Table of SynGAP1 Isoform α2 (UniProt Q96PV0-1) Missense Variants.
| c.dna | Variant | SGM Consensus | Domain | IUPred2 | ANCHOR2 | AlphaFold | MobiDB | ClinVar | gnomAD | ESM1b | AlphaMissense | REVEL | PSMutPred | FoldX | Rosetta | Foldetta | PremPS | PROVEAN | PolyPhen-2 HumDiv | PolyPhen-2 HumVar | FATHMM | SIFT | PAM | Physical | SASA | Normalized B-factor backbone | Normalized B-factor sidechain | SynGAP Structural Annotation | DOI | ||||||||||||||||||||||||||||||||||||||
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| Score | Prediction | Score | Prediction | pLDDT | disorder | disorder | Clinical Status | Review | Subm. | ID | Allele count | Allele freq. | LLR score | Prediction | Pathogenicity | Class | Optimized | Score | Prediction | IP RF | SP RF | Prediction | Average ΔΔG | Prediction | StdDev | ΔΔG | Prediction | ΔΔG | Prediction | ΔΔG | Prediction | Score | Prediction | pph2_prob | Prediction | pph2_prob | Prediction | Nervous System Score | Prediction | Prediction | Status | Conservation | Sequences | PAM250 | PAM120 | Hydropathy Δ | MW Δ | Average | Δ | Δ | StdDev | Δ | StdDev | Secondary | Tertiary bonds | Inside out | GAP-Ras interface | At membrane | No effect | MD Alert | Verdict | Description | |||||
| c.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 | 0.1498 | 0.2233 | -1.21 | Neutral | 0.993 | Probably Damaging | 0.733 | Possibly Damaging | 4.11 | Benign | 0.01 | Affected | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||||||||
| c.371C>G | A124G 2D  AIThe SynGAP1 missense variant A124G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to the variant being most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.699139 | Binding | 0.340 | 0.883 | 0.750 | -3.090 | Likely Benign | 0.164 | Likely Benign | Likely Benign | 0.055 | Likely Benign | 0.2433 | 0.5388 | -0.75 | Neutral | 0.934 | Possibly Damaging | 0.447 | Possibly Damaging | 4.06 | Benign | 0.04 | Affected | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.371C>T | A124V 2D  AIThe SynGAP1 A124V missense variant is listed in ClinVar (ID 1040523.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33432236‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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 computational evidence indicates a benign effect, and this consensus does not contradict the ClinVar “Uncertain” designation. 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 | 0.509769 | Disordered | 0.699139 | Binding | 0.340 | 0.883 | 0.750 | Conflicting | 2 | 6-33432236-C-T | 9 | 5.58e-6 | -4.259 | Likely Benign | 0.138 | Likely Benign | Likely Benign | 0.073 | Likely Benign | 0.1415 | 0.7433 | -1.52 | Neutral | 0.173 | Benign | 0.009 | Benign | 4.07 | Benign | 0.03 | Affected | 3.61 | 5 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||
| c.373C>A | P125T 2D  AIThe SynGAP1 missense variant P125T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.704227 | Binding | 0.373 | 0.878 | 0.625 | -4.780 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.215 | Likely Benign | 0.1502 | 0.4995 | -3.78 | Deleterious | 0.036 | Benign | 0.014 | Benign | 2.85 | Benign | 0.01 | Affected | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||
| c.373C>G | P125A 2D  AIThe SynGAP1 missense variant P125A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the majority of predictions and the high‑accuracy consensus, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.704227 | Binding | 0.373 | 0.878 | 0.625 | -3.936 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.124 | Likely Benign | 0.3341 | 0.4245 | -3.55 | Deleterious | 0.580 | Possibly Damaging | 0.140 | Benign | 2.88 | Benign | 0.02 | Affected | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| c.373C>T | P125S 2D  AIThe SynGAP1 missense variant P125S is listed in ClinVar (ID 837156.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict the ClinVar designation, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.704227 | Binding | 0.373 | 0.878 | 0.625 | Uncertain | 1 | -3.769 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.121 | Likely Benign | 0.3408 | 0.4594 | -3.57 | Deleterious | 0.580 | Possibly Damaging | 0.140 | Benign | 2.86 | Benign | 0.02 | Affected | 3.61 | 5 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||
| c.374C>A | P125H 2D  AIThe SynGAP1 missense variant P125H is not 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 and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2). Foldetta results are unavailable. Overall, the majority of conventional predictors (five pathogenic vs four benign) lean toward a pathogenic interpretation, but the single high‑accuracy benign prediction and the inconclusive SGM Consensus temper this view. No ClinVar annotation is present, so there is no reported status to contradict the computational predictions. 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 | -5.177 | Likely Benign | 0.583 | Likely Pathogenic | Likely Benign | 0.235 | Likely Benign | 0.1598 | 0.4263 | -4.18 | Deleterious | 0.996 | Probably Damaging | 0.750 | Possibly Damaging | 2.82 | Benign | 0.01 | Affected | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||
| 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 | 0.1461 | 0.2913 | -4.33 | Deleterious | 0.952 | Possibly Damaging | 0.521 | Possibly Damaging | 2.83 | Benign | 0.09 | Tolerated | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||
| c.374C>T | P125L 2D  AIThe SynGAP1 missense variant P125L is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign. Foldetta results are unavailable. Overall, the majority of evidence (5 benign vs 3 pathogenic, with one uncertain) 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. | 0.505461 | Disordered | 0.704227 | Binding | 0.373 | 0.878 | 0.625 | -4.565 | Likely Benign | 0.550 | Ambiguous | Likely Benign | 0.147 | Likely Benign | 0.2189 | 0.6478 | -4.82 | Deleterious | 0.906 | Possibly Damaging | 0.272 | Benign | 2.83 | Benign | 0.01 | Affected | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||
| c.376T>A | F126I 2D  AIThe SynGAP1 missense variant F126I is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree that the change is benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify it as benign. Only two tools predict pathogenicity—SIFT and AlphaMissense‑Default. High‑accuracy consensus methods reinforce the benign assessment: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” and AlphaMissense‑Optimized itself predicts benign. The protein‑folding stability predictor Foldetta was not available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.712056 | Binding | 0.316 | 0.874 | 0.500 | -2.919 | Likely Benign | 0.735 | Likely Pathogenic | Likely Benign | 0.044 | Likely Benign | 0.2569 | 0.2418 | -2.20 | Neutral | 0.160 | Benign | 0.045 | Benign | 3.95 | Benign | 0.00 | Affected | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||||||||
| c.376T>C | F126L 2D  AIThe SynGAP1 missense variant F126L is not reported 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 FATHMM. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, while the high‑accuracy AlphaMissense‑Optimized result is inconclusive and Foldetta data are unavailable. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict the ClinVar status, which contains no pathogenic claim. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.712056 | Binding | 0.316 | 0.874 | 0.500 | -0.992 | Likely Benign | 0.948 | Likely Pathogenic | Ambiguous | 0.091 | Likely Benign | 0.2780 | 0.3399 | -2.27 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.01 | Benign | 0.00 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||
| c.376T>G | F126V 2D  AIThe SynGAP1 missense variant F126V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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 for F126V, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.712056 | Binding | 0.316 | 0.874 | 0.500 | -1.584 | Likely Benign | 0.635 | Likely Pathogenic | Likely Benign | 0.086 | Likely Benign | 0.2496 | 0.2646 | -2.47 | Neutral | 0.160 | Benign | 0.045 | Benign | 3.98 | Benign | 0.00 | Affected | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||||||||
| c.377T>A | F126Y 2D  AIThe SynGAP1 missense variant F126Y has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, 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 impact, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.712056 | Binding | 0.316 | 0.874 | 0.500 | -3.519 | Likely Benign | 0.509 | Ambiguous | Likely Benign | 0.044 | Likely Benign | 0.1631 | 0.1907 | -1.29 | Neutral | 0.851 | Possibly Damaging | 0.221 | Benign | 3.90 | Benign | 0.00 | Affected | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||||||||
| c.377T>C | F126S 2D  AIThe SynGAP1 missense variant F126S is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree that the change is benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM all classify it as benign. In contrast, SIFT and AlphaMissense‑Default predict a pathogenic effect. AlphaMissense‑Optimized returns an uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available prediction for this residue. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” Overall, the majority of high‑accuracy tools (REVEL, PROVEAN, polyPhen‑2, ESM1b, FATHMM, and SGM‑Consensus) support a benign interpretation, while only two tools (SIFT, AlphaMissense‑Default) suggest pathogenicity. Given the preponderance of benign predictions and the absence of ClinVar evidence, the variant is most likely benign and does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.712056 | Binding | 0.316 | 0.874 | 0.500 | -0.234 | Likely Benign | 0.844 | Likely Pathogenic | Ambiguous | 0.086 | Likely Benign | 0.4833 | 0.0000 | -2.46 | Neutral | 0.160 | Benign | 0.045 | Benign | 3.96 | Benign | 0.00 | Affected | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||||||||
| c.377T>G | F126C 2D  AIThe SynGAP1 missense variant F126C is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, more tools predict pathogenicity (five) than benignity (three), and no ClinVar evidence contradicts this assessment. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.486429 | Structured | 0.712056 | Binding | 0.316 | 0.874 | 0.500 | -2.553 | Likely Benign | 0.824 | Likely Pathogenic | Ambiguous | 0.109 | Likely Benign | 0.2682 | 0.1270 | -3.19 | Deleterious | 0.952 | Possibly Damaging | 0.570 | Possibly Damaging | 3.88 | Benign | 0.00 | Affected | -4 | -2 | -0.3 | -44.04 | ||||||||||||||||||||||||||||||||||||
| c.378C>A | F126L 2D AIThe SynGAP1 missense variant F126L is not reported 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 FATHMM. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, while the high‑accuracy AlphaMissense‑Optimized result is inconclusive and Foldetta data are unavailable. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict the ClinVar status, which contains no pathogenic claim. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.712056 | Binding | 0.316 | 0.874 | 0.500 | -0.992 | Likely Benign | 0.948 | Likely Pathogenic | Ambiguous | 0.114 | Likely Benign | 0.2780 | 0.3399 | -2.27 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.01 | Benign | 0.00 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||
| c.378C>G | F126L 2D AIThe SynGAP1 missense variant F126L is not 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 FATHMM. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, while the high‑accuracy AlphaMissense‑Optimized result is inconclusive and Foldetta data are unavailable. Overall, the majority of evidence points to a benign impact; the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.712056 | Binding | 0.316 | 0.874 | 0.500 | -0.992 | Likely Benign | 0.948 | Likely Pathogenic | Ambiguous | 0.114 | Likely Benign | 0.2780 | 0.3399 | -2.27 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.01 | Benign | 0.00 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||
| c.379C>G | R127G 2D  AIThe SynGAP1 R127G missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN; it yields a “Likely Benign” classification (3 benign vs. 1 pathogenic). AlphaMissense‑Optimized also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.497853 | Structured | 0.711716 | Binding | 0.333 | 0.870 | 0.625 | -1.062 | Likely Benign | 0.700 | Likely Pathogenic | Likely Benign | 0.107 | Likely Benign | 0.3561 | 0.3037 | -2.17 | Neutral | 0.287 | Benign | 0.038 | Benign | 3.91 | Benign | 0.01 | Affected | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||
| c.379C>T | R127W 2D  AISynGAP1 missense variant R127W is listed in ClinVar with an Uncertain significance status and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 HumVar, ESM1b, and FATHMM, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is Uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta stability analysis is unavailable. Consequently, the evidence does not favor a clear benign or pathogenic outcome; the predictions are balanced and align with the ClinVar designation of Uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.497853 | Structured | 0.711716 | Binding | 0.333 | 0.870 | 0.625 | Uncertain | 1 | -4.776 | Likely Benign | 0.806 | Likely Pathogenic | Ambiguous | 0.118 | Likely Benign | 0.1583 | 0.3005 | -2.98 | Deleterious | 0.989 | Probably Damaging | 0.420 | Benign | 3.88 | Benign | 0.00 | Affected | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.380G>A | R127Q 2D  AIThe SynGAP1 missense variant R127Q (ClinVar ID 2898917.0) is listed as ClinVar status Uncertain and is present in gnomAD (6‑33432245‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta stability analysis is unavailable. Overall, the majority of computational evidence supports a benign effect, which is consistent with the ClinVar Uncertain status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.497853 | Structured | 0.711716 | Binding | 0.333 | 0.870 | 0.625 | Uncertain | 1 | 6-33432245-G-A | 6 | 3.72e-6 | -1.711 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.037 | Likely Benign | 0.3018 | 0.2852 | -1.04 | Neutral | 0.006 | Benign | 0.001 | Benign | 4.04 | Benign | 0.02 | Affected | 3.74 | 4 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||
| c.380G>C | R127P 2D  AIThe SynGAP1 missense variant R127P is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster around a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign. In contrast, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default predict pathogenicity. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also favors a benign outcome. No Foldetta stability assessment is available, so it does not influence the interpretation. Overall, the preponderance of evidence points to a benign effect for R127P, 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 | 0.497853 | Structured | 0.711716 | Binding | 0.333 | 0.870 | 0.625 | -0.375 | Likely Benign | 0.703 | Likely Pathogenic | Likely Benign | 0.187 | Likely Benign | 0.2295 | 0.3741 | -2.25 | Neutral | 0.748 | Possibly Damaging | 0.110 | Benign | 3.92 | Benign | 0.01 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||
| c.380G>T | R127L 2D  AIThe SynGAP1 missense variant R127L 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 the majority vote from 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. Overall, the majority of evidence points to a benign impact. There is no ClinVar annotation to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.497853 | Structured | 0.711716 | Binding | 0.333 | 0.870 | 0.625 | -0.626 | Likely Benign | 0.643 | Likely Pathogenic | Likely Benign | 0.127 | Likely Benign | 0.1965 | 0.3834 | -2.02 | Neutral | 0.080 | Benign | 0.012 | Benign | 3.92 | Benign | 0.01 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||
| c.382C>A | P128T 2D AIThe SynGAP1 missense variant P128T is listed in ClinVar with an “Uncertain” status (ClinVar ID 2801315.0) and is present in gnomAD (ID 6‑33432247‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.497853 | Structured | 0.713069 | Binding | 0.376 | 0.878 | 0.625 | Uncertain | 1 | 6-33432247-C-A | 1 | 6.20e-7 | -4.217 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.075 | Likely Benign | 0.2023 | 0.4053 | -0.96 | Neutral | 0.952 | Possibly Damaging | 0.500 | Possibly Damaging | 4.19 | Benign | 0.35 | Tolerated | 3.74 | 4 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||
| c.382C>G | P128A 2D AIThe SynGAP1 missense variant P128A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence supports a benign classification for P128A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.497853 | Structured | 0.713069 | Binding | 0.376 | 0.878 | 0.625 | -3.677 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.068 | Likely Benign | 0.3890 | 0.3353 | -0.64 | Neutral | 0.580 | Possibly Damaging | 0.140 | Benign | 4.21 | Benign | 0.75 | Tolerated | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| c.382C>T | P128S 2D AIThe SynGAP1 missense variant P128S is reported in gnomAD (variant ID 6‑33432247‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags it as pathogenic, creating a single discordant prediction. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.497853 | Structured | 0.713069 | Binding | 0.376 | 0.878 | 0.625 | 6-33432247-C-T | 1 | 6.20e-7 | -3.234 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.084 | Likely Benign | 0.3893 | 0.3697 | -1.35 | Neutral | 0.734 | Possibly Damaging | 0.243 | Benign | 4.20 | Benign | 0.24 | Tolerated | 3.74 | 4 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||
| c.383C>A | P128H 2D AIThe SynGAP1 missense variant P128H is not reported 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, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates Likely Benign; Foldetta results are unavailable. 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 | 0.497853 | Structured | 0.713069 | Binding | 0.376 | 0.878 | 0.625 | -4.806 | Likely Benign | 0.564 | Ambiguous | Likely Benign | 0.169 | Likely Benign | 0.2207 | 0.3414 | -1.90 | Neutral | 0.996 | Probably Damaging | 0.750 | Possibly Damaging | 4.14 | Benign | 0.03 | Affected | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1810 | 0.2401 | -1.76 | Neutral | 0.984 | Probably Damaging | 0.601 | Possibly Damaging | 4.19 | Benign | 0.08 | Tolerated | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.383C>T | P128L 2D AIThe SynGAP1 missense variant P128L is catalogued in gnomAD (6‑33432248‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM‑Consensus also indicates a likely benign outcome; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar status (none is reported). Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.497853 | Structured | 0.713069 | Binding | 0.376 | 0.878 | 0.625 | 6-33432248-C-T | 1 | 6.20e-7 | -4.791 | Likely Benign | 0.541 | Ambiguous | Likely Benign | 0.087 | Likely Benign | 0.2548 | 0.5137 | -0.47 | Neutral | 0.952 | Possibly Damaging | 0.500 | Possibly Damaging | 4.20 | Benign | 0.38 | Tolerated | 3.74 | 4 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||
