.923 | 0.750 | -6.929 | Likely Benign | 0.318 | Likely Benign | Likely Benign | 0.388 | Likely Benign | -1.10 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.26 | Pathogenic | 0.01 | Affected | 0.1009 | 0.4733 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2854G>C | G952R 2D AIThe SynGAP1 missense variant G952R is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that G952R is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.910621 | Binding | 0.341 | 0.926 | 0.750 | -5.974 | Likely Benign | 0.295 | Likely Benign | Likely Benign | 0.139 | Likely Benign | -0.93 | Neutral | 0.077 | Benign | 0.011 | Benign | 3.20 | Benign | 0.02 | Affected | 0.1145 | 0.4933 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.286G>C | G96R 2D AIThe SynGAP1 missense variant G96R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for G96R, 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 | 0.657645 | Disordered | 0.599491 | Binding | 0.335 | 0.871 | 0.625 | -3.872 | Likely Benign | 0.349 | Ambiguous | Likely Benign | 0.059 | Likely Benign | -0.91 | Neutral | 0.687 | Possibly Damaging | 0.062 | Benign | 4.19 | Benign | 0.00 | Affected | 0.1300 | 0.5031 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2902G>C | G968R 2D AIThe SynGAP1 missense variant G968R is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the evidence strongly supports a benign classification, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978316 | Disordered | 0.961360 | Binding | 0.327 | 0.896 | 0.750 | -4.492 | Likely Benign | 0.332 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -0.63 | Neutral | 0.005 | Benign | 0.012 | Benign | 4.19 | Benign | 0.08 | Tolerated | 0.0972 | 0.5017 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2905G>A | G969R 2D AIThe SynGAP1 missense variant G969R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.950334 | Disordered | 0.956572 | Binding | 0.405 | 0.898 | 0.750 | -4.783 | Likely Benign | 0.316 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -0.70 | Neutral | 0.611 | Possibly Damaging | 0.305 | Benign | 4.20 | Benign | 0.01 | Affected | 0.1039 | 0.5473 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2905G>C | G969R 2D AIThe SynGAP1 missense variant G969R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.950334 | Disordered | 0.956572 | Binding | 0.405 | 0.898 | 0.750 | -4.783 | Likely Benign | 0.316 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -0.70 | Neutral | 0.611 | Possibly Damaging | 0.305 | Benign | 4.20 | Benign | 0.01 | Affected | 0.1039 | 0.5473 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2917G>A | G973R 2D AIThe SynGAP1 missense variant G973R is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.959498 | Binding | 0.390 | 0.897 | 0.625 | -3.950 | Likely Benign | 0.329 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -0.37 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.16 | Benign | 0.01 | Affected | 0.0930 | 0.4532 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2917G>C | G973R 2D AIThe SynGAP1 missense variant G973R is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic call comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta results are not available for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.959498 | Binding | 0.390 | 0.897 | 0.625 | -3.950 | Likely Benign | 0.329 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -0.37 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.16 | Benign | 0.01 | Affected | 0.0930 | 0.4532 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2941G>C | G981R 2D AIThe SynGAP1 missense variant G981R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, 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 toward a benign impact, and this conclusion does not contradict any ClinVar annotation because none exists. Thus, the variant is most likely benign based on current predictive tools. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.798249 | Disordered | 0.970320 | Binding | 0.275 | 0.897 | 0.625 | -1.264 | Likely Benign | 0.953 | Likely Pathogenic | Ambiguous | 0.207 | Likely Benign | -2.11 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 3.74 | Benign | 0.00 | Affected | 0.0990 | 0.4776 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2971G>A | G991R 2D AIThe SynGAP1 missense variant G991R is listed in ClinVar (ID 1029090.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443523‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.745909 | Disordered | 0.911393 | Binding | 0.286 | 0.920 | 0.750 | Conflicting | 3 | 6-33443523-G-A | 8 | 4.96e-6 | -3.934 | Likely Benign | 0.411 | Ambiguous | Likely Benign | 0.102 | Likely Benign | -1.20 | Neutral | 0.984 | Probably Damaging | 0.772 | Possibly Damaging | 4.11 | Benign | 0.01 | Affected | 4.32 | 2 | 0.0956 | 0.4181 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||
| c.2971G>C | G991R 2D AIThe SynGAP1 missense variant G991R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the majority of evidence points to a benign effect for G991R, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.745909 | Disordered | 0.911393 | Binding | 0.286 | 0.920 | 0.750 | -3.934 | Likely Benign | 0.411 | Ambiguous | Likely Benign | 0.106 | Likely Benign | -1.20 | Neutral | 0.984 | Probably Damaging | 0.772 | Possibly Damaging | 4.11 | Benign | 0.01 | Affected | 4.32 | 2 | 0.0956 | 0.4181 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.3031G>A | G1011R 2D AIThe SynGAP1 missense variant G1011R is reported in gnomAD (variant ID 6‑33443583‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign, reflecting the majority of benign calls. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign effect for G1011R, and this conclusion does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.898380 | Binding | 0.332 | 0.869 | 0.625 | 6-33443583-G-A | -4.650 | Likely Benign | 0.609 | Likely Pathogenic | Likely Benign | 0.118 | Likely Benign | -0.79 | Neutral | 0.642 | Possibly Damaging | 0.494 | Possibly Damaging | 2.72 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1041 | 0.4415 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||
| c.3031G>C | G1011R 2D AIThe SynGAP1 missense variant G1011R is not reported in ClinVar and is absent from gnomAD, so no population frequency or clinical assertion data are available. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.898380 | Binding | 0.332 | 0.869 | 0.625 | -4.650 | Likely Benign | 0.609 | Likely Pathogenic | Likely Benign | 0.118 | Likely Benign | -0.79 | Neutral | 0.642 | Possibly Damaging | 0.494 | Possibly Damaging | 2.72 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1041 | 0.4415 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.3040G>C | G1014R 2D AIThe SynGAP1 missense variant G1014R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, PolyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM‑Consensus also indicates a likely benign outcome; however, the Foldetta protein‑folding stability assessment is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.914808 | Binding | 0.293 | 0.835 | 0.625 | -3.234 | Likely Benign | 0.562 | Ambiguous | Likely Benign | 0.067 | Likely Benign | -1.47 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 2.80 | Benign | 0.12 | Tolerated | 0.1044 | 0.4714 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.307G>C | G103R 2D AIThe SynGAP1 missense variant G103R is not reported 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). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.687376 | Binding | 0.381 | 0.877 | 0.625 | -3.384 | Likely Benign | 0.710 | Likely Pathogenic | Likely Benign | 0.100 | Likely Benign | 0.00 | Neutral | 0.949 | Possibly Damaging | 0.708 | Possibly Damaging | 4.27 | Benign | 0.00 | Affected | 0.1198 | 0.4362 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| 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 | -3.00 | Deleterious | 0.463 | Possibly Damaging | 0.194 | Benign | -0.74 | Pathogenic | 0.00 | Affected | 0.0924 | 0.4415 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3142G>A | G1048R 2D AIThe SynGAP1 missense variant G1048R is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools show a split: pathogenic calls come from REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar, whereas benign calls are made by PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign majority, and AlphaMissense‑Optimized itself predicts benign. The SGM‑Consensus, which aggregates these four predictors, reports a likely benign classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the absence of a ClinVar assertion; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | -4.305 | Likely Benign | 0.435 | Ambiguous | Likely Benign | 0.503 | Likely Pathogenic | -0.54 | Neutral | 0.919 | Possibly Damaging | 0.728 | Possibly Damaging | 2.54 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.0956 | 0.4332 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.3142G>C | G1048R 2D AIThe SynGAP1 missense variant G1048R is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM‑Consensus also indicates a likely benign outcome; the Foldetta protein‑folding stability assessment is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | Uncertain | 1 | -4.305 | Likely Benign | 0.435 | Ambiguous | Likely Benign | 0.503 | Likely Pathogenic | -0.54 | Neutral | 0.919 | Possibly Damaging | 0.728 | Possibly Damaging | 2.54 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.0956 | 0.4332 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.3148G>A | G1050R 2D AIThe SynGAP1 missense variant G1050R is catalogued in gnomAD (ID 6‑33443700‑G‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Only FATHMM predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign verdict, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.906802 | Binding | 0.370 | 0.928 | 0.875 | 6-33443700-G-A | 3 | 1.86e-6 | -6.637 | Likely Benign | 0.349 | Ambiguous | Likely Benign | 0.045 | Likely Benign | -0.68 | Neutral | 0.009 | Benign | 0.008 | Benign | 2.48 | Pathogenic | 0.06 | Tolerated | 3.77 | 5 | 0.0939 | 0.4532 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.3148G>C | G1050R 2D AIThe SynGAP1 missense variant G1050R is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. Only FATHMM predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority vote. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact; this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.906802 | Binding | 0.370 | 0.928 | 0.875 | -6.637 | Likely Benign | 0.349 | Ambiguous | Likely Benign | 0.045 | Likely Benign | -0.68 | Neutral | 0.009 | Benign | 0.008 | Benign | 2.48 | Pathogenic | 0.06 | Tolerated | 3.77 | 5 | 0.0939 | 0.4532 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.314C>G | S105W 2D AIThe SynGAP1 missense variant S105W is catalogued in gnomAD (ID 6‑33432179‑C‑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, reports a “Likely Benign” status, reflecting the majority of benign calls. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also leans benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence indicates that the variant is most likely benign, 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 | 0.788093 | Disordered | 0.669201 | Binding | 0.364 | 0.870 | 0.625 | 6-33432179-C-G | 2 | 1.24e-6 | -5.600 | Likely Benign | 0.606 | Likely Pathogenic | Likely Benign | 0.177 | Likely Benign | -2.28 | Neutral | 0.998 | Probably Damaging | 0.844 | Possibly Damaging | 3.97 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0705 | 0.4984 | -3 | -2 | -0.1 | 99.14 | ||||||||||||||||||||||||||||||||||
| c.3151G>C | G1051R 2D AIThe SynGAP1 missense variant G1051R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. Two tools (ESM1b and AlphaMissense‑Default) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it contains one pathogenic, one benign, and two uncertain calls, and Foldetta results are unavailable. Overall, the balance of evidence favors a benign classification. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.900141 | Binding | 0.358 | 0.936 | 0.875 | -7.907 | In-Between | 0.346 | Ambiguous | Likely Benign | 0.438 | Likely Benign | 0.20 | Neutral | 0.761 | Possibly Damaging | 0.305 | Benign | -0.74 | Pathogenic | 0.20 | Tolerated | 0.0956 | 0.4342 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.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 | -0.41 | Neutral | 0.990 | Probably Damaging | 0.798 | Possibly Damaging | 3.90 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.0976 | 0.4142 | -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 | -0.41 | Neutral | 0.990 | Probably Damaging | 0.798 | Possibly Damaging | 3.90 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.0976 | 0.4142 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| 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 | 0.29 | Neutral | 0.988 | Probably Damaging | 0.589 | Possibly Damaging | 4.05 | Benign | 0.42 | Tolerated | 0.1164 | 0.4342 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| 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 | -0.09 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 3.31 | Benign | 0.08 | Tolerated | 0.1013 | 0.4733 | -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 | -0.09 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 3.31 | Benign | 0.08 | Tolerated | 0.1013 | 0.4733 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| 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 | 0.12 | Neutral | 0.011 | Benign | 0.010 | Benign | 1.83 | Pathogenic | 0.13 | Tolerated | 0.1127 | 0.4533 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| 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 | 0.34 | Neutral | 0.174 | Benign | 0.140 | Benign | 5.29 | Benign | 0.00 | Affected | 0.1145 | 0.4342 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3175G>A | G1059R 2D AIThe SynGAP1 missense variant G1059R is listed in ClinVar with an uncertain significance and is present in the gnomAD database (ID 6‑33443727‑G‑A). Consensus among most in silico predictors leans toward a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized all report benign. In contrast, SIFT and ESM1b predict pathogenicity, while AlphaMissense‑Default remains uncertain. High‑accuracy assessment consolidates this view: AlphaMissense‑Optimized is benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a benign classification. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its influence is unavailable. Overall, the preponderance of computational evidence supports a benign interpretation, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | Conflicting | 2 | 6-33443727-G-A | 68 | 4.23e-5 | -8.452 | Likely Pathogenic | 0.376 | Ambiguous | Likely Benign | 0.333 | Likely Benign | -0.55 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.53 | Benign | 0.00 | Affected | 4.32 | 2 | 0.1052 | 0.4342 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||
| c.3175G>C | G1059R 2D AIThe SynGAP1 missense variant G1059R is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors shows a predominance of benign calls: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized all predict a benign effect, whereas SIFT and ESM1b predict pathogenicity; AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized is benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also returns a benign prediction. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence points to a benign impact for G1059R, and this conclusion is consistent with the absence of any ClinVar annotation or gnomAD observation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | -8.452 | Likely Pathogenic | 0.376 | Ambiguous | Likely Benign | 0.333 | Likely Benign | -0.55 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.53 | Benign | 0.00 | Affected | 4.32 | 2 | 0.1052 | 0.4342 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3178G>C | G1060R 2D AIThe SynGAP1 missense variant G1060R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for G1060R, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.979242 | Disordered | 0.913048 | Binding | 0.407 | 0.928 | 0.875 | -8.225 | Likely Pathogenic | 0.323 | Likely Benign | Likely Benign | 0.362 | Likely Benign | -0.29 | Neutral | 0.971 | Probably Damaging | 0.580 | Possibly Damaging | 2.63 | Benign | 0.17 | Tolerated | 0.1038 | 0.4342 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3181G>C | G1061R 2D AIThe SynGAP1 missense variant G1061R is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it contains two benign and two uncertain calls, and Foldetta results are unavailable. Overall, the balance of evidence favors a benign classification. This conclusion does not contradict ClinVar status, as the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.978672 | Disordered | 0.926729 | Binding | 0.394 | 0.923 | 0.875 | -7.721 | In-Between | 0.343 | Ambiguous | Likely Benign | 0.315 | Likely Benign | -0.17 | Neutral | 0.411 | Benign | 0.132 | Benign | 3.99 | Benign | 0.00 | Affected | 0.1037 | 0.4332 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3184G>A | G1062R 2D AIThe SynGAP1 missense variant G1062R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443736‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, polyPhen‑2 HumVar, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.976962 | Disordered | 0.936972 | Binding | 0.368 | 0.917 | 0.875 | Conflicting | 2 | 6-33443736-G-A | 7 | 4.35e-6 | -6.933 | Likely Benign | 0.353 | Ambiguous | Likely Benign | 0.403 | Likely Benign | -0.34 | Neutral | 0.797 | Possibly Damaging | 0.139 | Benign | 4.10 | Benign | 0.01 | Affected | 4.32 | 2 | 0.1013 | 0.4342 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||