| c.385T>A | S129T 2D  AIThe SynGAP1 missense variant S129T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is that the variant is most likely benign, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.713635 | Binding | 0.311 | 0.880 | 0.625 | -4.296 | Likely Benign | 0.171 | Likely Benign | Likely Benign | 0.134 | Likely Benign | 0.1251 | 0.5794 | 0.12 | Neutral | 0.016 | Benign | 0.021 | Benign | 4.14 | Benign | 0.85 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.385T>C | S129P 2D  AIThe SynGAP1 missense variant S129P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of tools, including the high‑accuracy predictors, indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.713635 | Binding | 0.311 | 0.880 | 0.625 | -2.469 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.220 | Likely Benign | 0.1998 | 0.4989 | -0.09 | Neutral | 0.454 | Possibly Damaging | 0.133 | Benign | 4.11 | Benign | 0.32 | Tolerated | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.385T>G | S129A 2D  AIThe SynGAP1 missense variant S129A is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors—including REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as benign. No tool predicts pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.713635 | Binding | 0.311 | 0.880 | 0.625 | -3.388 | Likely Benign | 0.134 | Likely Benign | Likely Benign | 0.090 | Likely Benign | 0.5031 | 0.4619 | Weaken | -0.08 | Neutral | 0.007 | Benign | 0.007 | Benign | 4.21 | Benign | 0.15 | Tolerated | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||
| 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 | 0.0523 | 0.5471 | -1.49 | Neutral | 0.888 | Possibly Damaging | 0.367 | Benign | 4.06 | Benign | 0.01 | Affected | -2 | -3 | -0.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.386C>T | S129L 2D  AIThe SynGAP1 missense variant S129L is catalogued in gnomAD (ID 6‑33432251‑C‑T) 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) 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 scores benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors benign. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the preponderance of evidence indicates that S129L 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 | 0.517562 | Disordered | 0.713635 | Binding | 0.311 | 0.880 | 0.625 | 6-33432251-C-T | 1 | 6.20e-7 | -4.487 | Likely Benign | 0.456 | Ambiguous | Likely Benign | 0.256 | Likely Benign | 0.0885 | 0.5249 | -0.18 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.14 | Benign | 0.05 | Affected | 3.74 | 4 | -2 | -3 | 4.6 | 26.08 | ||||||||||||||||||||||||||||||
| c.388C>A | Q130K 2D  AIThe SynGAP1 missense variant Q130K is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around benign: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy predictors—AlphaMissense‑Optimized and the SGM‑Consensus—both support a benign classification, whereas the pathogenic predictions come from polyPhen‑2 alone. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.718853 | Binding | 0.306 | 0.885 | 0.375 | -4.656 | Likely Benign | 0.540 | Ambiguous | Likely Benign | 0.058 | Likely Benign | 0.2017 | 0.4473 | -0.41 | Neutral | 0.924 | Possibly Damaging | 0.857 | Possibly Damaging | 4.20 | Benign | 0.07 | Tolerated | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||
| c.388C>G | Q130E 2D  AIThe SynGAP1 missense variant Q130E is reported in gnomAD (ID 6‑33432685‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority of the same four tools) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple prediction algorithms indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.718853 | Binding | 0.306 | 0.885 | 0.375 | 6-33432685-C-G | 2 | 1.24e-6 | -4.283 | Likely Benign | 0.251 | Likely Benign | Likely Benign | 0.060 | Likely Benign | 0.1620 | 0.2587 | -0.72 | Neutral | 0.924 | Possibly Damaging | 0.857 | Possibly Damaging | 4.19 | Benign | 0.08 | Tolerated | 4.32 | 2 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.389A>C | Q130P 2D  AIThe SynGAP1 missense variant Q130P 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 predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.718853 | Binding | 0.306 | 0.885 | 0.375 | -0.659 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.213 | Likely Benign | 0.2414 | 0.4466 | -0.10 | Neutral | 0.990 | Probably Damaging | 0.954 | Probably Damaging | 4.15 | Benign | 0.03 | Affected | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||
| c.389A>G | Q130R 2D  AIThe SynGAP1 missense variant Q130R is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus also reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a benign impact. This conclusion is consistent with the absence of a ClinVar assertion, so there is no contradiction with existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.718853 | Binding | 0.306 | 0.885 | 0.375 | -4.043 | Likely Benign | 0.478 | Ambiguous | Likely Benign | 0.166 | Likely Benign | 0.1697 | 0.2343 | -0.32 | Neutral | 0.967 | Probably Damaging | 0.901 | Possibly Damaging | 4.21 | Benign | 0.05 | Affected | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||
| c.389A>T | Q130L 2D  AIThe SynGAP1 missense variant Q130L is not reported 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 Q130L, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.718853 | Binding | 0.306 | 0.885 | 0.375 | -3.643 | Likely Benign | 0.278 | Likely Benign | Likely Benign | 0.167 | Likely Benign | 0.0975 | 0.5286 | -1.63 | Neutral | 0.967 | Probably Damaging | 0.901 | Possibly Damaging | 4.11 | Benign | 0.02 | Affected | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||
| c.390A>C | Q130H 2D  AIThe SynGAP1 missense variant Q130H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, SGM‑Consensus also predicts likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.718853 | Binding | 0.306 | 0.885 | 0.375 | -3.828 | Likely Benign | 0.387 | Ambiguous | Likely Benign | 0.074 | Likely Benign | 0.1727 | 0.3970 | -1.09 | Neutral | 0.990 | Probably Damaging | 0.969 | Probably Damaging | 4.10 | Benign | 0.01 | Affected | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.390A>T | Q130H 2D AIThe SynGAP1 missense variant Q130H is not reported in ClinVar and has no entry in gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT each predict a pathogenic impact. The AlphaMissense‑Default tool remains uncertain, and no Foldetta stability assessment is available. High‑accuracy tools specifically highlight benign predictions: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta data are missing. Overall, the balance of evidence points to a benign effect for the variant, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.718853 | Binding | 0.306 | 0.885 | 0.375 | -3.828 | Likely Benign | 0.387 | Ambiguous | Likely Benign | 0.074 | Likely Benign | 0.1727 | 0.3970 | -1.09 | Neutral | 0.990 | Probably Damaging | 0.969 | Probably Damaging | 4.10 | Benign | 0.01 | Affected | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.391G>A | G131S 2D  AIThe SynGAP1 missense variant G131S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.724779 | Binding | 0.302 | 0.891 | 0.250 | -2.953 | Likely Benign | 0.337 | Likely Benign | Likely Benign | 0.039 | Likely Benign | 0.2823 | 0.5338 | -2.75 | Deleterious | 0.115 | Benign | 0.026 | Benign | 4.10 | Benign | 0.02 | Affected | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1070 | 0.4667 | -3.82 | Deleterious | 0.983 | Probably Damaging | 0.656 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 3.61 | 5 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||
| c.391G>T | G131C 2D  AIThe SynGAP1 missense variant G131C 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, FATHMM, and AlphaMissense‑Optimized, whereas those that predict pathogenicity are PROVEAN, 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, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus again indicates Likely Pathogenic; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of tools predict pathogenicity, and this aligns with the SGM Consensus. Therefore, the variant is most likely pathogenic based on the available predictions, and this conclusion is consistent with the lack of ClinVar reporting rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.429200 | Structured | 0.724779 | Binding | 0.302 | 0.891 | 0.250 | -8.288 | Likely Pathogenic | 0.727 | Likely Pathogenic | Likely Benign | 0.155 | Likely Benign | 0.1339 | 0.4356 | -4.42 | Deleterious | 0.998 | Probably Damaging | 0.840 | Possibly Damaging | 3.88 | Benign | 0.00 | Affected | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||
| 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 | 0.2093 | 0.2550 | -3.29 | Deleterious | 0.888 | Possibly Damaging | 0.435 | Benign | 3.92 | Benign | 0.02 | Affected | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||
| c.392G>C | G131A 2D  AIThe SynGAP1 missense variant G131A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign. Foldetta results are unavailable. Overall, the majority of evidence (5 benign vs 3 pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.724779 | Binding | 0.302 | 0.891 | 0.250 | -4.891 | Likely Benign | 0.512 | Ambiguous | Likely Benign | 0.138 | Likely Benign | 0.3981 | 0.4814 | -2.96 | Deleterious | 0.620 | Possibly Damaging | 0.157 | Benign | 3.99 | Benign | 0.01 | Affected | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.392G>T | G131V 2D  AIThe SynGAP1 missense variant G131V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a tie and is therefore unavailable, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no result for this variant. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict any existing ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.724779 | Binding | 0.302 | 0.891 | 0.250 | -6.248 | Likely Benign | 0.795 | Likely Pathogenic | Ambiguous | 0.199 | Likely Benign | 0.1168 | 0.4175 | -4.25 | Deleterious | 0.983 | Probably Damaging | 0.559 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||
| c.394T>A | F132I 2D AISynGAP1 missense variant F132I is not 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic, two benign) and Foldetta results are unavailable. Because the majority of consensus tools predict benign and no ClinVar evidence contradicts this, the variant is most likely benign, although the pathogenic signal from AlphaMissense‑Optimized and the inconclusive SGM Consensus leave some uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.450668 | Structured | 0.727897 | Binding | 0.345 | 0.892 | 0.250 | -6.245 | Likely Benign | 0.974 | Likely Pathogenic | Likely Pathogenic | 0.211 | Likely Benign | 0.2306 | 0.1698 | -3.23 | Deleterious | 0.084 | Benign | 0.020 | Benign | 3.36 | Benign | 0.00 | Affected | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||||||||
| c.394T>C | F132L 2D AIThe SynGAP1 missense variant F132L is not reported in ClinVar (status: none) but is present in gnomAD (ID 6‑33432691‑T‑C). 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs 2 benign), and Foldetta (combining FoldX‑MD and Rosetta) has no available output. Overall, the majority of consensus tools lean toward a benign interpretation, and the single high‑accuracy pathogenic prediction is counterbalanced by inconclusive consensus and missing folding‑stability data. Thus, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.450668 | Structured | 0.727897 | Binding | 0.345 | 0.892 | 0.250 | 6-33432691-T-C | -5.401 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.165 | Likely Benign | 0.2564 | 0.2669 | -2.99 | Deleterious | 0.000 | Benign | 0.002 | Benign | 3.46 | Benign | 0.00 | Affected | 3.61 | 5 | 0 | 2 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||
| c.394T>G | F132V 2D AIThe SynGAP1 missense variant F132V is not 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 agree on a pathogenic effect are PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑confidence predictions indicate a pathogenic effect, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.450668 | Structured | 0.727897 | Binding | 0.345 | 0.892 | 0.250 | -7.637 | In-Between | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.328 | Likely Benign | 0.2349 | 0.1725 | -3.86 | Deleterious | 0.084 | Benign | 0.034 | Benign | 3.38 | Benign | 0.00 | Affected | -1 | -1 | 1.4 | -48.04 | ||||||||||||||||||||||||||||||||||||
| c.395T>A | F132Y 2D AIThe SynGAP1 missense variant F132Y is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, the majority of available predictions (five benign vs three pathogenic) suggest a benign impact. This consensus does not contradict any ClinVar annotation, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.450668 | Structured | 0.727897 | Binding | 0.345 | 0.892 | 0.250 | -8.220 | Likely Pathogenic | 0.839 | Likely Pathogenic | Ambiguous | 0.165 | Likely Benign | 0.1635 | 0.1526 | -1.98 | Neutral | 0.272 | Benign | 0.126 | Benign | 3.39 | Benign | 0.00 | Affected | 7 | 3 | -4.1 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.395T>C | F132S 2D AIThe SynGAP1 missense variant F132S is not 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. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the balance of evidence (five pathogenic vs four benign predictions) indicates that 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. | 0.450668 | Structured | 0.727897 | Binding | 0.345 | 0.892 | 0.250 | -4.177 | Likely Benign | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.329 | Likely Benign | 0.4869 | 0.0000 | -4.54 | Deleterious | 0.567 | Possibly Damaging | 0.249 | Benign | 3.31 | Benign | 0.00 | Affected | -3 | -2 | -3.6 | -60.10 | ||||||||||||||||||||||||||||||||||||
| c.395T>G | F132C 2D AIThe SynGAP1 missense variant F132C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Pathogenic” based on a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (derived from the four high‑accuracy predictors) also indicates likely pathogenic. Foldetta results are unavailable. 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 | 0.450668 | Structured | 0.727897 | Binding | 0.345 | 0.892 | 0.250 | -10.013 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.331 | Likely Benign | 0.2677 | 0.0925 | -4.55 | Deleterious | 0.938 | Possibly Damaging | 0.498 | Possibly Damaging | 3.29 | Benign | 0.00 | Affected | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||||||||
| c.396C>A | F132L 2D AIThe SynGAP1 missense variant F132L is not 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from 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 tools (AlphaMissense‑Optimized and AlphaMissense‑Default) both predict pathogenicity, while the consensus and stability analyses are inconclusive or missing. Overall, the majority of individual predictors and the high‑accuracy tools lean toward a pathogenic effect, 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. | 0.450668 | Structured | 0.727897 | Binding | 0.345 | 0.892 | 0.250 | -5.401 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.137 | Likely Benign | 0.2564 | 0.2669 | -2.99 | Deleterious | 0.000 | Benign | 0.002 | Benign | 3.46 | Benign | 0.00 | Affected | 3.61 | 5 | 0 | 2 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||
| c.396C>G | F132L 2D AIThe SynGAP1 missense variant F132L is not 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from 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 tools (AlphaMissense‑Optimized and AlphaMissense‑Default) both predict pathogenicity, whereas the consensus and stability analyses are inconclusive or missing. Overall, the majority of individual predictors and the two high‑accuracy tools suggest a pathogenic effect, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.450668 | Structured | 0.727897 | Binding | 0.345 | 0.892 | 0.250 | -5.401 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.137 | Likely Benign | 0.2564 | 0.2669 | -2.99 | Deleterious | 0.000 | Benign | 0.002 | Benign | 3.46 | Benign | 0.00 | Affected | 3.61 | 5 | 0 | 2 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||
| c.397C>A | L133M 2D  AIThe SynGAP1 missense variant L133M is not 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, and AlphaMissense‑Default; ESM1b and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta results are unavailable. Overall, the majority of standard predictors (four pathogenic vs. three benign) indicate a pathogenic impact, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.422041 | Structured | 0.718429 | Binding | 0.320 | 0.896 | 0.250 | -7.993 | In-Between | 0.841 | Likely Pathogenic | Ambiguous | 0.095 | Likely Benign | 0.0856 | 0.2229 | -0.77 | Neutral | 0.877 | Possibly Damaging | 0.580 | Possibly Damaging | 3.57 | Benign | 0.03 | Affected | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||
| c.397C>G | L133V 2D  AIThe SynGAP1 missense variant L133V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are limited: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign votes); Foldetta results are unavailable. Overall, the majority of evidence (five benign vs. three pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.422041 | Structured | 0.718429 | Binding | 0.320 | 0.896 | 0.250 | -8.429 | Likely Pathogenic | 0.848 | Likely Pathogenic | Ambiguous | 0.082 | Likely Benign | 0.1561 | 0.1883 | -1.27 | Neutral | 0.247 | Benign | 0.163 | Benign | 3.61 | Benign | 0.03 | Affected | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.398T>A | L133Q 2D  AIThe SynGAP1 missense variant L133Q 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 | 0.422041 | Structured | 0.718429 | Binding | 0.320 | 0.896 | 0.250 | -9.054 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.317 | Likely Benign | 0.1316 | 0.0879 | -2.65 | Deleterious | 0.535 | Possibly Damaging | 0.259 | Benign | 3.53 | Benign | 0.01 | Affected | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||
| c.398T>C | L133P 2D  AIThe SynGAP1 missense variant L133P is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. ESM1b remains uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic), yields a pathogenic consensus. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.422041 | Structured | 0.718429 | Binding | 0.320 | 0.896 | 0.250 | -7.744 | In-Between | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.342 | Likely Benign | 0.3270 | 0.1048 | -3.16 | Deleterious | 0.700 | Possibly Damaging | 0.483 | Possibly Damaging | 3.52 | Benign | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||
| c.398T>G | L133R 2D  AIThe SynGAP1 missense variant L133R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome (3 pathogenic vs. 1 benign votes). 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 majority of computational evidence supports a pathogenic classification for L133R, and this assessment 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 | 0.422041 | Structured | 0.718429 | Binding | 0.320 | 0.896 | 0.250 | -8.857 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.389 | Likely Benign | 0.1522 | 0.0479 | -2.57 | Deleterious | 0.002 | Benign | 0.005 | Benign | 3.55 | Benign | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0719 | 0.3528 | -2.54 | Deleterious | 0.380 | Benign | 0.147 | Benign | 3.84 | Benign | 0.00 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||
| c.400A>G | S134G 2D  AIThe SynGAP1 missense variant S134G 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) is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yielding a “Likely Benign” classification. 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 preponderance of evidence from multiple independent predictors and the high‑accuracy consensus indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.447574 | Structured | 0.695837 | Binding | 0.333 | 0.898 | 0.250 | -6.722 | Likely Benign | 0.457 | Ambiguous | Likely Benign | 0.120 | Likely Benign | 0.2268 | 0.4008 | -2.19 | Neutral | 0.034 | Benign | 0.035 | Benign | 3.84 | Benign | 0.00 | Affected | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.400A>T | S134C 2D  AIThe SynGAP1 missense variant S134C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen2_HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen2_HumDiv, 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 results are unavailable. Overall, the majority of tools and the consensus prediction lean toward pathogenicity, which is not contradicted by ClinVar (no entry) but is opposed by the AlphaMissense‑Optimized benign call. 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 | -9.184 | Likely Pathogenic | 0.774 | Likely Pathogenic | Likely Benign | 0.247 | Likely Benign | 0.0767 | 0.5151 | -3.12 | Deleterious | 0.876 | Possibly Damaging | 0.417 | Benign | 3.79 | Benign | 0.00 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.401G>A | S134N 2D  AIThe SynGAP1 missense variant S134N is listed in ClinVar with an “Uncertain” status (ClinVar ID 2819575.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Those that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The remaining tools—AlphaMissense‑Optimized and the SGM‑Consensus—are inconclusive; the consensus score is “Likely Benign” based on a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta) has no available result. Overall, the balance of evidence points to a benign impact, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.447574 | Structured | 0.695837 | Binding | 0.333 | 0.898 | 0.250 | Uncertain | 1 | -5.534 | Likely Benign | 0.813 | Likely Pathogenic | Ambiguous | 0.075 | Likely Benign | 0.0964 | 0.4381 | -1.62 | Neutral | 0.001 | Benign | 0.002 | Benign | 3.90 | Benign | 0.00 | Affected | 3.61 | 5 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||
| c.401G>C | S134T 2D AIThe SynGAP1 missense variant S134T is listed in gnomAD (ID 6‑33432698‑G‑C) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact; this conclusion is not contradicted by ClinVar, which contains no classification for S134T. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.447574 | Structured | 0.695837 | Binding | 0.333 | 0.898 | 0.250 | 6-33432698-G-C | 1 | 6.32e-7 | -5.187 | Likely Benign | 0.563 | Ambiguous | Likely Benign | 0.069 | Likely Benign | 0.1083 | 0.5326 | -1.76 | Neutral | 0.034 | Benign | 0.047 | Benign | 3.85 | Benign | 0.00 | Affected | 3.61 | 5 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||
| c.401G>T | S134I 2D  AIThe SynGAP1 missense variant S134I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. 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 | -8.860 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.230 | Likely Benign | 0.0683 | 0.5191 | -3.27 | Deleterious | 0.041 | Benign | 0.031 | Benign | 3.81 | Benign | 0.00 | Affected | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0719 | 0.3528 | -2.54 | Deleterious | 0.380 | Benign | 0.147 | Benign | 3.84 | Benign | 0.00 | Affected | 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 | 0.0719 | 0.3528 | -2.54 | Deleterious | 0.380 | Benign | 0.147 | Benign | 3.84 | Benign | 0.00 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||
| c.403C>G | R135G 2D AIThe SynGAP1 missense variant R135G is not reported in ClinVar and is absent from gnomAD. Consensus from standard in silico predictors shows a split: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM, while pathogenic calls come from PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments give a pathogenic result from AlphaMissense‑Optimized, an inconclusive SGM Consensus (a 2‑vs‑2 vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and no Foldetta data. Because the majority of tools predict benign and the high‑accuracy methods are either pathogenic or inconclusive, the overall evidence leans toward a benign effect. This conclusion does not conflict with the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.465241 | Structured | 0.676514 | Binding | 0.380 | 0.898 | 0.250 | -5.799 | Likely Benign | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.240 | Likely Benign | 0.3559 | 0.3273 | -3.17 | Deleterious | 0.000 | Benign | 0.000 | Benign | 3.69 | Benign | 0.01 | Affected | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||
| c.404G>A | R135Q 2D AIThe SynGAP1 missense variant R135Q is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33432701‑G‑A). Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; pathogenic predictions come from SIFT, ESM1b, and AlphaMissense‑Default. The remaining high‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑to‑2 tie, and Foldetta stability analysis is not available. Overall, the balance of evidence favors a benign effect, and this conclusion does not conflict with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.465241 | Structured | 0.676514 | Binding | 0.380 | 0.898 | 0.250 | Uncertain | 1 | 6-33432701-G-A | 5 | 3.84e-6 | -8.011 | Likely Pathogenic | 0.853 | Likely Pathogenic | Ambiguous | 0.087 | Likely Benign | 0.3153 | 0.2741 | -1.94 | Neutral | 0.327 | Benign | 0.100 | Benign | 3.76 | Benign | 0.02 | Affected | 3.61 | 5 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||||
| c.404G>C | R135P 2D AIThe SynGAP1 missense variant R135P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. In silico predictors that classify the variant as benign include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy tools give a pathogenic signal: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic; Foldetta results are unavailable. Overall, the majority of predictions (seven pathogenic vs. three benign) indicate that the variant is most likely pathogenic, and this assessment is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.465241 | Structured | 0.676514 | Binding | 0.380 | 0.898 | 0.250 | -9.512 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.139 | Likely Benign | 0.2052 | 0.4535 | -3.19 | Deleterious | 0.609 | Possibly Damaging | 0.308 | Benign | 3.68 | Benign | 0.01 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||
| c.404G>T | R135L 2D AIThe SynGAP1 missense variant R135L is not 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 agree on a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. The high‑accuracy assessment shows AlphaMissense‑Optimized predicts pathogenicity. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic), also indicates pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions, including the high‑accuracy tools, support a pathogenic 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. | 0.465241 | Structured | 0.676514 | Binding | 0.380 | 0.898 | 0.250 | -7.372 | In-Between | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.164 | Likely Benign | 0.1962 | 0.4727 | -3.61 | Deleterious | 0.308 | Benign | 0.122 | Benign | 3.70 | Benign | 0.01 | Affected | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||||
| c.406C>G | R136G 2D AIThe SynGAP1 missense variant R136G is not reported in ClinVar and is absent from gnomAD. Consensus from standard in‑silico predictors shows a split: benign calls come from REVEL, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic calls arise from PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.433034 | Structured | 0.657394 | Binding | 0.351 | 0.894 | 0.250 | -10.641 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.246 | Likely Benign | 0.3581 | 0.3585 | -3.46 | Deleterious | 0.487 | Possibly Damaging | 0.211 | Benign | 3.47 | Benign | 0.00 | Affected | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||
| c.406C>T | R136W 2D AIThe SynGAP1 missense variant R136W is listed in ClinVar (ID 1479441.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, 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 a deleterious effect, 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 impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.433034 | Structured | 0.657394 | Binding | 0.351 | 0.894 | 0.250 | Uncertain | 2 | -10.453 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.237 | Likely Benign | 0.1189 | 0.3827 | -4.71 | Deleterious | 0.965 | Probably Damaging | 0.416 | Benign | 3.45 | Benign | 0.00 | Affected | 3.61 | 5 | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||
| c.407G>A | R136Q 2D AIThe SynGAP1 R136Q variant is listed in ClinVar as benign and is present in gnomAD (6‑33432704‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized returns an uncertain result. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive due to a 2‑vs‑2 split, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no reported result for this variant. Based on the available predictions, the variant is most likely benign, which aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.433034 | Structured | 0.657394 | Binding | 0.351 | 0.894 | 0.250 | Benign | 1 | 6-33432704-G-A | 13 | 9.17e-6 | -11.146 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.190 | Likely Benign | 0.3171 | 0.2460 | -2.26 | Neutral | 0.957 | Probably Damaging | 0.342 | Benign | 3.52 | Benign | 0.01 | Affected | 3.61 | 5 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||||
| c.407G>C | R136P 2D AIThe SynGAP1 missense variant R136P is listed in ClinVar (ID 579340.0) with an “Uncertain” status 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—predict a pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates 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 points to a pathogenic effect, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.433034 | Structured | 0.657394 | Binding | 0.351 | 0.894 | 0.250 | Uncertain | 1 | -11.952 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.277 | Likely Benign | 0.2063 | 0.4426 | -3.72 | Deleterious | 0.910 | Possibly Damaging | 0.578 | Possibly Damaging | 3.47 | Benign | 0.00 | Affected | 3.61 | 5 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||
| c.407G>T | R136L 2D AIThe SynGAP1 missense variant R136L is catalogued in gnomAD (ID 6‑33432704‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; pathogenic predictions arise from PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, and the SGM‑Consensus (majority vote) also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a pathogenic impact, and this assessment does not conflict with ClinVar, which currently has no classification for R136L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.433034 | Structured | 0.657394 | Binding | 0.351 | 0.894 | 0.250 | 6-33432704-G-T | 1 | 7.05e-7 | -11.512 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.347 | Likely Benign | 0.1718 | 0.4475 | -4.19 | Deleterious | 0.190 | Benign | 0.037 | Benign | 3.48 | Benign | 0.01 | Affected | 3.61 | 5 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||
| c.409C>A | L137I 2D  AIThe SynGAP1 missense variant L137I is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM. Tools that agree on a pathogenic effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign), and Foldetta results are unavailable. Overall, the majority of predictions (5 pathogenic vs. 3 benign) indicate a likely pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant has no existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.553315 | Disordered | 0.639549 | Binding | 0.377 | 0.897 | 0.375 | -8.870 | Likely Pathogenic | 0.914 | Likely Pathogenic | Ambiguous | 0.113 | Likely Benign | 0.0932 | 0.3102 | -1.22 | Neutral | 0.993 | Probably Damaging | 0.967 | Probably Damaging | 3.73 | Benign | 0.00 | Affected | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||||||||
| c.409C>G | L137V 2D AIThe SynGAP1 missense variant L137V is not 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 predict a pathogenic effect are 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 (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑confidence predictors (six out of nine) indicate a pathogenic impact, whereas three predict benign. Thus, 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. | 0.553315 | Disordered | 0.639549 | Binding | 0.377 | 0.897 | 0.375 | -8.621 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 0.118 | Likely Benign | 0.1533 | 0.2612 | -1.75 | Neutral | 0.993 | Probably Damaging | 0.967 | Probably Damaging | 3.73 | Benign | 0.00 | Affected | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.410T>A | L137Q 2D AIThe SynGAP1 missense variant L137Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM. All other evaluated algorithms—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled “Likely Pathogenic.” The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of 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 | 0.553315 | Disordered | 0.639549 | Binding | 0.377 | 0.897 | 0.375 | -12.246 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.356 | Likely Benign | 0.1137 | 0.1049 | -3.43 | Deleterious | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 3.60 | Benign | 0.00 | Affected | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||
| c.410T>C | L137P 2D AIThe SynGAP1 missense variant L137P 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—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 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 indicates it is likely pathogenic. The Foldetta protein‑folding stability analysis is unavailable 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 | 0.553315 | Disordered | 0.639549 | Binding | 0.377 | 0.897 | 0.375 | -11.067 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.377 | Likely Benign | 0.3620 | 0.1177 | -3.77 | Deleterious | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 3.59 | Benign | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||
| c.410T>G | L137R 2D AIThe SynGAP1 missense variant L137R is not 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. All other evaluated 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)—predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. 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 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 | 0.553315 | Disordered | 0.639549 | Binding | 0.377 | 0.897 | 0.375 | -11.595 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.334 | Likely Benign | 0.1300 | 0.0691 | -3.50 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 3.60 | Benign | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||
| c.412A>C | K138Q 2D  AIThe SynGAP1 missense variant K138Q is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments are mixed: AlphaMissense‑Optimized predicts pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of tools (five pathogenic vs. four benign) indicate a pathogenic impact. There is no ClinVar entry to contradict this assessment, so the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.590140 | Disordered | 0.619482 | Binding | 0.349 | 0.901 | 0.375 | -8.122 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.173 | Likely Benign | 0.4171 | 0.1272 | -2.15 | Neutral | 0.700 | Possibly Damaging | 0.310 | Benign | 3.58 | Benign | 0.01 | Affected | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||||||||
| c.412A>G | K138E 2D  AIThe SynGAP1 missense variant K138E is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 vs 2). AlphaMissense‑Optimized specifically predicts pathogenicity, while Foldetta (combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the majority of predictions lean toward a benign outcome (5 benign vs 4 pathogenic), 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. | 0.590140 | Disordered | 0.619482 | Binding | 0.349 | 0.901 | 0.375 | -11.902 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.212 | Likely Benign | 0.3611 | 0.0974 | -2.13 | Neutral | 0.247 | Benign | 0.125 | Benign | 3.60 | Benign | 0.01 | Affected | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||||||||
| c.413A>C | K138T 2D  AIThe SynGAP1 missense variant K138T is not 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, 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 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of predictions lean toward a benign impact, with no high‑accuracy consensus supporting pathogenicity. Thus, the variant is most likely benign based on current computational evidence, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.590140 | Disordered | 0.619482 | Binding | 0.349 | 0.901 | 0.375 | -5.143 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.195 | Likely Benign | 0.1940 | 0.2806 | -3.45 | Deleterious | 0.141 | Benign | 0.123 | Benign | 3.56 | Benign | 0.01 | Affected | 0 | -1 | 3.2 | -27.07 | ||||||||||||||||||||||||||||||||||||