| c.3184G>C | G1062R 2D AIThe SynGAP1 missense variant G1062R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicating a likely benign outcome, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.976962 | Disordered | 0.936972 | Binding | 0.368 | 0.917 | 0.875 | -6.933 | Likely Benign | 0.353 | Ambiguous | Likely Benign | 0.413 | Likely Benign | -0.34 | Neutral | 0.797 | Possibly Damaging | 0.139 | Benign | 4.10 | Benign | 0.01 | Affected | 4.32 | 2 | 0.1013 | 0.4342 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.3187G>C | G1063R 2D AIThe SynGAP1 missense variant G1063R is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the collective evidence strongly supports a benign classification, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.975134 | Disordered | 0.945784 | Binding | 0.394 | 0.913 | 0.875 | -5.711 | Likely Benign | 0.391 | Ambiguous | Likely Benign | 0.078 | Likely Benign | 0.55 | Neutral | 0.411 | Benign | 0.114 | Benign | 4.28 | Benign | 0.09 | Tolerated | 0.1037 | 0.5133 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.31G>A | G11R 2D AIThe SynGAP1 missense variant G11R is catalogued in gnomAD (ID 6‑33420295‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions come from polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign 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 | 0.444081 | Structured | 0.501027 | Binding | 0.348 | 0.915 | 0.375 | 6-33420295-G-A | -3.418 | Likely Benign | 0.428 | Ambiguous | Likely Benign | 0.102 | Likely Benign | -0.47 | Neutral | 0.498 | Possibly Damaging | 0.026 | Benign | 3.92 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1022 | 0.4596 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||
| c.31G>C | G11R 2D AIThe SynGAP1 missense variant G11R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote 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 collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.444081 | Structured | 0.501027 | Binding | 0.348 | 0.915 | 0.375 | -3.418 | Likely Benign | 0.428 | Ambiguous | Likely Benign | 0.109 | Likely Benign | -0.47 | Neutral | 0.498 | Possibly Damaging | 0.026 | Benign | 3.92 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1022 | 0.4596 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| 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 | -2.61 | Deleterious | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 4.06 | Benign | 0.00 | Affected | 0.0980 | 0.4482 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| 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 | -3.13 | Deleterious | 0.896 | Possibly Damaging | 0.325 | Benign | 2.42 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.0934 | 0.4415 | -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 | -3.13 | Deleterious | 0.896 | Possibly Damaging | 0.325 | Benign | 2.42 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.0934 | 0.4415 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| 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 | -2.05 | Neutral | 0.992 | Probably Damaging | 0.906 | Possibly Damaging | 1.92 | Pathogenic | 0.00 | Affected | 0.0986 | 0.5217 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3337G>C | G1113R 2D AIThe SynGAP1 missense variant G1113R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign based on current predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | -4.765 | Likely Benign | 0.618 | Likely Pathogenic | Likely Benign | 0.063 | Likely Benign | -1.54 | Neutral | 0.986 | Probably Damaging | 0.848 | Possibly Damaging | 2.65 | Benign | 0.64 | Tolerated | 0.0939 | 0.4426 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3346G>A | G1116R 2D AIThe SynGAP1 missense variant G1116R is not reported 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 results are unavailable, so they do not influence the assessment. Overall, the majority of computational evidence points to a benign effect for G1116R, 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 | 0.873279 | Binding | 0.320 | 0.909 | 0.750 | -6.379 | Likely Benign | 0.495 | Ambiguous | Likely Benign | 0.368 | Likely Benign | -0.60 | Neutral | 0.922 | Possibly Damaging | 0.657 | Possibly Damaging | 4.18 | Benign | 0.04 | Affected | 0.0925 | 0.4342 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3346G>C | G1116R 2D AIThe SynGAP1 missense variant G1116R is not reported 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 results are unavailable, so they do not influence the assessment. Overall, the majority of computational evidence points to a benign effect for G1116R, 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 | 0.873279 | Binding | 0.320 | 0.909 | 0.750 | -6.379 | Likely Benign | 0.495 | Ambiguous | Likely Benign | 0.368 | Likely Benign | -0.60 | Neutral | 0.922 | Possibly Damaging | 0.657 | Possibly Damaging | 4.18 | Benign | 0.04 | Affected | 0.0925 | 0.4342 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3349G>C | G1117R 2D AIThe SynGAP1 missense variant G1117R is not reported in ClinVar and is absent from gnomAD. Consensus among most in silico predictors is benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized all classify the change as tolerated or benign. No tool predicts pathogenicity. Two predictors (ESM1b and AlphaMissense‑Default) return uncertain results, but these do not alter the overall benign consensus. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta data are unavailable. Consequently, the variant is most likely benign, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.882776 | Disordered | 0.853192 | Binding | 0.323 | 0.914 | 0.750 | -7.132 | In-Between | 0.519 | Ambiguous | Likely Benign | 0.253 | Likely Benign | -0.68 | Neutral | 0.006 | Benign | 0.008 | Benign | 4.62 | Benign | 0.08 | Tolerated | 0.0937 | 0.4542 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.334G>A | G112R 2D AIThe SynGAP1 missense variant G112R is not 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, SIFT, 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 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of standard predictors lean toward a benign impact, and this is not contradicted by any ClinVar annotation. 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. | 0.728858 | Disordered | 0.640153 | Binding | 0.332 | 0.867 | 0.750 | -3.680 | Likely Benign | 0.866 | Likely Pathogenic | Ambiguous | 0.141 | Likely Benign | -3.31 | Deleterious | 0.002 | Benign | 0.004 | Benign | 3.94 | Benign | 0.00 | Affected | 0.0983 | 0.3978 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.334G>C | G112R 2D AIThe SynGAP1 missense variant G112R is not 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, SIFT, 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 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of standard predictors lean toward a benign impact, and this is not contradicted by any ClinVar annotation. 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. | 0.728858 | Disordered | 0.640153 | Binding | 0.332 | 0.867 | 0.750 | -3.680 | Likely Benign | 0.866 | Likely Pathogenic | Ambiguous | 0.142 | Likely Benign | -3.31 | Deleterious | 0.002 | Benign | 0.004 | Benign | 3.94 | Benign | 0.00 | Affected | 0.0983 | 0.3978 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3355G>A | G1119R 2D AIThe SynGAP1 missense variant G1119R is listed in ClinVar as benign and is present in gnomAD (ID 6‑33443907‑G‑A). 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 impact. 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 evidence points to a benign effect, aligning with the ClinVar classification; there is no contradiction between the predictions and the reported ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.827927 | Disordered | 0.818538 | Binding | 0.339 | 0.928 | 0.875 | Benign | 1 | 6-33443907-G-A | 64 | 4.23e-5 | -8.489 | Likely Pathogenic | 0.473 | Ambiguous | Likely Benign | 0.303 | Likely Benign | 0.10 | Neutral | 0.969 | Probably Damaging | 0.462 | Possibly Damaging | 4.03 | Benign | 0.10 | Tolerated | 4.32 | 2 | 0.1112 | 0.4733 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||
| c.3355G>C | G1119R 2D AIThe SynGAP1 missense variant G1119R 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 assessment shows AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.827927 | Disordered | 0.818538 | Binding | 0.339 | 0.928 | 0.875 | -8.489 | Likely Pathogenic | 0.473 | Ambiguous | Likely Benign | 0.289 | Likely Benign | 0.10 | Neutral | 0.969 | Probably Damaging | 0.462 | Possibly Damaging | 4.03 | Benign | 0.10 | Tolerated | 4.32 | 2 | 0.1112 | 0.4733 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3358G>C | G1120R 2D AIThe SynGAP1 missense variant G1120R is not 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign impact for G1120R, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.871313 | Disordered | 0.804931 | Binding | 0.335 | 0.925 | 0.875 | -8.784 | Likely Pathogenic | 0.565 | Likely Pathogenic | Likely Benign | 0.333 | Likely Benign | -0.77 | Neutral | 0.666 | Possibly Damaging | 0.221 | Benign | 3.60 | Benign | 0.05 | Affected | 0.0994 | 0.4142 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3364G>C | G1122R 2D AIThe SynGAP1 missense variant G1122R is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, SIFT, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence (six benign versus three pathogenic predictions, plus a benign consensus) indicates that the variant 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. | 0.896620 | Disordered | 0.814918 | Binding | 0.357 | 0.932 | 0.875 | -9.063 | Likely Pathogenic | 0.507 | Ambiguous | Likely Benign | 0.319 | Likely Benign | -0.05 | Neutral | 0.639 | Possibly Damaging | 0.351 | Benign | 4.64 | Benign | 0.05 | Affected | 0.0976 | 0.4342 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3367G>C | G1123R 2D AIThe SynGAP1 missense variant G1123R is not reported in ClinVar (no entry) and is absent from gnomAD. Consensus from routine in silico predictors shows a split: benign calls come from REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls arise from polyPhen‑2 HumDiv and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessment further supports a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign outcome, and no Foldetta stability data are available. Consequently, the overall evidence points to a benign effect for G1123R. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.837511 | Disordered | 0.827246 | Binding | 0.346 | 0.934 | 0.875 | -9.104 | Likely Pathogenic | 0.525 | Ambiguous | Likely Benign | 0.330 | Likely Benign | -0.46 | Neutral | 0.802 | Possibly Damaging | 0.435 | Benign | 4.34 | Benign | 0.57 | Tolerated | 0.0933 | 0.4342 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3370G>A | G1124R 2D AISynGAP1 missense variant G1124R is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443922‑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 benign. High‑accuracy methods give AlphaMissense‑Optimized as benign; the SGM Consensus also supports benign. Foldetta, a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the ensemble of predictions leans toward a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.837511 | Disordered | 0.833401 | Binding | 0.341 | 0.931 | 0.875 | Conflicting | 3 | 6-33443922-G-A | 24 | 1.60e-5 | -8.918 | Likely Pathogenic | 0.534 | Ambiguous | Likely Benign | 0.243 | Likely Benign | -0.58 | Neutral | 0.002 | Benign | 0.002 | Benign | 4.81 | Benign | 0.01 | Affected | 3.77 | 5 | 0.0935 | 0.4332 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||
| c.3370G>C | G1124R 2D AIThe SynGAP1 missense variant G1124R 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, while SIFT and ESM1b predict pathogenicity. The AlphaMissense‑Default tool is uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized is benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also returns benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the balance of evidence points to a benign impact for G1124R, 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. | 0.837511 | Disordered | 0.833401 | Binding | 0.341 | 0.931 | 0.875 | -8.918 | Likely Pathogenic | 0.534 | Ambiguous | Likely Benign | 0.239 | Likely Benign | -0.58 | Neutral | 0.002 | Benign | 0.002 | Benign | 4.81 | Benign | 0.01 | Affected | 3.77 | 5 | 0.0935 | 0.4332 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3373G>A | G1125R 2D AIThe SynGAP1 missense variant G1125R is catalogued in gnomAD (ID 6‑33443925‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. AlphaMissense‑Default remains uncertain. A high‑accuracy consensus (SGM) that aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a benign majority vote. AlphaMissense‑Optimized also reports benign. No Foldetta stability assessment is available. Collectively, the majority of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.835839 | Binding | 0.339 | 0.923 | 0.875 | 6-33443925-G-A | -8.463 | Likely Pathogenic | 0.542 | Ambiguous | Likely Benign | 0.291 | Likely Benign | -0.54 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 4.56 | Benign | 0.04 | Affected | 3.77 | 5 | 0.0980 | 0.4332 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.3373G>C | G1125R 2D AIThe SynGAP1 missense variant G1125R is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443925‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b all 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’s protein‑folding stability result is unavailable. Overall, the balance of evidence, particularly from the high‑accuracy tools, indicates that the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.835839 | Binding | 0.339 | 0.923 | 0.875 | 6-33443925-G-C | 1 | 6.68e-7 | -8.463 | Likely Pathogenic | 0.542 | Ambiguous | Likely Benign | 0.290 | Likely Benign | -0.54 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 4.56 | Benign | 0.04 | Affected | 3.77 | 5 | 0.0980 | 0.4332 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.3376G>C | G1126R 2D AIThe SynGAP1 missense variant G1126R is not 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, polyPhen‑2 HumVar, and SIFT. Two tools—ESM1b and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is uncertain due to a 2‑to‑2 split between benign and uncertain calls; Foldetta’s protein‑folding stability analysis is unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict any ClinVar annotation because no ClinVar record exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.837209 | Binding | 0.345 | 0.918 | 0.875 | -7.760 | In-Between | 0.522 | Ambiguous | Likely Benign | 0.345 | Likely Benign | -0.56 | Neutral | 0.971 | Probably Damaging | 0.597 | Possibly Damaging | 4.77 | Benign | 0.01 | Affected | 0.0946 | 0.4532 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3379G>A | G1127R 2D AIThe SynGAP1 missense variant G1127R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443931‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.852422 | Binding | 0.344 | 0.915 | 0.875 | Uncertain | 1 | 6-33443931-G-A | 2 | 1.34e-6 | -5.949 | Likely Benign | 0.629 | Likely Pathogenic | Likely Benign | 0.341 | Likely Benign | -0.87 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.86 | Benign | 0.12 | Tolerated | 4.32 | 4 | 0.0929 | 0.4532 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||
| c.3379G>C | G1127R 2D AIThe SynGAP1 missense variant G1127R is listed in ClinVar (ID 2967461.0) with an “Uncertain” clinical significance and is present in gnomAD (6‑33443931‑G‑C). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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 preponderance of evidence indicates that G1127R is most likely benign, which does not contradict the ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.852422 | Binding | 0.344 | 0.915 | 0.875 | Conflicting | 2 | 6-33443931-G-C | 16 | 1.07e-5 | -5.949 | Likely Benign | 0.629 | Likely Pathogenic | Likely Benign | 0.341 | Likely Benign | -0.87 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.86 | Benign | 0.12 | Tolerated | 4.32 | 4 | 0.0929 | 0.4532 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||
| c.337G>A | G113R 2D AIThe SynGAP1 missense variant G113R is not reported in ClinVar and is absent from 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, while 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 outputs) has no available result for this variant. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.639486 | Binding | 0.350 | 0.870 | 0.750 | -3.904 | Likely Benign | 0.791 | Likely Pathogenic | Ambiguous | 0.087 | Likely Benign | -1.50 | Neutral | 0.267 | Benign | 0.080 | Benign | 4.16 | Benign | 0.03 | Affected | 0.1025 | 0.4138 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.337G>C | G113R 2D AIThe SynGAP1 missense variant G113R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM all classify it as benign. In contrast, SIFT and AlphaMissense‑Default predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized score is uncertain, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as likely benign. Protein‑folding stability analysis via Foldetta is unavailable for this residue. Overall, the preponderance of evidence points to a benign effect, and this assessment does not conflict with the absence of a ClinVar classification. Thus, the variant is most likely benign, and this conclusion is consistent with the lack of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.639486 | Binding | 0.350 | 0.870 | 0.750 | -3.904 | Likely Benign | 0.791 | Likely Pathogenic | Ambiguous | 0.088 | Likely Benign | -1.50 | Neutral | 0.267 | Benign | 0.080 | Benign | 4.16 | Benign | 0.03 | Affected | 0.1025 | 0.4138 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3382G>A | G1128R 2D AIThe SynGAP1 missense variant G1128R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports 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 | 0.896620 | Disordered | 0.865136 | Binding | 0.309 | 0.911 | 0.875 | -5.009 | Likely Benign | 0.692 | Likely Pathogenic | Likely Benign | 0.396 | Likely Benign | -0.79 | Neutral | 0.846 | Possibly Damaging | 0.346 | Benign | 4.38 | Benign | 0.12 | Tolerated | 0.0950 | 0.4725 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3382G>C | G1128R 2D AIThe SynGAP1 missense variant G1128R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports 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 | 0.896620 | Disordered | 0.865136 | Binding | 0.309 | 0.911 | 0.875 | -5.009 | Likely Benign | 0.692 | Likely Pathogenic | Likely Benign | 0.397 | Likely Benign | -0.79 | Neutral | 0.846 | Possibly Damaging | 0.346 | Benign | 4.38 | Benign | 0.12 | Tolerated | 0.0950 | 0.4725 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3494C>G | S1165W 2D AIThe SynGAP1 missense variant S1165W 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 come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome; Foldetta stability analysis is unavailable. Overall, the evidence is split, with an equal number of tools supporting benign versus pathogenic effects. Consequently, the variant is most likely pathogenic based on the current computational predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.835017 | Binding | 0.308 | 0.807 | 0.375 | -6.419 | Likely Benign | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.195 | Likely Benign | -2.29 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.54 | Benign | 0.02 | Affected | 0.0671 | 0.4807 | -2 | -3 | -0.