| c.413A>G | K138R 2D  AIThe SynGAP1 missense variant K138R 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 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate 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, classifies the variant as Likely Benign. High‑accuracy assessments further support this view: AlphaMissense‑Optimized reports a benign effect, and the SGM‑Consensus likewise indicates Likely Benign; Foldetta results are unavailable. Taken together, the preponderance of evidence points to a benign impact for K138R, and this conclusion does not conflict with the absence of a ClinVar assertion. 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. | Likely Benign | 0.590140 | Disordered | 0.619482 | Binding | 0.349 | 0.901 | 0.375 | -5.135 | Likely Benign | 0.406 | Ambiguous | Likely Benign | 0.115 | Likely Benign | 0.4555 | 0.1036 | -1.58 | Neutral | 0.247 | Benign | 0.163 | Benign | 3.66 | Benign | 0.02 | Affected | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||||||||
| c.413A>T | K138I 2D  AIThe SynGAP1 missense variant K138I is not 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 outcome: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.590140 | Disordered | 0.619482 | Binding | 0.349 | 0.901 | 0.375 | -9.366 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.295 | Likely Benign | 0.1003 | 0.3054 | -4.74 | Deleterious | 0.535 | Possibly Damaging | 0.259 | Benign | 3.53 | Benign | 0.00 | Affected | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||||||||||||
| c.414A>C | K138N 2D  AIThe SynGAP1 missense variant K138N is not 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. The remaining tool, ESM1b, yields an uncertain result. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors pathogenicity. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that K138N is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.590140 | Disordered | 0.619482 | Binding | 0.349 | 0.901 | 0.375 | -7.920 | In-Between | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.093 | Likely Benign | 0.3438 | 0.1627 | -2.77 | Deleterious | 0.700 | Possibly Damaging | 0.310 | Benign | 3.56 | Benign | 0.01 | Affected | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||
| c.414A>T | K138N 2D AIThe SynGAP1 missense variant K138N is not 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. The remaining tool, ESM1b, yields an uncertain result. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors pathogenicity. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that K138N is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.590140 | Disordered | 0.619482 | Binding | 0.349 | 0.901 | 0.375 | -7.920 | In-Between | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.093 | Likely Benign | 0.3438 | 0.1627 | -2.77 | Deleterious | 0.700 | Possibly Damaging | 0.310 | Benign | 3.56 | Benign | 0.01 | Affected | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||
| 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 | 0.1004 | 0.2971 | -2.07 | Neutral | 0.380 | Benign | 0.136 | Benign | 4.16 | Benign | 0.12 | Tolerated | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| c.415A>G | S139G 2D AIThe SynGAP1 missense variant S139G is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool predicts pathogenicity. The high‑accuracy consensus, SGM‑Consensus, also reports the variant as Likely Benign, and AlphaMissense‑Optimized confirms a benign prediction. Foldetta, a protein‑folding stability method, has no available result for this variant. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.553315 | Disordered | 0.600637 | Binding | 0.353 | 0.900 | 0.250 | 1.647 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.116 | Likely Benign | 0.2712 | 0.3414 | 1.29 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.29 | Benign | 1.00 | Tolerated | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.415A>T | S139C 2D AIThe SynGAP1 missense variant S139C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority of the four high‑accuracy tools) also yields benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that the S139C variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.553315 | Disordered | 0.600637 | Binding | 0.353 | 0.900 | 0.250 | -6.964 | Likely Benign | 0.689 | Likely Pathogenic | Likely Benign | 0.087 | Likely Benign | 0.1273 | 0.4546 | -2.43 | Neutral | 0.876 | Possibly Damaging | 0.319 | Benign | 4.07 | Benign | 0.06 | Tolerated | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.416G>A | S139N 2D AIThe SynGAP1 missense variant S139N is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33432713‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.553315 | Disordered | 0.600637 | Binding | 0.353 | 0.900 | 0.250 | Uncertain | 1 | 6-33432713-G-A | 3 | 2.22e-6 | -4.584 | Likely Benign | 0.688 | Likely Pathogenic | Likely Benign | 0.109 | Likely Benign | 0.1526 | 0.3614 | -0.75 | Neutral | 0.149 | Benign | 0.047 | Benign | 4.14 | Benign | 0.24 | Tolerated | 3.61 | 5 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||
| c.416G>C | S139T 2D AIThe SynGAP1 missense variant S139T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The high‑accuracy consensus (SGM‑Consensus) also indicates a likely benign classification, and AlphaMissense‑Optimized independently predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the majority of computational evidence supports a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.553315 | Disordered | 0.600637 | Binding | 0.353 | 0.900 | 0.250 | -4.518 | Likely Benign | 0.463 | Ambiguous | Likely Benign | 0.122 | Likely Benign | 0.1655 | 0.4416 | -1.70 | Neutral | 0.034 | Benign | 0.023 | Benign | 4.13 | Benign | 0.25 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.416G>T | S139I 2D AIThe SynGAP1 missense variant S139I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; pathogenic predictions come from PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy tools points to a pathogenic effect. This conclusion is consistent with the absence of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.553315 | Disordered | 0.600637 | Binding | 0.353 | 0.900 | 0.250 | -9.228 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.203 | Likely Benign | 0.0948 | 0.4796 | -3.36 | Deleterious | 0.380 | Benign | 0.102 | Benign | 4.09 | Benign | 0.03 | Affected | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1004 | 0.2971 | -2.07 | Neutral | 0.380 | Benign | 0.136 | Benign | 4.16 | Benign | 0.12 | Tolerated | 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 | 0.1004 | 0.2971 | -2.07 | Neutral | 0.380 | Benign | 0.136 | Benign | 4.16 | Benign | 0.12 | Tolerated | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| c.418T>A | S140T 2D AIThe SynGAP1 missense variant S140T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, whereas the SGM‑Consensus (majority vote) remains Likely Benign. Foldetta predictions are unavailable. Overall, the balance of evidence, particularly the SGM‑Consensus and the majority of benign‑predicting tools, suggests that the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.476583 | Structured | 0.587898 | Binding | 0.321 | 0.896 | 0.625 | -6.336 | Likely Benign | 0.873 | Likely Pathogenic | Ambiguous | 0.132 | Likely Benign | 0.1069 | 0.5722 | -1.94 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 3.59 | Benign | 0.03 | Affected | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.418T>C | S140P 2D AIThe SynGAP1 missense variant S140P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools specifically show AlphaMissense‑Optimized as pathogenic, while SGM Consensus and Foldetta are unavailable. Overall, the majority of evidence points to a pathogenic impact for S140P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.476583 | Structured | 0.587898 | Binding | 0.321 | 0.896 | 0.625 | -4.089 | Likely Benign | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.287 | Likely Benign | 0.1726 | 0.5117 | -2.59 | Deleterious | 0.995 | Probably Damaging | 0.979 | Probably Damaging | 3.52 | Benign | 0.08 | Tolerated | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||||
| c.418T>G | S140A 2D AIThe SynGAP1 missense variant S140A is not 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. The high‑accuracy AlphaMissense‑Optimized tool rates the variant as uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split; Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs. three benign) indicate a pathogenic impact. There is no ClinVar entry to contradict this assessment, so 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. | 0.476583 | Structured | 0.587898 | Binding | 0.321 | 0.896 | 0.625 | -9.068 | Likely Pathogenic | 0.805 | Likely Pathogenic | Ambiguous | 0.141 | Likely Benign | 0.4449 | 0.4320 | -1.83 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 3.62 | Benign | 0.05 | Affected | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||
| 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 | 0.0597 | 0.5849 | -3.88 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 3.48 | Benign | 0.00 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||
| c.419C>G | S140C 2D AIThe SynGAP1 missense variant S140C 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 S140C 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 | -10.103 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.170 | Likely Benign | 0.0811 | 0.5709 | -3.11 | Deleterious | 0.999 | Probably Damaging | 0.990 | Probably Damaging | 3.49 | Benign | 0.01 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0565 | 0.5988 | -3.83 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 3.48 | Benign | 0.00 | Affected | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||
| c.421A>C | I141L 2D  AIThe SynGAP1 missense variant I141L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Only AlphaMissense‑Default predicts a pathogenic outcome, while AlphaMissense‑Optimized is uncertain. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) is not available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.465241 | Structured | 0.577021 | Binding | 0.367 | 0.877 | 0.500 | -6.563 | Likely Benign | 0.787 | Likely Pathogenic | Ambiguous | 0.156 | Likely Benign | 0.0742 | 0.3180 | -1.00 | Neutral | 0.016 | Benign | 0.013 | Benign | 3.84 | Benign | 0.10 | Tolerated | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||
| c.421A>G | I141V 2D  AIThe SynGAP1 I141V missense variant is catalogued in gnomAD (ID 6‑33432718‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM) and pathogenic (SIFT, AlphaMissense‑Default). The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome. Foldetta, a protein‑folding stability predictor that integrates FoldX‑MD and Rosetta outputs, has no reported result for this variant. Overall, the preponderance of evidence points to a benign effect, and this assessment aligns with the lack of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.465241 | Structured | 0.577021 | Binding | 0.367 | 0.877 | 0.500 | 6-33432718-A-G | 1 | 6.42e-7 | -4.030 | Likely Benign | 0.785 | Likely Pathogenic | Ambiguous | 0.125 | Likely Benign | 0.1101 | 0.3464 | -0.58 | Neutral | 0.016 | Benign | 0.021 | Benign | 3.74 | Benign | 0.03 | Affected | 3.61 | 5 | 3 | 4 | -0.3 | -14.03 | ||||||||||||||||||||||||||||||
| c.421A>T | I141F 2D  AIThe SynGAP1 missense variant I141F is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2). Foldetta results are unavailable. Overall, the balance of evidence slightly favors a benign interpretation, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.465241 | Structured | 0.577021 | Binding | 0.367 | 0.877 | 0.500 | -9.621 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.221 | Likely Benign | 0.0489 | 0.2775 | -1.82 | Neutral | 0.001 | Benign | 0.002 | Benign | 3.57 | Benign | 0.01 | Affected | 1 | 0 | -1.7 | 34.02 | ||||||||||||||||||||||||||||||||||||
| c.422T>A | I141N 2D  AIThe SynGAP1 missense variant I141N is not reported in ClinVar and is absent from gnomAD. Consensus from standard prediction algorithms shows a split: benign predictions come from REVEL, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic. Foldetta stability analysis is unavailable. Overall, the majority of evidence points toward a pathogenic impact for I141N. 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 | 0.465241 | Structured | 0.577021 | Binding | 0.367 | 0.877 | 0.500 | -12.417 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.258 | Likely Benign | 0.1047 | 0.0270 | -3.90 | Deleterious | 0.799 | Possibly Damaging | 0.424 | Benign | 3.54 | Benign | 0.00 | Affected | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||||||||
| c.422T>C | I141T 2D  AIThe SynGAP1 missense variant I141T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote) also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant, so its contribution is unavailable. Overall, the majority of computational evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.465241 | Structured | 0.577021 | Binding | 0.367 | 0.877 | 0.500 | -10.580 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.251 | Likely Benign | 0.1165 | 0.1214 | -2.81 | Deleterious | 0.272 | Benign | 0.167 | Benign | 3.57 | Benign | 0.00 | Affected | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||||||||
| c.422T>G | I141S 2D  AIThe SynGAP1 missense variant I141S 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, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus also as Likely Pathogenic; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points toward a pathogenic impact for I141S, 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 | 0.465241 | Structured | 0.577021 | Binding | 0.367 | 0.877 | 0.500 | -11.874 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.267 | Likely Benign | 0.2885 | 0.0840 | -3.28 | Deleterious | 0.567 | Possibly Damaging | 0.249 | Benign | 3.56 | Benign | 0.00 | Affected | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||||||||
| c.423C>G | I141M 2D  AIThe SynGAP1 I141M variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, whereas the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the predictions are mixed, with an equal split between benign and pathogenic calls and no definitive evidence from Foldetta. Thus, the variant is most likely benign based on the current computational evidence, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.465241 | Structured | 0.577021 | Binding | 0.367 | 0.877 | 0.500 | -7.437 | In-Between | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.112 | Likely Benign | 0.0664 | 0.2661 | -1.54 | Neutral | 0.567 | Possibly Damaging | 0.332 | Benign | 3.57 | Benign | 0.01 | Affected | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||||||||||||
| c.424A>C | K142Q 2D AIThe SynGAP1 missense variant K142Q 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 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 pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. No Foldetta stability analysis is available for this variant. Overall, the preponderance of computational evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.461924 | Structured | 0.558796 | Binding | 0.374 | 0.859 | 0.500 | -11.295 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.191 | Likely Benign | 0.4232 | 0.1132 | -2.50 | Deleterious | 0.700 | Possibly Damaging | 0.383 | Benign | 3.50 | Benign | 0.00 | Affected | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||
| c.424A>G | K142E 2D AIThe SynGAP1 missense variant K142E is not reported in ClinVar (no ClinVar entry) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. 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 Pathogenic, and the SGM‑Consensus (majority vote) also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions point to a pathogenic effect, 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 | 0.461924 | Structured | 0.558796 | Binding | 0.374 | 0.859 | 0.500 | -14.450 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.249 | Likely Benign | 0.3644 | 0.0952 | -2.59 | Deleterious | 0.247 | Benign | 0.125 | Benign | 3.49 | Benign | 0.00 | Affected | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||||
| c.425A>C | K142T 2D AIThe SynGAP1 missense variant K142T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, 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; Foldetta results are unavailable. Based on the collective evidence, 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 | 0.461924 | Structured | 0.558796 | Binding | 0.374 | 0.859 | 0.500 | -12.013 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.251 | Likely Benign | 0.2034 | 0.2708 | -3.77 | Deleterious | 0.247 | Benign | 0.166 | Benign | 3.47 | Benign | 0.00 | Affected | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||
| c.425A>G | K142R 2D AIThe SynGAP1 missense variant K142R is not 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—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also favors benign (2 benign vs. 1 pathogenic, 1 uncertain). Foldetta results are unavailable, so they do not influence the assessment. Overall, the collective evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.461924 | Structured | 0.558796 | Binding | 0.374 | 0.859 | 0.500 | -9.327 | Likely Pathogenic | 0.361 | Ambiguous | Likely Benign | 0.157 | Likely Benign | 0.4459 | 0.0858 | -1.87 | Neutral | 0.399 | Benign | 0.212 | Benign | 3.65 | Benign | 0.00 | Affected | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||||||||
| c.425A>T | K142I 2D AIThe SynGAP1 missense variant K142I is not 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. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.461924 | Structured | 0.558796 | Binding | 0.374 | 0.859 | 0.500 | -14.597 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.296 | Likely Benign | 0.1005 | 0.3173 | -4.81 | Deleterious | 0.700 | Possibly Damaging | 0.403 | Benign | 3.44 | Benign | 0.00 | Affected | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||||||||||||
| c.426A>C | K142N 2D AIThe SynGAP1 missense variant K142N is not 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 pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic effect, 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 | 0.461924 | Structured | 0.558796 | Binding | 0.374 | 0.859 | 0.500 | -12.169 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.097 | Likely Benign | 0.3586 | 0.1437 | -3.13 | Deleterious | 0.700 | Possibly Damaging | 0.383 | Benign | 3.47 | Benign | 0.00 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||