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3557C>G | S1186W 2D AIThe SynGAP1 missense variant S1186W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. ESM1b remains uncertain. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic)—also favors pathogenic. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that S1186W is most likely pathogenic, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.562014 | Disordered | 0.506433 | Binding | 0.634 | 0.636 | 0.625 | -7.814 | In-Between | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.214 | Likely Benign | -3.43 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.62 | Benign | 0.01 | Affected | 0.0556 | 0.4158 | -2 | -3 | -0.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.358G>C | G120R 2D AIThe SynGAP1 missense variant G120R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. Only AlphaMissense‑Default predicts a pathogenic outcome. When predictions are grouped, the benign consensus includes eight tools, whereas the pathogenic consensus contains a single tool. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign effect, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a likely benign classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that G120R is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.659993 | Binding | 0.359 | 0.887 | 0.750 | -4.406 | Likely Benign | 0.745 | Likely Pathogenic | Likely Benign | 0.022 | Likely Benign | -0.33 | Neutral | 0.089 | Benign | 0.047 | Benign | 4.26 | Benign | 0.14 | Tolerated | 0.1050 | 0.4345 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3790G>C | G1264R 2D AIThe SynGAP1 missense variant G1264R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those predicting a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to the variant being most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -4.482 | Likely Benign | 0.759 | Likely Pathogenic | Likely Benign | 0.094 | Likely Benign | -1.82 | Neutral | 0.934 | Possibly Damaging | 0.541 | Possibly Damaging | 2.73 | Benign | 0.09 | Tolerated | 0.0861 | 0.3860 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.386C>G | S129W 2D AIThe SynGAP1 missense variant S129W is not reported 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 high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign, and AlphaMissense‑Optimized is uncertain. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign impact. 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 | 0.517562 | Disordered | 0.713635 | Binding | 0.311 | 0.880 | 0.625 | -5.008 | Likely Benign | 0.824 | Likely Pathogenic | Ambiguous | 0.108 | Likely Benign | -1.49 | Neutral | 0.888 | Possibly Damaging | 0.367 | Benign | 4.06 | Benign | 0.01 | Affected | 0.0523 | 0.5471 | -2 | -3 | -0.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3907G>C | G1303R 2D AIThe SynGAP1 missense variant G1303R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic effect, whereas REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict a benign outcome. Grouping by consensus, the benign‑predicating tools outnumber the pathogenic ones. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized classifies the variant as benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b, FATHMM, and PROVEAN—also reports a likely benign status. No Foldetta stability analysis is available for this residue. Overall, the preponderance of evidence points to a benign effect for G1303R, 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 | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | -3.093 | Likely Benign | 0.536 | Ambiguous | Likely Benign | 0.364 | Likely Benign | -1.84 | Neutral | 0.970 | Probably Damaging | 0.787 | Possibly Damaging | 2.81 | Benign | 0.05 | Affected | 0.1024 | 0.3596 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.391G>C | G131R 2D AIThe SynGAP1 missense variant G131R 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive due to a 2‑to‑2 split and therefore does not contribute evidence. 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 tools predict a pathogenic effect, and the variant is most likely pathogenic based on current predictions, which does not contradict the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.724779 | Binding | 0.302 | 0.891 | 0.250 | Uncertain | 1 | -6.564 | Likely Benign | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.099 | Likely Benign | -3.82 | Deleterious | 0.983 | Probably Damaging | 0.656 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 3.61 | 5 | 0.1070 | 0.4667 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||
| c.3949G>C | G1317R 2D AIThe SynGAP1 missense variant G1317R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability prediction is available for this variant. Overall, the computational evidence overwhelmingly suggests that G1317R 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 | 0.908098 | Disordered | 0.971158 | Binding | 0.385 | 0.879 | 0.750 | -3.646 | Likely Benign | 0.619 | Likely Pathogenic | Likely Benign | 0.176 | Likely Benign | -2.17 | Neutral | 0.834 | Possibly Damaging | 0.307 | Benign | 4.04 | Benign | 0.00 | Affected | 0.1018 | 0.3791 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.4003G>C | G1335R 2D AIThe SynGAP1 missense variant G1335R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: benign predictions come from REVEL and ESM1b, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. Foldetta results are not available. Overall, the preponderance of evidence supports a pathogenic classification for G1335R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.891961 | Disordered | 0.967705 | Binding | 0.323 | 0.724 | 0.750 | -4.921 | Likely Benign | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.394 | Likely Benign | -5.06 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.02 | Pathogenic | 0.00 | Affected | 0.1071 | 0.5024 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.643G>C | G215R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G215R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the majority of algorithms (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. Four methods (FoldX, Rosetta, Foldetta, premPS) return uncertain results and are not considered evidence for either side. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, while Foldetta’s stability prediction is inconclusive. Taken together, the preponderance of evidence points to a pathogenic effect for G215R. This conclusion is consistent with the absence of a ClinVar entry and does not contradict any existing database annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.155435 | Structured | 0.382818 | Uncertain | 0.791 | 0.291 | 0.000 | -12.654 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 1.75 | Ambiguous | 0.1 | 1.25 | Ambiguous | 1.50 | Ambiguous | 0.56 | Ambiguous | 0.823 | Likely Pathogenic | -6.84 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 5.71 | Benign | 0.01 | Affected | 0.1048 | 0.4890 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.679G>A | G227R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G227R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, the majority of other in silico predictors classify the variant as pathogenic: SGM‑Consensus, REVEL, FoldX, Rosetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized (premPS is inconclusive). High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a pathogenic effect. Overall, the preponderance of evidence points to a pathogenic classification for G227R, with no conflict from ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.106997 | Structured | 0.329995 | Uncertain | 0.800 | 0.329 | 0.250 | -9.776 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.31 | Destabilizing | 0.3 | 5.29 | Destabilizing | 3.80 | Destabilizing | 0.90 | Ambiguous | 0.765 | Likely Pathogenic | -6.49 | Deleterious | 0.020 | Benign | 0.018 | Benign | 6.02 | Benign | 0.01 | Affected | 3.43 | 12 | 0.0997 | 0.4195 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||
| c.679G>C | G227R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G227R is not reported in ClinVar (no ClinVar ID) but is present in gnomAD (ID 6‑33435530‑G‑C). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that agree on a pathogenic effect comprise REVEL, FoldX, Rosetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta. The premPS score is uncertain and does not influence the consensus. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Based on the overwhelming agreement among high‑confidence predictors, the variant is most likely pathogenic; this conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.106997 | Structured | 0.329995 | Uncertain | 0.800 | 0.329 | 0.250 | 6-33435530-G-C | 1 | 6.20e-7 | -9.776 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.31 | Destabilizing | 0.3 | 5.29 | Destabilizing | 3.80 | Destabilizing | 0.90 | Ambiguous | 0.765 | Likely Pathogenic | -6.49 | Deleterious | 0.020 | Benign | 0.018 | Benign | 6.02 | Benign | 0.01 | Affected | 3.43 | 12 | 0.0997 | 0.4195 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||
| c.76G>A | G26R 2D AIThe SynGAP1 missense variant G26R is listed in ClinVar as a benign alteration (ClinVar ID 1521495.0) and is present in the gnomAD database (gnomAD ID 6‑33423485‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence supports a benign impact, aligning with the ClinVar designation and indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.438291 | Uncertain | 0.351 | 0.878 | 0.375 | Benign | 1 | 6-33423485-G-A | 3 | 1.86e-6 | -2.946 | Likely Benign | 0.678 | Likely Pathogenic | Likely Benign | 0.189 | Likely Benign | -2.22 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 3.87 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1097 | 0.4407 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||
| c.76G>C | G26R 2D AIThe SynGAP1 missense variant G26R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of the four high‑accuracy tools) also yields benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence—including the high‑accuracy consensus—indicates that G26R is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.438291 | Uncertain | 0.351 | 0.878 | 0.375 | -2.946 | Likely Benign | 0.678 | Likely Pathogenic | Likely Benign | 0.189 | Likely Benign | -2.22 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 3.87 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1097 | 0.4407 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.907G>A | G303R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G303R is catalogued in gnomAD (6-33437812-G-A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome; the remaining tools (FoldX, Foldetta, premPS, ESM1b) are inconclusive. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, while Foldetta remains uncertain. Taken together, the majority of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.450668 | Structured | 0.271087 | Uncertain | 0.630 | 0.254 | 0.250 | 6-33437812-G-A | 1 | 6.20e-7 | -7.493 | In-Between | 0.724 | Likely Pathogenic | Likely Benign | 1.44 | Ambiguous | 0.4 | 0.23 | Likely Benign | 0.84 | Ambiguous | 0.73 | Ambiguous | 0.048 | Likely Benign | -1.38 | Neutral | 0.001 | Benign | 0.003 | Benign | 3.99 | Benign | 0.06 | Tolerated | 3.55 | 18 | 0.0839 | 0.4490 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||
| c.907G>C | G303R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G303R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome. The remaining tools—FoldX, Foldetta, premPS, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, while Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.450668 | Structured | 0.271087 | Uncertain | 0.630 | 0.254 | 0.250 | -7.493 | In-Between | 0.724 | Likely Pathogenic | Likely Benign | 1.44 | Ambiguous | 0.4 | 0.23 | Likely Benign | 0.84 | Ambiguous | 0.73 | Ambiguous | 0.048 | Likely Benign | -1.38 | Neutral | 0.001 | Benign | 0.003 | Benign | 3.99 | Benign | 0.06 | Tolerated | 3.55 | 18 | 0.0839 | 0.4490 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||
| c.925G>C | G309R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G309R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely pathogenic outcome. No tool in the dataset predicts a benign effect. Uncertainty remains for FoldX, Rosetta, Foldetta, and premPS, which are listed as uncertain and do not influence the overall assessment. High‑accuracy evaluations show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.338439 | Uncertain | 0.882 | 0.342 | 0.125 | -14.375 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 1.99 | Ambiguous | 0.5 | 0.52 | Ambiguous | 1.26 | Ambiguous | 0.55 | Ambiguous | 0.572 | Likely Pathogenic | -7.35 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.70 | Pathogenic | 0.04 | Affected | 0.0964 | 0.5097 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1063G>T | G355W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G355W is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL and premPS, and pathogenic predictions from SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as inconclusive, SGM‑Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not 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 Pathogenic | C2 | 0.155435 | Structured | 0.388832 | Uncertain | 0.810 | 0.354 | 0.125 | -12.316 | Likely Pathogenic | 0.938 | Likely Pathogenic | Ambiguous | 1.16 | Ambiguous | 0.5 | 0.88 | Ambiguous | 1.02 | Ambiguous | 0.18 | Likely Benign | 0.455 | Likely Benign | -6.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.73 | Pathogenic | 0.00 | Affected | 0.0796 | 0.4360 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||
| c.1114G>T | G372W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G372W has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include premPS, PROVEAN, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, FoldX, polyPhen‑2 HumDiv, SIFT, ESM1b, and FATHMM. The remaining tools (Rosetta, Foldetta, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.433034 | Structured | 0.430335 | Uncertain | 0.322 | 0.774 | 0.375 | -8.262 | Likely Pathogenic | 0.478 | Ambiguous | Likely Benign | 2.28 | Destabilizing | 0.5 | 1.14 | Ambiguous | 1.71 | Ambiguous | 0.21 | Likely Benign | 0.649 | Likely Pathogenic | -1.25 | Neutral | 0.657 | Possibly Damaging | 0.075 | Benign | -0.74 | Pathogenic | 0.00 | Affected | 0.1057 | 0.4368 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||
| c.1123G>T | G375W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G375W is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438028‑G‑T). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of evidence, including the high‑accuracy tools, points to a pathogenic effect for G375W. This conclusion is consistent with the absence of a ClinVar classification, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.604312 | Disordered | 0.428340 | Uncertain | 0.301 | 0.836 | 0.625 | 6-33438028-G-T | -9.654 | Likely Pathogenic | 0.464 | Ambiguous | Likely Benign | 4.33 | Destabilizing | 2.0 | 7.01 | Destabilizing | 5.67 | Destabilizing | 0.22 | Likely Benign | 0.450 | Likely Benign | -1.26 | Neutral | 0.992 | Probably Damaging | 0.869 | Possibly Damaging | 1.31 | Pathogenic | 0.01 | Affected | 4.32 | 12 | 0.0992 | 0.4368 | -2 | -7 | -0.5 | 129.16 | |||||||||||||||||||||||||||
| c.1141G>T | G381W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G381W is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438046‑G‑T). Prediction tools that agree on a benign effect include premPS, PROVEAN, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments give AlphaMissense‑Optimized a benign call, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) a pathogenic call, and Foldetta (combining FoldX‑MD and Rosetta outputs) a pathogenic call. No prediction or folding result is missing or inconclusive. Overall, the majority of tools and the high‑accuracy methods indicate a pathogenic impact. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.724957 | Disordered | 0.431692 | Uncertain | 0.301 | 0.951 | 0.750 | 6-33438046-G-T | 1 | 6.24e-7 | -10.173 | Likely Pathogenic | 0.438 | Ambiguous | Likely Benign | 8.81 | Destabilizing | 2.0 | 3.17 | Destabilizing | 5.99 | Destabilizing | 0.02 | Likely Benign | 0.576 | Likely Pathogenic | -1.04 | Neutral | 0.996 | Probably Damaging | 0.920 | Probably Damaging | 1.31 | Pathogenic | 0.01 | Affected | 4.32 | 9 | 0.0993 | 0.4000 | -2 | -7 | -0.5 | 129.16 | |||||||||||||||||||||||||
| c.1147G>T | G383W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G383W is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438052‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as benign, and Foldetta as pathogenic. Because the majority of conventional predictors favor pathogenicity while the high‑accuracy subset is split, the overall evidence leans toward a pathogenic interpretation. This conclusion does not conflict with the ClinVar uncertain status, which reflects the current lack of definitive clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.728858 | Disordered | 0.429104 | Uncertain | 0.296 | 0.949 | 0.750 | Uncertain | 1 | 6-33438052-G-T | 1 | 6.22e-7 | -10.161 | Likely Pathogenic | 0.439 | Ambiguous | Likely Benign | 5.81 | Destabilizing | 3.6 | 4.44 | Destabilizing | 5.13 | Destabilizing | 0.08 | Likely Benign | 0.469 | Likely Benign | -1.01 | Neutral | 0.959 | Probably Damaging | 0.704 | Possibly Damaging | 4.09 | Benign | 0.00 | Affected | 4.32 | 7 | 0.0972 | 0.3785 | -2 | -7 | -0.5 | 129.16 | |||||||||||||||||||||||
| c.1156G>T | G386W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G386W is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Computational predictors that classify the change as benign include REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. High‑accuracy assessments give a benign verdict from AlphaMissense‑Optimized, a benign consensus from the SGM method (majority of the four contributing tools are benign), and a pathogenic result from Foldetta. Uncertain calls from AlphaMissense‑Default and Rosetta are treated as unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not conflict with the lack of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.733139 | Disordered | 0.424156 | Uncertain | 0.334 | 0.898 | 0.750 | -10.389 | Likely Pathogenic | 0.519 | Ambiguous | Likely Benign | 6.07 | Destabilizing | 5.5 | 1.28 | Ambiguous | 3.68 | Destabilizing | -0.23 | Likely Benign | 0.471 | Likely Benign | -0.85 | Neutral | 0.996 | Probably Damaging | 0.920 | Probably Damaging | 3.90 | Benign | 0.00 | Affected | 0.1058 | 0.4676 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||