| c.426A>T | K142N 2D AIThe SynGAP1 missense variant K142N is not 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 pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic effect, 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 | 0.461924 | Structured | 0.558796 | Binding | 0.374 | 0.859 | 0.500 | -12.169 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.096 | Likely Benign | 0.3586 | 0.1437 | -3.13 | Deleterious | 0.700 | Possibly Damaging | 0.383 | Benign | 3.47 | Benign | 0.00 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||
| c.427C>G | R143G 2D AIThe SynGAP1 missense variant R143G is not reported in ClinVar and is absent from gnomAD. In silico predictors that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Predictors that agree on a pathogenic effect include PROVEAN, SIFT, ESM1b, 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 pathogenicity. 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 independent tools points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, as no ClinVar annotation exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.575842 | Disordered | 0.538584 | Binding | 0.338 | 0.838 | 0.625 | -12.686 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.151 | Likely Benign | 0.3502 | 0.3547 | -3.86 | Deleterious | 0.319 | Benign | 0.124 | Benign | 3.51 | Benign | 0.00 | Affected | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||
| c.428G>A | R143Q 2D AIThe SynGAP1 missense variant R143Q is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33432725‑G‑A). 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 methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs 2 benign), and Foldetta stability analysis is unavailable. Overall, the majority of predictions (5 pathogenic vs 4 benign) and the pathogenic call from AlphaMissense‑Optimized suggest that the variant is most likely pathogenic. 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. | 0.575842 | Disordered | 0.538584 | Binding | 0.338 | 0.838 | 0.625 | 6-33432725-G-A | 2 | 1.35e-6 | -12.110 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.181 | Likely Benign | 0.3255 | 0.2678 | -2.48 | Neutral | 0.678 | Possibly Damaging | 0.176 | Benign | 3.53 | Benign | 0.00 | Affected | 3.61 | 5 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||||||
| c.428G>C | R143P 2D AIThe SynGAP1 missense variant R143P is listed in gnomAD (ID 6‑33432725‑G‑C) but has no ClinVar entry. Functional prediction tools show mixed results: benign calls come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic calls come from PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic.” Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not return a result for this variant. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.575842 | Disordered | 0.538584 | Binding | 0.338 | 0.838 | 0.625 | 6-33432725-G-C | 2 | 1.35e-6 | -14.564 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.292 | Likely Benign | 0.2063 | 0.4457 | -3.74 | Deleterious | 0.001 | Benign | 0.000 | Benign | 3.49 | Benign | 0.00 | Affected | 3.61 | 5 | -2 | 0 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||
| c.428G>T | R143L 2D AIThe SynGAP1 missense variant R143L is listed in ClinVar with no submitted interpretation and is present in gnomAD (ID 6‑33432725‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect comprise PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic; the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.575842 | Disordered | 0.538584 | Binding | 0.338 | 0.838 | 0.625 | 6-33432725-G-T | 1 | 6.77e-7 | -14.250 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.316 | Likely Benign | 0.1758 | 0.4886 | -4.37 | Deleterious | 0.319 | Benign | 0.124 | Benign | 3.52 | Benign | 0.00 | Affected | 3.61 | 5 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||
| c.430A>C | T144P 2D  AIThe SynGAP1 missense variant T144P 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict pathogenicity are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the 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 likely pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the majority of predictions and the consensus call indicate 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 | 0.666105 | Disordered | 0.524000 | Binding | 0.335 | 0.838 | 0.625 | -11.920 | Likely Pathogenic | 0.775 | Likely Pathogenic | Likely Benign | 0.159 | Likely Benign | 0.2508 | 0.5271 | -2.66 | Deleterious | 0.000 | Benign | 0.000 | Benign | 3.76 | Benign | 0.00 | Affected | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||
| c.430A>G | T144A 2D  AIThe SynGAP1 missense variant T144A 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 high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.666105 | Disordered | 0.524000 | Binding | 0.335 | 0.838 | 0.625 | -4.007 | Likely Benign | 0.440 | Ambiguous | Likely Benign | 0.065 | Likely Benign | 0.4777 | 0.4131 | -2.24 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.95 | Benign | 0.00 | Affected | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.430A>T | T144S 2D  AIThe SynGAP1 missense variant T144S 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 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default, while ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for T144S. 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. | 0.666105 | Disordered | 0.524000 | Binding | 0.335 | 0.838 | 0.625 | -7.730 | In-Between | 0.672 | Likely Pathogenic | Likely Benign | 0.081 | Likely Benign | 0.4039 | 0.4183 | -1.90 | Neutral | 0.018 | Benign | 0.016 | Benign | 3.84 | Benign | 0.00 | Affected | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.431C>A | T144K 2D  AIThe SynGAP1 T144K variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect comprise PROVEAN, 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 further support a deleterious outcome: 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 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 | 0.666105 | Disordered | 0.524000 | Binding | 0.335 | 0.838 | 0.625 | -15.436 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.164 | Likely Benign | 0.1462 | 0.3179 | -2.83 | Deleterious | 0.180 | Benign | 0.063 | Benign | 3.76 | Benign | 0.00 | Affected | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||
| c.431C>G | T144R 2D  AIThe SynGAP1 missense variant T144R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign calls come from REVEL, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic effect. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the aggregate 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 | 0.666105 | Disordered | 0.524000 | Binding | 0.335 | 0.838 | 0.625 | -13.331 | Likely Pathogenic | 0.922 | Likely Pathogenic | Ambiguous | 0.177 | Likely Benign | 0.1188 | 0.2823 | -2.83 | Deleterious | 0.609 | Possibly Damaging | 0.150 | Benign | 3.75 | Benign | 0.00 | Affected | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||||||||
| c.431C>T | T144M 2D  AIThe SynGAP1 missense variant T144M is listed in ClinVar with an “Uncertain” status (ClinVar ID 2231966.0) and is present in the gnomAD database (gnomAD ID 6‑33432728‑C‑T). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM‑Consensus as “Likely Pathogenic,” and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the majority of computational predictions lean toward a pathogenic impact, and this assessment does not contradict the ClinVar designation of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.666105 | Disordered | 0.524000 | Binding | 0.335 | 0.838 | 0.625 | Uncertain | 2 | 6-33432728-C-T | 2 | 1.30e-6 | -11.228 | Likely Pathogenic | 0.922 | Likely Pathogenic | Ambiguous | 0.118 | Likely Benign | 0.1504 | 0.6510 | -3.16 | Deleterious | 0.913 | Possibly Damaging | 0.333 | Benign | 3.73 | Benign | 0.00 | Affected | 3.61 | 5 | -1 | -1 | 2.6 | 30.09 | ||||||||||||||||||||||||||||
| c.433A>C | K145Q 2D AIThe SynGAP1 missense variant K145Q is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Computational predictions are split: benign calls come from REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls come from polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy tools give no definitive verdict: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Consequently, the variant is neither clearly benign nor pathogenic according to current predictions, and there is no ClinVar annotation to contradict this ambiguous computational assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.671169 | Disordered | 0.516174 | Binding | 0.321 | 0.835 | 0.625 | -9.676 | Likely Pathogenic | 0.955 | Likely Pathogenic | Ambiguous | 0.163 | Likely Benign | 0.4233 | 0.1478 | -2.34 | Neutral | 0.700 | Possibly Damaging | 0.383 | Benign | 3.65 | Benign | 0.00 | Affected | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||||||||
| c.433A>G | K145E 2D AIThe SynGAP1 missense variant K145E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic predictions arise from PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of high‑confidence tools predict a pathogenic impact, and this conclusion does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.671169 | Disordered | 0.516174 | Binding | 0.321 | 0.835 | 0.625 | -12.571 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.245 | Likely Benign | 0.3638 | 0.1179 | -2.51 | Deleterious | 0.247 | Benign | 0.125 | Benign | 3.68 | Benign | 0.00 | Affected | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||||
| c.434A>C | K145T 2D AIThe SynGAP1 missense variant K145T is not reported in ClinVar and is absent from gnomAD. Computational assessment shows a split: benign predictions from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, whereas pathogenic predictions come from PROVEAN, SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN, classifies the change as Likely Pathogenic. High‑accuracy tools further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus itself is a high‑confidence prediction; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic impact for K145T. Thus, the variant is most likely pathogenic, and there is no ClinVar annotation to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.671169 | Disordered | 0.516174 | Binding | 0.321 | 0.835 | 0.625 | -8.519 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.224 | Likely Benign | 0.1965 | 0.3611 | -3.54 | Deleterious | 0.247 | Benign | 0.166 | Benign | 3.63 | Benign | 0.00 | Affected | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||
| c.434A>G | K145R 2D AIThe SynGAP1 missense variant K145R is listed in gnomAD (ID 6‑33432731‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the change as benign or likely benign. Only SIFT predicts a pathogenic outcome, while ESM1b remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports a benign effect, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status, as none is currently assigned to the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.516174 | Binding | 0.321 | 0.835 | 0.625 | 6-33432731-A-G | 1 | 6.20e-7 | -7.685 | In-Between | 0.214 | Likely Benign | Likely Benign | 0.128 | Likely Benign | 0.4661 | 0.1242 | -1.58 | Neutral | 0.399 | Benign | 0.212 | Benign | 3.71 | Benign | 0.00 | Affected | 3.61 | 5 | 2 | 3 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||
| c.434A>T | K145M 2D  AIThe SynGAP1 missense variant K145M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the 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 further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic. Foldetta results are unavailable. Overall, the preponderance of evidence indicates that K145M 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 | 0.671169 | Disordered | 0.516174 | Binding | 0.321 | 0.835 | 0.625 | -9.884 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.245 | Likely Benign | 0.1041 | 0.4427 | -3.47 | Deleterious | 0.964 | Probably Damaging | 0.650 | Possibly Damaging | 3.59 | Benign | 0.00 | Affected | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||
| c.435G>C | K145N 2D AIThe SynGAP1 missense variant K145N is not 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 are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (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 evidence points toward a pathogenic impact for K145N, 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 | 0.671169 | Disordered | 0.516174 | Binding | 0.321 | 0.835 | 0.625 | -8.718 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.109 | Likely Benign | 0.3430 | 0.1832 | -2.76 | Deleterious | 0.700 | Possibly Damaging | 0.383 | Benign | 3.65 | Benign | 0.00 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||
| c.435G>T | K145N 2D AIThe SynGAP1 missense variant K145N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL (score 0.45), polyPhen‑2 HumVar (benign), and FATHMM (benign). Pathogenic predictions arise from PROVEAN (deleterious), polyPhen‑2 HumDiv (probably damaging), SIFT (deleterious), ESM1b (damaging), AlphaMissense‑Default (pathogenic), and AlphaMissense‑Optimized (pathogenic). The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus also indicates Likely Pathogenic. Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic effect, and this is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.671169 | Disordered | 0.516174 | Binding | 0.321 | 0.835 | 0.625 | -8.718 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.109 | Likely Benign | 0.3430 | 0.1832 | -2.76 | Deleterious | 0.700 | Possibly Damaging | 0.383 | Benign | 3.65 | Benign | 0.00 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||
| c.436T>A | S146T 2D AIThe SynGAP1 missense variant S146T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a tie (two pathogenic, two benign) and thus unavailable; Foldetta results are not provided. Overall, the majority of evidence (five benign vs. three pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.541878 | Disordered | 0.508612 | Binding | 0.349 | 0.837 | 0.625 | -9.795 | Likely Pathogenic | 0.786 | Likely Pathogenic | Ambiguous | 0.113 | Likely Benign | 0.1267 | 0.5075 | -2.09 | Neutral | 0.084 | Benign | 0.042 | Benign | 3.65 | Benign | 0.00 | Affected | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.436T>C | S146P 2D AIThe SynGAP1 missense variant S146P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic predictions arise from PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates likely pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic effect for S146P, and this conclusion is not contradicted by ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.541878 | Disordered | 0.508612 | Binding | 0.349 | 0.837 | 0.625 | -13.292 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.215 | Likely Benign | 0.1934 | 0.4627 | -3.11 | Deleterious | 0.392 | Benign | 0.230 | Benign | 3.60 | Benign | 0.00 | Affected | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.436T>G | S146A 2D AIThe SynGAP1 missense variant S146A is not reported 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. 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. | 0.541878 | Disordered | 0.508612 | Binding | 0.349 | 0.837 | 0.625 | -14.042 | Likely Pathogenic | 0.721 | Likely Pathogenic | Likely Benign | 0.097 | Likely Benign | 0.4435 | 0.3708 | -1.81 | Neutral | 0.000 | Benign | 0.002 | Benign | 3.71 | Benign | 0.00 | Affected | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||
| c.437C>T | S146L 2D AIThe SynGAP1 missense variant S146L is not 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. In contrast, tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) which classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM‑Consensus as Likely Pathogenic; Foldetta results are not available. Overall, the majority of predictions indicate a pathogenic impact, and this is consistent with the lack of ClinVar annotation—there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.541878 | Disordered | 0.508612 | Binding | 0.349 | 0.837 | 0.625 | -15.179 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.130 | Likely Benign | 0.0856 | 0.4975 | -3.77 | Deleterious | 0.084 | Benign | 0.063 | Benign | 3.63 | Benign | 0.00 | Affected | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||||||||
| c.439C>A | Q147K 2D AIThe SynGAP1 missense variant Q147K is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of available 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. | 0.541878 | Disordered | 0.503877 | Binding | 0.349 | 0.840 | 0.625 | -12.562 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.084 | Likely Benign | 0.2012 | 0.3351 | -2.12 | Neutral | 0.018 | Benign | 0.025 | Benign | 3.94 | Benign | 0.03 | Affected | 1 | 1 | -0.4 | 0.04 | ||||||||||||||||||||||||||||||||||||
| c.439C>G | Q147E 2D AIThe SynGAP1 missense variant Q147E is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. The high‑accuracy AlphaMissense‑Optimized result is unavailable, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie (2 pathogenic, 2 benign) and is therefore considered uncertain. Foldetta, which would assess protein‑folding stability, has no reported output for this variant, so its result is unavailable. Overall, the majority of evidence (five benign vs. three pathogenic) points to a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.541878 | Disordered | 0.503877 | Binding | 0.349 | 0.840 | 0.625 | -10.347 | Likely Pathogenic | 0.840 | Likely Pathogenic | Ambiguous | 0.093 | Likely Benign | 0.1561 | 0.1838 | -1.47 | Neutral | 0.018 | Benign | 0.025 | Benign | 3.94 | Benign | 0.02 | Affected | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||||
| c.440A>C | Q147P 2D AIThe SynGAP1 missense variant Q147P is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls arise from PROVEAN, SIFT, ESM1b and AlphaMissense‑Default. Grouping by consensus, four tools predict benign and four predict pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Overall, the balance of evidence, especially the SGM Consensus and the majority of individual predictors, indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.541878 | Disordered | 0.503877 | Binding | 0.349 | 0.840 | 0.625 | -14.132 | Likely Pathogenic | 0.797 | Likely Pathogenic | Ambiguous | 0.264 | Likely Benign | 0.2350 | 0.4402 | -3.03 | Deleterious | 0.232 | Benign | 0.147 | Benign | 3.87 | Benign | 0.01 | Affected | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||