| c.1168G>T | G390W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G390W is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include AlphaMissense‑Optimized, premPS, and PROVEAN, whereas the remaining tools—REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts benign, but the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic verdict, and Foldetta also indicates pathogenic. With the majority of evidence pointing to a deleterious effect, the variant is most likely pathogenic, 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. | C2 | 0.626927 | Disordered | 0.413274 | Uncertain | 0.304 | 0.763 | 0.875 | -9.405 | Likely Pathogenic | 0.487 | Ambiguous | Likely Benign | 3.69 | Destabilizing | 1.9 | 5.31 | Destabilizing | 4.50 | Destabilizing | 0.14 | Likely Benign | 0.639 | Likely Pathogenic | -1.11 | Neutral | 0.987 | Probably Damaging | 0.744 | Possibly Damaging | 1.31 | Pathogenic | 0.00 | Affected | 0.0917 | 0.4368 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||
| c.157G>T | G53W 2D AIThe SynGAP1 missense variant G53W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM. Tools that agree on a pathogenic effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign). Foldetta results are unavailable. Overall, the majority of available predictions (six pathogenic vs. three benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.268042 | Structured | 0.460894 | Uncertain | 0.386 | 0.666 | 0.000 | -11.012 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.243 | Likely Benign | -1.69 | Neutral | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 4.08 | Benign | 0.00 | Affected | 0.0678 | 0.5071 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||||||
| c.1825G>T | G609W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G609W (ClinVar ID 4327030) is not found in gnomAD. Prediction tools that classify the variant as benign include premPS and AlphaMissense‑Optimized, whereas the majority of other in silico predictors (SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM) predict it to be pathogenic; Rosetta, Foldetta, and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence from pathogenic‑oriented tools and the SGM Consensus supports a pathogenic effect, which is consistent with the ClinVar classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | 1 | -13.074 | Likely Pathogenic | 0.525 | Ambiguous | Likely Benign | 3.14 | Destabilizing | 0.7 | -0.87 | Ambiguous | 1.14 | Ambiguous | 0.28 | Likely Benign | 0.566 | Likely Pathogenic | -4.70 | Deleterious | 0.999 | Probably Damaging | 0.976 | Probably Damaging | -1.47 | Pathogenic | 0.01 | Affected | 0.0935 | 0.3181 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||
| c.2248G>T | G750W 2D AIThe SynGAP1 missense variant G750W is not 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 AlphaMissense‑Optimized, while the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all classify the variant as damaging. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Overall, the preponderance of evidence from multiple in silico predictors indicates that G750W 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 | 0.618285 | Disordered | 0.646832 | Binding | 0.348 | 0.866 | 0.625 | -8.433 | Likely Pathogenic | 0.427 | Ambiguous | Likely Benign | 0.135 | Likely Benign | -3.30 | Deleterious | 1.000 | Probably Damaging | 0.994 | Probably Damaging | 2.41 | Pathogenic | 0.00 | Affected | 0.0738 | 0.4009 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.2548G>T | G850W 2D AIThe SynGAP1 missense variant G850W is not 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, 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 inconclusive (two benign, two uncertain), and Foldetta data are unavailable. Overall, the balance of evidence (four benign vs. three pathogenic predictions, with a benign high‑accuracy result and no contradictory ClinVar annotation) indicates that the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.648219 | Disordered | 0.540897 | Binding | 0.312 | 0.820 | 0.500 | -7.826 | In-Between | 0.351 | Ambiguous | Likely Benign | 0.170 | Likely Benign | -1.94 | Neutral | 0.996 | Probably Damaging | 0.933 | Probably Damaging | 4.16 | Benign | 0.00 | Affected | 0.0734 | 0.4002 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||||||
| c.2599G>T | G867W 2D AIThe SynGAP1 missense variant G867W 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, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus 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 evidence points toward a pathogenic effect, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.517562 | Disordered | 0.657954 | Binding | 0.285 | 0.801 | 0.250 | -8.983 | Likely Pathogenic | 0.776 | Likely Pathogenic | Likely Benign | 0.163 | Likely Benign | -2.95 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.64 | Benign | 0.01 | Affected | 0.0726 | 0.4584 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.2644G>T | G882W 2D AIThe SynGAP1 missense variant G882W has no ClinVar entry and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains pathogenic; Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion does not conflict with the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.690604 | Disordered | 0.632888 | Binding | 0.306 | 0.878 | 0.250 | -8.637 | Likely Pathogenic | 0.606 | Likely Pathogenic | Likely Benign | 0.166 | Likely Benign | -2.35 | Neutral | 0.983 | Probably Damaging | 0.813 | Possibly Damaging | 2.01 | Pathogenic | 0.00 | Affected | 0.0829 | 0.4616 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.2680G>T | G894W 2D AIThe SynGAP1 missense variant G894W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, 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, which assesses protein‑folding stability, has no available output for this variant. Overall, the majority of evaluated predictors (five pathogenic vs. three benign) lean toward a pathogenic interpretation. Because there is no ClinVar annotation to contradict this assessment, the variant is most likely pathogenic based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.788093 | Disordered | 0.425700 | Uncertain | 0.310 | 0.925 | 0.750 | -6.927 | Likely Benign | 0.814 | Likely Pathogenic | Ambiguous | 0.177 | Likely Benign | -2.70 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.59 | Benign | 0.00 | Affected | 0.0698 | 0.4184 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||||||
| c.274G>T | G92W 2D AIThe SynGAP1 missense variant G92W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of available predictions (five pathogenic vs. three benign) suggest a pathogenic impact. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.575842 | Disordered | 0.537848 | Binding | 0.337 | 0.874 | 0.625 | -6.502 | Likely Benign | 0.789 | Likely Pathogenic | Ambiguous | 0.224 | Likely Benign | -2.61 | Deleterious | 1.000 | Probably Damaging | 0.979 | Probably Damaging | 3.95 | Benign | 0.00 | Affected | 0.0640 | 0.4546 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||||||
| c.2812G>T | G938W 2D AIThe SynGAP1 missense variant G938W is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs. four benign) indicate that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar annotation exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.905695 | Disordered | 0.949795 | Binding | 0.318 | 0.883 | 0.625 | -8.763 | Likely Pathogenic | 0.604 | Likely Pathogenic | Likely Benign | 0.194 | Likely Benign | -1.71 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.70 | Benign | 0.04 | Affected | 0.0762 | 0.4008 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||||||