| c.440A>G | Q147R 2D AIThe SynGAP1 missense variant Q147R is not reported 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, and FATHMM. Tools that agree on a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a 2‑to‑2 split, and Foldetta results are unavailable. Overall, more tools predict a benign outcome (five vs. three pathogenic predictions, with one uncertain). Therefore, the variant is most likely benign 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. | 0.541878 | Disordered | 0.503877 | Binding | 0.349 | 0.840 | 0.625 | -12.301 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.166 | Likely Benign | 0.1760 | 0.1042 | -2.22 | Neutral | 0.079 | Benign | 0.052 | Benign | 3.91 | Benign | 0.02 | Affected | 1 | 1 | -1.0 | 28.06 | ||||||||||||||||||||||||||||||||||||
| c.440A>T | Q147L 2D AIThe SynGAP1 missense variant Q147L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default; the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic. Foldetta results are unavailable. Overall, the majority of evidence points toward a pathogenic interpretation, and this is not contradicted by any ClinVar classification because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.541878 | Disordered | 0.503877 | Binding | 0.349 | 0.840 | 0.625 | -9.879 | Likely Pathogenic | 0.740 | Likely Pathogenic | Likely Benign | 0.185 | Likely Benign | 0.0861 | 0.4927 | -3.51 | Deleterious | 0.079 | Benign | 0.037 | Benign | 3.92 | Benign | 0.03 | Affected | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||
| c.441A>C | Q147H 2D AIThe SynGAP1 missense variant Q147H is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls arise from PROVEAN, SIFT, ESM1b and AlphaMissense‑Default. Grouping by consensus, four tools predict benign and four predict pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Overall, the balance of evidence, especially the SGM Consensus and the majority of individual predictors, indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.541878 | Disordered | 0.503877 | Binding | 0.349 | 0.840 | 0.625 | -9.759 | Likely Pathogenic | 0.955 | Likely Pathogenic | Ambiguous | 0.102 | Likely Benign | 0.1528 | 0.3220 | -2.70 | Deleterious | 0.380 | Benign | 0.265 | Benign | 3.87 | Benign | 0.01 | Affected | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.441A>T | Q147H 2D AIThe SynGAP1 missense variant Q147H is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls arise from PROVEAN, SIFT, ESM1b and AlphaMissense‑Default. Grouping by consensus, four tools predict benign and four predict pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Taken together, the balance of evidence favors a pathogenic interpretation, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.541878 | Disordered | 0.503877 | Binding | 0.349 | 0.840 | 0.625 | -9.759 | Likely Pathogenic | 0.955 | Likely Pathogenic | Ambiguous | 0.102 | Likely Benign | 0.1528 | 0.3220 | -2.70 | Deleterious | 0.380 | Benign | 0.265 | Benign | 3.87 | Benign | 0.01 | Affected | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.442C>A | P148T 2D AIThe SynGAP1 missense variant P148T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this conclusion, so the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.500109 | Binding | 0.372 | 0.837 | 0.625 | -4.762 | Likely Benign | 0.781 | Likely Pathogenic | Likely Benign | 0.108 | Likely Benign | 0.1698 | 0.4850 | -1.39 | Neutral | 1.000 | Probably Damaging | 0.994 | Probably Damaging | 4.03 | Benign | 0.15 | Tolerated | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||
| c.442C>G | P148A 2D AIThe SynGAP1 missense variant P148A is catalogued in gnomAD (ID 6‑33432739‑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, is “Likely Benign” because three of the four contributing tools predict benign. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.500109 | Binding | 0.372 | 0.837 | 0.625 | 6-33432739-C-G | 1 | 6.33e-7 | -6.890 | Likely Benign | 0.729 | Likely Pathogenic | Likely Benign | 0.117 | Likely Benign | 0.3134 | 0.4123 | -2.31 | Neutral | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 4.00 | Benign | 0.03 | Affected | 3.61 | 5 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||
| c.442C>T | P148S 2D AIThe SynGAP1 missense variant P148S is not reported in ClinVar (ClinVar status: not listed) and is present in gnomAD (ID 6‑33432739‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.500109 | Binding | 0.372 | 0.837 | 0.625 | 6-33432739-C-T | 1 | 6.33e-7 | -3.258 | Likely Benign | 0.874 | Likely Pathogenic | Ambiguous | 0.102 | Likely Benign | 0.3143 | 0.4597 | -1.81 | Neutral | 1.000 | Probably Damaging | 0.994 | Probably Damaging | 4.05 | Benign | 0.39 | Tolerated | 3.61 | 5 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||
| c.443C>A | P148H 2D AIThe SynGAP1 missense variant P148H is not 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, 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 P148H, 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 | 0.653063 | Disordered | 0.500109 | Binding | 0.372 | 0.837 | 0.625 | -11.034 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.169 | Likely Benign | 0.1881 | 0.3847 | -3.21 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.90 | Benign | 0.00 | Affected | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1615 | 0.3100 | -3.17 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.92 | Benign | 0.01 | Affected | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.443C>T | P148L 2D AIThe SynGAP1 missense variant P148L 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) indicate a pathogenic impact. The high‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta results are unavailable. Overall, the consensus of the majority of tools points to a pathogenic effect. Because there is no ClinVar classification to contradict this, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.653063 | Disordered | 0.500109 | Binding | 0.372 | 0.837 | 0.625 | -10.375 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 0.185 | Likely Benign | 0.2229 | 0.5714 | -3.29 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.93 | Benign | 0.01 | Affected | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||
| c.445A>C | K149Q 2D AIThe SynGAP1 missense variant K149Q is not 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 takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 vs 2). AlphaMissense‑Optimized predicts pathogenic, while Foldetta (combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the balance of evidence (five pathogenic vs. four benign predictions) indicates that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.562014 | Disordered | 0.501681 | Binding | 0.302 | 0.839 | 0.625 | -11.430 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.190 | Likely Benign | 0.5243 | 0.1454 | Weaken | -1.99 | Neutral | 0.535 | Possibly Damaging | 0.310 | Benign | 3.61 | Benign | 0.00 | Affected | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||
| c.445A>G | K149E 2D AIThe SynGAP1 missense variant K149E is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields an equal split (2 vs 2) and is therefore considered unavailable. AlphaMissense‑Optimized, a high‑accuracy predictor, classifies the variant as pathogenic, while Foldetta (combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the majority of standard tools (five benign vs. four pathogenic) lean toward a benign interpretation, and this is consistent with the lack of ClinVar evidence. 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. | 0.562014 | Disordered | 0.501681 | Binding | 0.302 | 0.839 | 0.625 | -12.148 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.231 | Likely Benign | 0.4636 | 0.1022 | -2.17 | Neutral | 0.141 | Benign | 0.062 | Benign | 3.59 | Benign | 0.00 | Affected | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||||||||
| c.446A>C | K149T 2D AIThe SynGAP1 missense variant K149T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar), and FATHMM, while pathogenic calls arise from PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote) also indicates Likely Pathogenic. Foldetta results are unavailable, so no stability evidence is provided. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.562014 | Disordered | 0.501681 | Binding | 0.302 | 0.839 | 0.625 | -11.948 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.260 | Likely Benign | 0.2398 | 0.3473 | -3.53 | Deleterious | 0.141 | Benign | 0.091 | Benign | 3.56 | Benign | 0.00 | Affected | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||
| c.446A>G | K149R 2D AIThe SynGAP1 missense variant K149R is not 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. 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 predicts 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 combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that K149R 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. | 0.562014 | Disordered | 0.501681 | Binding | 0.302 | 0.839 | 0.625 | -8.237 | Likely Pathogenic | 0.406 | Ambiguous | Likely Benign | 0.143 | Likely Benign | 0.5639 | 0.1169 | Weaken | -1.70 | Neutral | 0.247 | Benign | 0.125 | Benign | 3.70 | Benign | 0.00 | Affected | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||||||||
| c.446A>T | K149I 2D AIThe SynGAP1 missense variant K149I 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 lack of benign consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.562014 | Disordered | 0.501681 | Binding | 0.302 | 0.839 | 0.625 | -14.426 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.305 | Likely Benign | 0.1477 | 0.3965 | -4.72 | Deleterious | 0.535 | Possibly Damaging | 0.403 | Benign | 3.53 | Benign | 0.00 | Affected | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||||||||||||
| c.447A>C | K149N 2D AIThe SynGAP1 missense variant K149N is not reported in ClinVar and has no entry in gnomAD, indicating it is not catalogued in these databases. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a majority pathogenic vote (3 pathogenic vs. 1 benign) and is labeled “Likely Pathogenic.” AlphaMissense‑Optimized independently predicts pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the majority of computational evidence points to a pathogenic impact, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.562014 | Disordered | 0.501681 | Binding | 0.302 | 0.839 | 0.625 | -9.275 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.121 | Likely Benign | 0.4427 | 0.1559 | -2.85 | Deleterious | 0.141 | Benign | 0.123 | Benign | 3.56 | Benign | 0.00 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||
| c.447A>T | K149N 2D AIThe SynGAP1 missense variant K149N 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 predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic predictions arise from PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates likely pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic effect for K149N, 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 | 0.562014 | Disordered | 0.501681 | Binding | 0.302 | 0.839 | 0.625 | -9.275 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.121 | Likely Benign | 0.4427 | 0.1559 | -2.85 | Deleterious | 0.141 | Benign | 0.123 | Benign | 3.56 | Benign | 0.00 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||
| c.448C>A | L150I 2D AIThe SynGAP1 missense variant L150I is not 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 agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are less definitive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign), and Foldetta results are unavailable. Overall, the majority of available predictions (five pathogenic vs. three benign) indicate a likely pathogenic impact for the variant. This conclusion is not contradicted by ClinVar status, as the variant has no existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.494003 | Structured | 0.505752 | Binding | 0.299 | 0.839 | 0.625 | -10.118 | Likely Pathogenic | 0.886 | Likely Pathogenic | Ambiguous | 0.080 | Likely Benign | 0.0894 | 0.3468 | -1.25 | Neutral | 0.993 | Probably Damaging | 0.967 | Probably Damaging | 3.74 | Benign | 0.00 | Affected | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||||||||
| c.448C>G | L150V 2D AIThe SynGAP1 missense variant L150V is not 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 and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (5 pathogenic vs. 3 benign) indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.494003 | Structured | 0.505752 | Binding | 0.299 | 0.839 | 0.625 | -10.375 | Likely Pathogenic | 0.927 | Likely Pathogenic | Ambiguous | 0.113 | Likely Benign | 0.1473 | 0.3178 | -1.84 | Neutral | 0.993 | Probably Damaging | 0.967 | Probably Damaging | 3.74 | Benign | 0.00 | Affected | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.448C>T | L150F 2D  AIThe SynGAP1 missense variant L150F is not 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, 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 pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, and the SGM‑Consensus 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 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 | 0.494003 | Structured | 0.505752 | Binding | 0.299 | 0.839 | 0.625 | -12.459 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.105 | Likely Benign | 0.0580 | 0.3112 | -2.56 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 3.69 | Benign | 0.00 | Affected | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||
| c.449T>A | L150H 2D  AIThe SynGAP1 missense variant L150H is not 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, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic (3 pathogenic vs. 1 benign). AlphaMissense‑Optimized alone 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 from multiple independent predictors indicates that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.494003 | Structured | 0.505752 | Binding | 0.299 | 0.839 | 0.625 | -14.892 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.303 | Likely Benign | 0.1011 | 0.0519 | -4.09 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 3.64 | Benign | 0.00 | Affected | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||
| c.449T>C | L150P 2D AIThe SynGAP1 missense variant L150P 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—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 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 indicates it is likely pathogenic. The Foldetta protein‑folding stability analysis is unavailable 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 | 0.494003 | Structured | 0.505752 | Binding | 0.299 | 0.839 | 0.625 | -12.881 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.320 | Likely Benign | 0.3557 | 0.1543 | -3.90 | Deleterious | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 3.64 | Benign | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||
| c.449T>G | L150R 2D AIThe SynGAP1 missense variant L150R is not 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, and PROVEAN) all indicate pathogenicity. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus also reports it as 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 points to a pathogenic effect for the SynGAP1 L150R variant, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.494003 | Structured | 0.505752 | Binding | 0.299 | 0.839 | 0.625 | -14.879 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.290 | Likely Benign | 0.1275 | 0.0719 | -3.16 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 3.67 | Benign | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||
| c.451G>A | D151N 2D  AIThe SynGAP1 missense variant D151N has no ClinVar entry (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). 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—predict it to be pathogenic. The SGM‑Consensus result (Likely Pathogenic) is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus as Likely Pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence from multiple in silico predictors indicates that D151N is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.529623 | Disordered | 0.503277 | Binding | 0.342 | 0.841 | 0.625 | -8.479 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.185 | Likely Benign | 0.1346 | 0.8186 | -2.51 | Deleterious | 0.993 | Probably Damaging | 0.984 | Probably Damaging | 3.90 | Benign | 0.01 | Affected | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||
| c.451G>C | D151H 2D  AIThe SynGAP1 missense variant D151H is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33432748‑G‑C). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all 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.” No Foldetta stability result is available for this variant. Overall, the majority of computational evidence indicates that D151H is most likely pathogenic, which does not contradict the current ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.529623 | Disordered | 0.503277 | Binding | 0.342 | 0.841 | 0.625 | Uncertain | 1 | 6-33432748-G-C | 2 | 1.26e-6 | -11.747 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.335 | Likely Benign | 0.1543 | 0.8419 | -3.90 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 3.86 | Benign | 0.00 | Affected | 3.61 | 5 | -1 | 1 | 0.3 | 22.05 | ||||||||||||||||||||||||||||
| c.451G>T | D151Y 2D  AIThe SynGAP1 D151Y variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and 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). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels 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 D151Y 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 | 0.529623 | Disordered | 0.503277 | Binding | 0.342 | 0.841 | 0.625 | -13.174 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.340 | Likely Benign | 0.0567 | 0.7560 | -5.16 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 3.85 | Benign | 0.00 | Affected | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||
| c.452A>C | D151A 2D  AIThe SynGAP1 D151A missense variant is listed in gnomAD (ID 6‑33432749‑A‑C) but has no ClinVar entry. Functional prediction tools fall into two groups: benign predictions come from 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 pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus 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 majority of evidence points to a pathogenic impact, and this conclusion 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 Pathogenic | 0.529623 | Disordered | 0.503277 | Binding | 0.342 | 0.841 | 0.625 | 6-33432749-A-C | 1 | 6.21e-7 | -9.693 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.326 | Likely Benign | 0.4286 | 0.7424 | -4.51 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 3.91 | Benign | 0.01 | Affected | 3.61 | 5 | -2 | 0 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||