| c.2839G>T | G947W 2D AIThe SynGAP1 missense variant G947W has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. 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 exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988695 | Disordered | 0.850554 | Binding | 0.358 | 0.919 | 0.750 | -10.819 | Likely Pathogenic | 0.285 | Likely Benign | Likely Benign | 0.349 | Likely Benign | -1.21 | Neutral | 0.983 | Probably Damaging | 0.868 | Possibly Damaging | 4.90 | Benign | 0.01 | Affected | 0.0914 | 0.4059 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.2917G>T | G973W 2D AIThe SynGAP1 missense variant G973W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized reports Benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for G973W, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.959498 | Binding | 0.390 | 0.897 | 0.625 | -6.896 | Likely Benign | 0.329 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -1.53 | Neutral | 0.983 | Probably Damaging | 0.813 | Possibly Damaging | 4.10 | Benign | 0.00 | Affected | 0.0846 | 0.4046 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.2971G>T | G991W 2D AIThe SynGAP1 missense variant G991W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.745909 | Disordered | 0.911393 | Binding | 0.286 | 0.920 | 0.750 | -6.281 | Likely Benign | 0.336 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -2.32 | Neutral | 0.997 | Probably Damaging | 0.975 | Probably Damaging | 4.07 | Benign | 0.00 | Affected | 0.0745 | 0.3654 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3142G>T | G1048W 2D AIThe SynGAP1 missense variant G1048W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | -8.803 | Likely Pathogenic | 0.340 | Likely Benign | Likely Benign | 0.498 | Likely Benign | -1.52 | Neutral | 0.996 | Probably Damaging | 0.961 | Probably Damaging | 2.54 | Benign | 0.02 | Affected | 0.0852 | 0.4046 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.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 | -0.90 | Neutral | 0.997 | Probably Damaging | 0.946 | Probably Damaging | 3.90 | Benign | 0.02 | Affected | 0.0872 | 0.4046 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| 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 | -0.77 | Neutral | 0.997 | Probably Damaging | 0.946 | Probably Damaging | 3.28 | Benign | 0.01 | Affected | 0.0899 | 0.4246 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3175G>T | G1059W 2D AIThe SynGAP1 missense variant G1059W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | -11.549 | Likely Pathogenic | 0.312 | Likely Benign | Likely Benign | 0.446 | Likely Benign | -1.18 | Neutral | 0.983 | Probably Damaging | 0.813 | Possibly Damaging | 2.53 | Benign | 0.00 | Affected | 0.0925 | 0.4046 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3184G>T | G1062W 2D AIThe SynGAP1 missense variant G1062W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which labels the variant as “Likely Benign.” Pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b, all of which classify the change as damaging. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.976962 | Disordered | 0.936972 | Binding | 0.368 | 0.917 | 0.875 | -9.667 | Likely Pathogenic | 0.315 | Likely Benign | Likely Benign | 0.401 | Likely Benign | -1.38 | Neutral | 0.993 | Probably Damaging | 0.890 | Possibly Damaging | 4.09 | Benign | 0.00 | Affected | 0.0908 | 0.4246 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.31G>T | G11W 2D AIThe SynGAP1 missense variant G11W is catalogued in gnomAD (ID 6‑33420295‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions come from polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.444081 | Structured | 0.501027 | Binding | 0.348 | 0.915 | 0.375 | 6-33420295-G-T | -5.819 | Likely Benign | 0.403 | Ambiguous | Likely Benign | 0.096 | Likely Benign | -0.67 | Neutral | 0.959 | Probably Damaging | 0.318 | Benign | 3.87 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0747 | 0.4731 | -2 | -7 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||
| 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 | -3.45 | Deleterious | 1.000 | Probably Damaging | 0.988 | Probably Damaging | 2.37 | Pathogenic | 0.00 | Affected | 0.0840 | 0.4610 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3346G>T | G1116W 2D AIThe SynGAP1 missense variant G1116W is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443898‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b all 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’s protein‑folding stability result is unavailable. Taken together, the majority of reliable predictors and the consensus high‑accuracy tools indicate a benign effect. This conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.889439 | Disordered | 0.873279 | Binding | 0.320 | 0.909 | 0.750 | 6-33443898-G-T | -9.448 | Likely Pathogenic | 0.356 | Ambiguous | Likely Benign | 0.405 | Likely Benign | -1.27 | Neutral | 0.996 | Probably Damaging | 0.946 | Probably Damaging | 4.04 | Benign | 0.01 | Affected | 4.32 | 2 | 0.0776 | 0.4046 | -2 | -7 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||
| c.334G>T | G112W 2D AIThe SynGAP1 missense variant G112W is not 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 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, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic interpretation. This conclusion is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.728858 | Disordered | 0.640153 | Binding | 0.332 | 0.867 | 0.750 | -6.382 | Likely Benign | 0.720 | Likely Pathogenic | Likely Benign | 0.190 | Likely Benign | -3.98 | Deleterious | 0.983 | Probably Damaging | 0.778 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 0.0631 | 0.4212 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||||||
| c.3355G>T | G1119W 2D AIThe SynGAP1 missense variant G1119W is reported in gnomAD (ID 6‑33443907‑G‑T) but has no ClinVar entry. 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, SIFT, and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are unavailable. Overall, the majority of computational evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.818538 | Binding | 0.339 | 0.928 | 0.875 | 6-33443907-G-T | -10.904 | Likely Pathogenic | 0.336 | Likely Benign | Likely Benign | 0.386 | Likely Benign | -1.19 | Neutral | 0.997 | Probably Damaging | 0.949 | Probably Damaging | 3.90 | Benign | 0.02 | Affected | 4.32 | 2 | 0.0948 | 0.4059 | -2 | -7 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||
| c.3373G>T | G1125W 2D AIThe SynGAP1 missense variant G1125W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors a benign outcome. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the balance of evidence, especially from the high‑accuracy tools, points to a benign classification. This conclusion is not contradicted by any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.835839 | Binding | 0.339 | 0.923 | 0.875 | -11.684 | Likely Pathogenic | 0.372 | Ambiguous | Likely Benign | 0.402 | Likely Benign | -1.10 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 4.50 | Benign | 0.00 | Affected | 0.0924 | 0.4046 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||||||
| c.3379G>T | G1127W 2D AIThe SynGAP1 missense variant G1127W is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443931‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b all 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’s protein‑folding stability result is unavailable. Overall, the balance of evidence, particularly from the high‑accuracy tools, indicates that the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.899122 | Disordered | 0.852422 | Binding | 0.344 | 0.915 | 0.875 | 6-33443931-G-T | 3 | 2.01e-6 | -9.850 | Likely Pathogenic | 0.418 | Ambiguous | Likely Benign | 0.394 | Likely Benign | -1.36 | Neutral | 0.983 | Probably Damaging | 0.665 | Possibly Damaging | 4.79 | Benign | 0.03 | Affected | 4.32 | 4 | 0.0782 | 0.4032 | -2 | -7 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||
| c.337G>T | G113W 2D AIThe SynGAP1 missense variant G113W is not reported 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 (six benign versus four 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 | 0.784345 | Disordered | 0.639486 | Binding | 0.350 | 0.870 | 0.750 | -5.635 | Likely Benign | 0.620 | Likely Pathogenic | Likely Benign | 0.162 | Likely Benign | -2.44 | Neutral | 0.983 | Probably Damaging | 0.717 | Possibly Damaging | 4.10 | Benign | 0.01 | Affected | 0.0700 | 0.4462 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3382G>T | G1128W 2D AIThe SynGAP1 missense variant G1128W is not 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), FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields an inconclusive result (two benign, two uncertain), and Foldetta data are unavailable. Overall, the balance of evidence favors a benign classification. This conclusion does not contradict ClinVar status, as the variant has no existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.896620 | Disordered | 0.865136 | Binding | 0.309 | 0.911 | 0.875 | -7.341 | In-Between | 0.402 | Ambiguous | Likely Benign | 0.464 | Likely Benign | -1.36 | Neutral | 0.011 | Benign | 0.008 | Benign | 4.36 | Benign | 0.02 | Affected | 0.0796 | 0.4540 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||||||
| c.907G>T | G303W 2D 3DClick to see structure in 3D Viewer AIClinVar reports no entry for this SynGAP1 G303W variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta’s stability prediction is also unavailable. Overall, the evidence is evenly split between benign and pathogenic predictions, providing no clear bias toward either outcome. This balanced prediction does not contradict ClinVar status, which currently has no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.450668 | Structured | 0.271087 | Uncertain | 0.630 | 0.254 | 0.250 | -9.041 | Likely Pathogenic | 0.579 | Likely Pathogenic | Likely Benign | 1.69 | Ambiguous | 0.3 | 1.11 | Ambiguous | 1.40 | Ambiguous | 0.28 | Likely Benign | 0.157 | Likely Benign | -1.63 | Neutral | 0.983 | Probably Damaging | 0.813 | Possibly Damaging | 3.93 | Benign | 0.00 | Affected | 0.0663 | 0.4553 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||
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