| c.452A>G | D151G 2D  AIThe SynGAP1 D151G missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are made by 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—predict a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic, and the SGM‑Consensus confirms a likely pathogenic status. No Foldetta stability analysis is available for this residue. Overall, the preponderance of evidence indicates that D151G is most likely pathogenic, and this assessment does not conflict with any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.529623 | Disordered | 0.503277 | Binding | 0.342 | 0.841 | 0.625 | -10.409 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.349 | Likely Benign | 0.4452 | 0.7037 | -3.91 | Deleterious | 0.993 | Probably Damaging | 0.984 | Probably Damaging | 3.87 | Benign | 0.01 | Affected | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||
| c.452A>T | D151V 2D  AIThe SynGAP1 D151V variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and 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 (which is “Likely Pathogenic” based on a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is likely pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from multiple in silico predictors indicates that D151V 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 | 0.529623 | Disordered | 0.503277 | Binding | 0.342 | 0.841 | 0.625 | -11.927 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.380 | Likely Benign | 0.0864 | 0.7781 | -5.19 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 3.88 | Benign | 0.00 | Affected | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||
| c.453C>A | D151E 2D  AIThe SynGAP1 D151E variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM‑Consensus as “Likely Benign,” and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.529623 | Disordered | 0.503277 | Binding | 0.342 | 0.841 | 0.625 | Uncertain | 1 | -5.662 | Likely Benign | 0.886 | Likely Pathogenic | Ambiguous | 0.142 | Likely Benign | 0.1494 | 0.7919 | -2.02 | Neutral | 0.984 | Probably Damaging | 0.967 | Probably Damaging | 3.99 | Benign | 0.11 | Tolerated | 3.61 | 5 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||
| c.453C>G | D151E 2D AIThe SynGAP1 missense variant D151E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Benign classification, and AlphaMissense‑Optimized remains uncertain. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which has no entry for D151E. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.529623 | Disordered | 0.503277 | Binding | 0.342 | 0.841 | 0.625 | -5.662 | Likely Benign | 0.886 | Likely Pathogenic | Ambiguous | 0.142 | Likely Benign | 0.1494 | 0.7919 | -2.02 | Neutral | 0.984 | Probably Damaging | 0.967 | Probably Damaging | 3.99 | Benign | 0.11 | Tolerated | 3.61 | 5 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||
| c.454C>G | R152G 2D AIThe SynGAP1 missense variant R152G is not 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 score (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that R152G 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 | 0.500158 | Binding | 0.319 | 0.842 | 0.625 | -11.043 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.169 | Likely Benign | 0.3633 | 0.3956 | -4.13 | Deleterious | 0.993 | Probably Damaging | 0.982 | Probably Damaging | 3.83 | Benign | 0.00 | Affected | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||
| c.454C>T | R152W 2D AIThe SynGAP1 missense variant R152W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the 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 | 0.618285 | Disordered | 0.500158 | Binding | 0.319 | 0.842 | 0.625 | -11.783 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.163 | Likely Benign | 0.1550 | 0.4564 | -4.66 | Deleterious | 1.000 | Probably Damaging | 0.990 | Probably Damaging | 3.79 | Benign | 0.00 | Affected | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.455G>A | R152Q 2D AIThe SynGAP1 missense variant R152Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33432752‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, whereas those that predict a pathogenic effect are 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, is inconclusive (two pathogenic, two benign). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus remains unavailable, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no reported result for this variant. Overall, the preponderance of evidence (seven pathogenic versus three benign predictions) indicates that the variant is most likely pathogenic, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.618285 | Disordered | 0.500158 | Binding | 0.319 | 0.842 | 0.625 | Uncertain | 1 | 6-33432752-G-A | 5 | 3.14e-6 | -10.336 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.181 | Likely Benign | 0.3618 | 0.2996 | -2.34 | Neutral | 0.997 | Probably Damaging | 0.968 | Probably Damaging | 3.89 | Benign | 0.00 | Affected | 3.61 | 5 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||||
| c.455G>C | R152P 2D AIThe SynGAP1 missense variant R152P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, 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 also pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus as pathogenic; Foldetta results are unavailable. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.618285 | Disordered | 0.500158 | Binding | 0.319 | 0.842 | 0.625 | -11.499 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.332 | Likely Benign | 0.2302 | 0.4838 | -4.00 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 3.82 | Benign | 0.00 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||
| c.455G>T | R152L 2D AIThe SynGAP1 missense variant R152L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the 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 further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic. Foldetta results are unavailable. Overall, the preponderance of evidence indicates that R152L 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 | 0.618285 | Disordered | 0.500158 | Binding | 0.319 | 0.842 | 0.625 | -11.501 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.331 | Likely Benign | 0.2032 | 0.5249 | -3.85 | Deleterious | 0.993 | Probably Damaging | 0.982 | Probably Damaging | 3.83 | Benign | 0.00 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||
| c.457A>C | T153P 2D AIThe SynGAP1 missense variant T153P is not reported 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 leans toward a benign interpretation. This conclusion does not conflict with ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.502105 | Binding | 0.297 | 0.818 | 0.625 | -7.092 | In-Between | 0.374 | Ambiguous | Likely Benign | 0.269 | Likely Benign | 0.2270 | 0.3660 | -1.67 | Neutral | 0.983 | Probably Damaging | 0.725 | Possibly Damaging | 4.09 | Benign | 0.03 | Affected | 0 | -1 | -0.9 | -3.99 | ||||||||||||||||||||||||||||||||||||
| c.457A>G | T153A 2D AIThe SynGAP1 missense variant T153A is not reported in ClinVar and has no entry in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.501700 | Disordered | 0.502105 | Binding | 0.297 | 0.818 | 0.625 | -3.016 | Likely Benign | 0.234 | Likely Benign | Likely Benign | 0.173 | Likely Benign | 0.4430 | 0.2985 | -1.54 | Neutral | 0.620 | Possibly Damaging | 0.220 | Benign | 4.15 | Benign | 0.05 | Affected | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.457A>T | T153S 2D AIThe SynGAP1 missense variant T153S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.501700 | Disordered | 0.502105 | Binding | 0.297 | 0.818 | 0.625 | -1.890 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 0.118 | Likely Benign | 0.3756 | 0.2886 | -0.50 | Neutral | 0.235 | Benign | 0.039 | Benign | 4.19 | Benign | 0.14 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.458C>A | T153N 2D  AIThe SynGAP1 missense variant T153N is listed in ClinVar (ID 984906.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) predict pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence supports a benign classification, and this is consistent with the ClinVar “Uncertain” designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.501700 | Disordered | 0.502105 | Binding | 0.297 | 0.818 | 0.625 | Conflicting | 3 | -0.739 | Likely Benign | 0.226 | Likely Benign | Likely Benign | 0.161 | Likely Benign | 0.1313 | 0.3363 | 0.88 | Neutral | 0.888 | Possibly Damaging | 0.537 | Possibly Damaging | 4.23 | Benign | 0.81 | Tolerated | 3.61 | 5 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||||
| c.458C>G | T153S 2D AIThe SynGAP1 missense variant T153S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.501700 | Disordered | 0.502105 | Binding | 0.297 | 0.818 | 0.625 | -1.890 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 0.066 | Likely Benign | 0.3756 | 0.2886 | -0.50 | Neutral | 0.235 | Benign | 0.039 | Benign | 4.19 | Benign | 0.14 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.458C>T | T153I 2D  AIThe SynGAP1 missense variant T153I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM. Those that predict a pathogenic effect comprise polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are limited: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of available predictions (5 pathogenic vs. 3 benign) indicate a pathogenic impact. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.502105 | Binding | 0.297 | 0.818 | 0.625 | -8.809 | Likely Pathogenic | 0.898 | Likely Pathogenic | Ambiguous | 0.159 | Likely Benign | 0.0839 | 0.4571 | -2.00 | Neutral | 0.983 | Probably Damaging | 0.725 | Possibly Damaging | 4.08 | Benign | 0.01 | Affected | 0 | -1 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||||||||
| 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 | 0.0997 | 0.3298 | -1.73 | Neutral | 0.990 | Probably Damaging | 0.723 | Possibly Damaging | 4.10 | Benign | 0.14 | Tolerated | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| c.460A>G | S154G 2D AIThe SynGAP1 missense variant S154G is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -5.482 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.074 | Likely Benign | 0.2790 | 0.3944 | -0.83 | Neutral | 0.006 | Benign | 0.008 | Benign | 4.05 | Benign | 0.11 | Tolerated | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.460A>T | S154C 2D AIThe SynGAP1 missense variant S154C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. ESM1b is uncertain, and Foldetta results are unavailable. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. With the majority of evidence pointing to a benign outcome and no conflicting ClinVar annotation, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -7.728 | In-Between | 0.244 | Likely Benign | Likely Benign | 0.100 | Likely Benign | 0.1288 | 0.5042 | -1.83 | Neutral | 0.997 | Probably Damaging | 0.841 | Possibly Damaging | 4.01 | Benign | 0.04 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.461G>A | S154N 2D AIThe SynGAP1 missense variant S154N is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools largely support a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports it as likely benign. Only one tool, polyPhen‑2 HumDiv, predicts a pathogenic outcome, and AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) likewise indicates likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar annotation or gnomAD observation. The variant is most likely benign based on predictions, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -6.604 | Likely Benign | 0.385 | Ambiguous | Likely Benign | 0.074 | Likely Benign | 0.1545 | 0.4298 | -1.00 | Neutral | 0.900 | Possibly Damaging | 0.434 | Benign | 4.10 | Benign | 0.22 | Tolerated | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||
| c.461G>C | S154T 2D AIThe SynGAP1 missense variant S154T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of tools, including the high‑accuracy methods, indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -5.313 | Likely Benign | 0.155 | Likely Benign | Likely Benign | 0.167 | Likely Benign | 0.1686 | 0.5099 | -0.32 | Neutral | 0.900 | Possibly Damaging | 0.434 | Benign | 4.13 | Benign | 0.99 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.461G>T | S154I 2D AIThe SynGAP1 missense variant S154I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic) and therefore unavailable as evidence. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not provided and is treated as unavailable. High‑accuracy predictions therefore indicate a benign outcome (AlphaMissense‑Optimized) with no decisive evidence from SGM Consensus or Foldetta. Overall, the variant is most likely benign, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -10.061 | Likely Pathogenic | 0.665 | Likely Pathogenic | Likely Benign | 0.105 | Likely Benign | 0.0953 | 0.5123 | -2.24 | Neutral | 0.990 | Probably Damaging | 0.797 | Possibly Damaging | 4.03 | Benign | 0.07 | Tolerated | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||
| c.462C>A | S154R 2D AIThe SynGAP1 missense variant S154R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, more tools (five) predict pathogenicity than benign (four), and the high‑accuracy AlphaMissense‑Optimized also indicates pathogenicity. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -9.119 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.072 | Likely Benign | 0.0997 | 0.3298 | -1.73 | Neutral | 0.990 | Probably Damaging | 0.723 | Possibly Damaging | 4.10 | Benign | 0.14 | Tolerated | 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 | 0.0997 | 0.3298 | -1.73 | Neutral | 0.990 | Probably Damaging | 0.723 | Possibly Damaging | 4.10 | Benign | 0.14 | Tolerated | 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 | 0.0712 | 0.3528 | -2.74 | Deleterious | 0.995 | Probably Damaging | 0.979 | Probably Damaging | 3.88 | Benign | 0.00 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||
| c.463A>G | S155G 2D AIThe SynGAP1 missense variant S155G is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic, two benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools specifically indicate a benign outcome from AlphaMissense‑Optimized, while SGM Consensus and Foldetta are unavailable. Overall, the balance of evidence leans toward a pathogenic interpretation, and this assessment does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.497853 | Structured | 0.515359 | Binding | 0.292 | 0.787 | 0.500 | -9.243 | Likely Pathogenic | 0.628 | Likely Pathogenic | Likely Benign | 0.152 | Likely Benign | 0.2416 | 0.3976 | -1.84 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 3.81 | Benign | 0.00 | Affected | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||||
| c.463A>T | S155C 2D AIThe SynGAP1 missense variant S155C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, 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, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, while the SGM‑Consensus remains Likely Pathogenic; Foldetta results are unavailable. Overall, the majority of predictions lean toward pathogenicity, but this conclusion conflicts with the benign prediction from AlphaMissense‑Optimized and the lack of ClinVar evidence. Thus, the variant is most likely pathogenic based on the prevailing predictions, though the evidence is not unequivocal. 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 | -11.903 | Likely Pathogenic | 0.756 | Likely Pathogenic | Likely Benign | 0.238 | Likely Benign | 0.0826 | 0.5681 | -2.53 | Deleterious | 0.999 | Probably Damaging | 0.990 | Probably Damaging | 3.78 | Benign | 0.00 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.464G>A | S155N 2D AIThe SynGAP1 missense variant S155N is not 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 mixed or unavailable results: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no reported result. Overall, the majority of available predictions (five pathogenic vs. three benign) indicate a pathogenic impact. There is no ClinVar entry to contradict this assessment, so the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.497853 | Structured | 0.515359 | Binding | 0.292 | 0.787 | 0.500 | -9.428 | Likely Pathogenic | 0.907 | Likely Pathogenic | Ambiguous | 0.166 | Likely Benign | 0.1033 | 0.4549 | -1.69 | Neutral | 0.981 | Probably Damaging | 0.954 | Probably Damaging | 3.84 | Benign | 0.00 | Affected | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||
| c.464G>C | S155T 2D AIThe SynGAP1 missense variant S155T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors a benign outcome. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of reliable predictors and the consensus analysis indicate that S155T is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.497853 | Structured | 0.515359 | Binding | 0.292 | 0.787 | 0.500 | -8.635 | Likely Pathogenic | 0.523 | Ambiguous | Likely Benign | 0.153 | Likely Benign | 0.1151 | 0.5694 | -1.60 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 3.84 | Benign | 0.00 | Affected | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.464G>T | S155I 2D AIThe SynGAP1 missense variant S155I 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 the Foldetta stability analysis is unavailable. Taken together, the majority of evidence points to a pathogenic impact for S155I. 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 | -11.298 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.264 | Likely Benign | 0.0764 | 0.5711 | -2.70 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 3.81 | Benign | 0.00 | Affected | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0712 | 0.3528 | -2.74 | Deleterious | 0.995 | Probably Damaging | 0.979 | Probably Damaging | 3.88 | Benign | 0.00 | Affected | 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 | 0.0712 | 0.3528 | -2.74 | Deleterious | 0.995 | Probably Damaging | 0.979 | Probably Damaging | 3.88 | Benign | 0.00 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||
| c.466T>A | F156I 2D AIThe SynGAP1 missense variant F156I is not 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 aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑confidence predictors (six out of nine) indicate a pathogenic impact, whereas three predict benign. Consequently, 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. | 0.476583 | Structured | 0.521964 | Binding | 0.284 | 0.785 | 0.500 | -10.505 | Likely Pathogenic | 0.959 | Likely Pathogenic | Likely Pathogenic | 0.194 | Likely Benign | 0.1960 | 0.1938 | -2.38 | Neutral | 0.981 | Probably Damaging | 0.966 | Probably Damaging | 3.99 | Benign | 0.00 | Affected | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||||||||
| c.466T>C | F156L 2D AIThe SynGAP1 missense variant F156L is not 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 tools that agree on a pathogenic effect include polyPhen‑2 (HumDiv and HumVar), SIFT, 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) leans toward benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of conventional tools predict pathogenicity, but the high‑accuracy consensus is ambiguous. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.476583 | Structured | 0.521964 | Binding | 0.284 | 0.785 | 0.500 | -7.437 | In-Between | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.180 | Likely Benign | 0.2067 | 0.3109 | -2.31 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 4.04 | Benign | 0.00 | Affected | 2 | 0 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||
| c.466T>G | F156V 2D AIThe SynGAP1 missense variant F156V is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of algorithms—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—classify the change as pathogenic. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is uncertain, but the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic status. Foldetta, a protein‑folding stability predictor that integrates FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the preponderance of evidence points to a pathogenic effect for F156V, and this conclusion does not conflict with the current ClinVar annotation, which is absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.476583 | Structured | 0.521964 | Binding | 0.284 | 0.785 | 0.500 | -11.945 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.246 | Likely Benign | 0.2177 | 0.2166 | -2.91 | Deleterious | 0.981 | Probably Damaging | 0.954 | Probably Damaging | 4.03 | Benign | 0.00 | Affected | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||||||||
| c.467T>A | F156Y 2D AIThe SynGAP1 missense variant F156Y is not 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 a majority of tools (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a tie (2 pathogenic vs. 2 benign) and thus unavailable; Foldetta predictions are not provided. Overall, the balance of evidence (5 pathogenic vs. 3 benign predictions) indicates that the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.476583 | Structured | 0.521964 | Binding | 0.284 | 0.785 | 0.500 | -11.811 | Likely Pathogenic | 0.869 | Likely Pathogenic | Ambiguous | 0.136 | Likely Benign | 0.1363 | 0.1419 | -1.51 | Neutral | 0.981 | Probably Damaging | 0.931 | Probably Damaging | 3.96 | Benign | 0.00 | Affected | 7 | 3 | -4.1 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.467T>C | F156S 2D AIThe SynGAP1 missense variant F156S 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 predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Pathogenic” based on a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (derived from the same set of high‑accuracy predictors) also indicates a likely pathogenic outcome. Foldetta results are unavailable, so they do 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 | 0.476583 | Structured | 0.521964 | Binding | 0.284 | 0.785 | 0.500 | -14.082 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.282 | Likely Benign | 0.5183 | 0.0200 | Weaken | -3.62 | Deleterious | 0.995 | Probably Damaging | 0.979 | Probably Damaging | 3.97 | Benign | 0.00 | Affected | -3 | -2 | -3.6 | -60.10 | ||||||||||||||||||||||||||||||||||
| c.467T>G | F156C 2D AIThe SynGAP1 missense variant F156C is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional 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 from 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 analysis is available for this variant. Overall, the majority of predictions, including the high‑accuracy tools, indicate that F156C 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 | 0.476583 | Structured | 0.521964 | Binding | 0.284 | 0.785 | 0.500 | Uncertain | 1 | -13.658 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.297 | Likely Benign | 0.3030 | 0.1291 | -3.54 | Deleterious | 0.999 | Probably Damaging | 0.990 | Probably Damaging | 3.92 | Benign | 0.00 | Affected | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||||||
| c.468T>A | F156L 2D AIThe SynGAP1 missense variant F156L is not 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 tools that agree on a pathogenic effect include polyPhen‑2 (HumDiv and HumVar), SIFT, 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) leans toward benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of conventional tools predict pathogenicity, but the high‑accuracy consensus is ambiguous. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.476583 | Structured | 0.521964 | Binding | 0.284 | 0.785 | 0.500 | -7.437 | In-Between | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.164 | Likely Benign | 0.2067 | 0.3109 | -2.31 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 4.04 | Benign | 0.00 | Affected | 2 | 0 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||
| c.468T>G | F156L 2D AISynGAP1 missense variant F156L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, whereas tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (benign)—leans toward benign. Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the preponderance of conventional tools indicates a pathogenic effect, and the high‑accuracy predictions are mixed; no ClinVar entry exists to contradict the assessment. Therefore, 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. | 0.476583 | Structured | 0.521964 | Binding | 0.284 | 0.785 | 0.500 | -7.437 | In-Between | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.163 | Likely Benign | 0.2067 | 0.3109 | -2.31 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 4.04 | Benign | 0.00 | Affected | 2 | 0 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||
| c.469C>A | R157S 2D  AIThe SynGAP1 R157S missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM, while the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. ESM1b remains uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic majority vote (2 pathogenic, 1 benign, 1 uncertain). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that R157S is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.483068 | Structured | 0.523978 | Binding | 0.306 | 0.777 | 0.375 | -7.573 | In-Between | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.211 | Likely Benign | 0.3484 | 0.2563 | -2.82 | Deleterious | 0.993 | Probably Damaging | 0.982 | Probably Damaging | 3.85 | Benign | 0.00 | Affected | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||
| c.469C>G | R157G 2D AIThe SynGAP1 R157G missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized yields an Uncertain result, SGM‑Consensus indicates Likely Pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.483068 | Structured | 0.523978 | Binding | 0.306 | 0.777 | 0.375 | -9.125 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | 0.252 | Likely Benign | 0.3892 | 0.2567 | -3.52 | Deleterious | 0.993 | Probably Damaging | 0.982 | Probably Damaging | 3.80 | Benign | 0.00 | Affected | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||
| c.469C>T | R157C 2D  AIThe SynGAP1 missense variant R157C is listed in gnomAD (ID 6‑33432766‑C‑T) but has no ClinVar entry. Functional prediction tools split in two groups: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (which is “Likely Pathogenic”). AlphaMissense‑Optimized returns an uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available prediction for this variant. High‑accuracy assessments therefore indicate a likely pathogenic consensus from SGM‑Consensus, an uncertain AlphaMissense‑Optimized score, and no Foldetta data. Overall, the majority of evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.483068 | Structured | 0.523978 | Binding | 0.306 | 0.777 | 0.375 | 6-33432766-C-T | 7 | 4.34e-6 | -11.524 | Likely Pathogenic | 0.880 | Likely Pathogenic | Ambiguous | 0.237 | Likely Benign | 0.3696 | 0.2092 | -4.02 | Deleterious | 1.000 | Probably Damaging | 0.990 | Probably Damaging | 3.77 | Benign | 0.00 | Affected | 3.74 | 4 | -3 | -4 | 7.0 | -53.05 | ||||||||||||||||||||||||||||||
| c.470G>A | R157H 2D  AIThe SynGAP1 missense variant R157H (ClinVar ID 2065231.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33432767‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant. Overall, the balance of predictions leans toward pathogenic, but the high‑accuracy tools do not provide a definitive verdict. This assessment does not contradict the ClinVar status, which remains Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.483068 | Structured | 0.523978 | Binding | 0.306 | 0.777 | 0.375 | Uncertain | 1 | 6-33432767-G-A | 1 | 6.20e-7 | -10.235 | Likely Pathogenic | 0.604 | Likely Pathogenic | Likely Benign | 0.254 | Likely Benign | 0.2981 | 0.1449 | -2.23 | Neutral | 0.999 | Probably Damaging | 0.987 | Probably Damaging | 3.80 | Benign | 0.00 | Affected | 3.74 | 4 | 2 | 0 | 1.3 | -19.05 | |||||||||||||||||||||||||||||
| c.470G>C | R157P 2D AIThe SynGAP1 missense variant R157P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM. All other evaluated 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)—predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus indicates it is likely pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic; this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.483068 | Structured | 0.523978 | Binding | 0.306 | 0.777 | 0.375 | -11.463 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.450 | Likely Benign | 0.2438 | 0.3438 | -3.38 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 3.79 | Benign | 0.00 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||
| c.470G>T | R157L 2D AIThe SynGAP1 missense variant R157L is not 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, and AlphaMissense‑Default all classify the variant as damaging. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Overall, the preponderance of evidence 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 | 0.483068 | Structured | 0.523978 | Binding | 0.306 | 0.777 | 0.375 | -8.978 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.330 | Likely Benign | 0.2015 | 0.3709 | -3.13 | Deleterious | 0.993 | Probably Damaging | 0.982 | Probably Damaging | 3.81 | Benign | 0.00 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||
| c.472C>A | Q158K 2D AIThe SynGAP1 missense variant Q158K is not reported in ClinVar and has no entry in gnomAD, indicating it is not catalogued in these databases. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus indicates likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the computational evidence strongly suggests the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.527565 | Binding | 0.286 | 0.750 | 0.375 | -6.795 | Likely Benign | 0.481 | Ambiguous | Likely Benign | 0.069 | Likely Benign | 0.1851 | 0.3869 | -0.86 | Neutral | 0.276 | Benign | 0.121 | Benign | 4.20 | Benign | 0.15 | Tolerated | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||
| c.472C>G | Q158E 2D AIThe SynGAP1 missense variant Q158E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only ESM1b predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign consensus. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.527565 | Binding | 0.286 | 0.750 | 0.375 | -11.133 | Likely Pathogenic | 0.196 | Likely Benign | Likely Benign | 0.063 | Likely Benign | 0.1420 | 0.2223 | -0.54 | Neutral | 0.143 | Benign | 0.078 | Benign | 4.20 | Benign | 0.09 | Tolerated | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||
| c.473A>C | Q158P 2D AIThe SynGAP1 missense variant Q158P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for Q158P, 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 | 0.480142 | Structured | 0.527565 | Binding | 0.286 | 0.750 | 0.375 | -6.120 | Likely Benign | 0.150 | Likely Benign | Likely Benign | 0.192 | Likely Benign | 0.2167 | 0.4190 | -0.99 | Neutral | 0.851 | Possibly Damaging | 0.374 | Benign | 4.12 | Benign | 0.03 | Affected | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||
| c.473A>G | Q158R 2D AIThe SynGAP1 missense variant Q158R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. The predictions do not contradict ClinVar status, as ClinVar contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.527565 | Binding | 0.286 | 0.750 | 0.375 | -6.873 | Likely Benign | 0.438 | Ambiguous | Likely Benign | 0.090 | Likely Benign | 0.1527 | 0.1498 | -0.85 | Neutral | 0.276 | Benign | 0.121 | Benign | 4.14 | Benign | 0.11 | Tolerated | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||
| c.473A>T | Q158L 2D AIThe SynGAP1 missense variant Q158L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for Q158L, 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 | 0.480142 | Structured | 0.527565 | Binding | 0.286 | 0.750 | 0.375 | -5.965 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.141 | Likely Benign | 0.0711 | 0.4832 | -1.11 | Neutral | 0.652 | Possibly Damaging | 0.160 | Benign | 4.14 | Benign | 0.03 | Affected | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||
| c.474G>C | Q158H 2D AIThe SynGAP1 missense variant Q158H is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.527565 | Binding | 0.286 | 0.750 | 0.375 | -2.990 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.084 | Likely Benign | 0.1403 | 0.3774 | 0.02 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.19 | Benign | 0.51 | Tolerated | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.474G>T | Q158H 2D AIThe SynGAP1 missense variant Q158H is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.527565 | Binding | 0.286 | 0.750 | 0.375 | -2.990 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.084 | Likely Benign | 0.1403 | 0.3774 | 0.02 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.19 | Benign | 0.51 | Tolerated | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.475A>C | I159L 2D AIThe SynGAP1 missense variant I159L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. ESM1b is uncertain, and the SGM‑Consensus (majority vote 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 not available. Overall, the majority of evidence points to a benign impact for I159L, 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 | 0.454136 | Structured | 0.529953 | Binding | 0.278 | 0.731 | 0.125 | -7.936 | In-Between | 0.195 | Likely Benign | Likely Benign | 0.128 | Likely Benign | 0.0776 | 0.2652 | -0.39 | Neutral | 0.904 | Possibly Damaging | 0.847 | Possibly Damaging | 4.04 | Benign | 0.00 | Affected | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||
| c.475A>G | I159V 2D AIThe SynGAP1 I159V missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b; 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, PROVEAN) yields a benign consensus (2 benign vs. 1 pathogenic, with one 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. | 0.454136 | Structured | 0.529953 | Binding | 0.278 | 0.731 | 0.125 | -9.714 | Likely Pathogenic | 0.384 | Ambiguous | Likely Benign | 0.113 | Likely Benign | 0.1111 | 0.2736 | -0.25 | Neutral | 0.803 | Possibly Damaging | 0.847 | Possibly Damaging | 3.98 | Benign | 0.00 | Affected | 4 | 3 | -0.3 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.475A>T | I159F 2D AIThe SynGAP1 missense variant I159F is not 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, polyPhen‑2 HumVar, SIFT, 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 (2 benign vs. 1 pathogenic, 1 uncertain). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the balance of evidence, particularly from the high‑accuracy tools, points to 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. | 0.454136 | Structured | 0.529953 | Binding | 0.278 | 0.731 | 0.125 | -9.530 | Likely Pathogenic | 0.447 | Ambiguous | Likely Benign | 0.200 | Likely Benign | 0.0490 | 0.2446 | -1.41 | Neutral | 0.995 | Probably Damaging | 0.979 | Probably Damaging | 3.87 | Benign | 0.00 | Affected | 1 | 0 | -1.7 | 34.02 | ||||||||||||||||||||||||||||||||||||
| c.476T>A | I159N 2D AIThe SynGAP1 missense variant I159N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑vs‑2 split. Foldetta, which would assess protein‑folding stability, has no available output for this variant. Overall, the majority of tools (five out of eight) predict pathogenicity, while three predict benign and one is uncertain. Thus, the variant is most likely pathogenic based on current computational predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.454136 | Structured | 0.529953 | Binding | 0.278 | 0.731 | 0.125 | -14.684 | Likely Pathogenic | 0.891 | Likely Pathogenic | Ambiguous | 0.218 | Likely Benign | 0.0919 | 0.0342 | -1.93 | Neutral | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 3.82 | Benign | 0.00 | Affected | -2 | -3 | -8.0 | 0.94 | ||||||||||||||||||||||||||||||||||||
| c.476T>C | I159T 2D AIThe SynGAP1 missense variant I159T is not 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 predict a pathogenic effect comprise polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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 AlphaMissense‑Optimized predicts pathogenic, while AlphaMissense‑Default also predicts pathogenic. Given that six of the seven individual tools predict pathogenicity versus three predicting benign, the variant is most likely pathogenic. 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. | 0.454136 | Structured | 0.529953 | Binding | 0.278 | 0.731 | 0.125 | -12.422 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.218 | Likely Benign | 0.1069 | 0.0685 | -1.69 | Neutral | 0.981 | Probably Damaging | 0.966 | Probably Damaging | 3.86 | Benign | 0.00 | Affected | 0 | -1 | -5.2 | -12.05 | ||||||||||||||||||||||||||||||||||||
| c.476T>G | I159S 2D AIThe SynGAP1 missense variant I159S is not 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 are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool rates the variant as uncertain, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of available predictions (five pathogenic vs. three benign) lean toward pathogenicity. 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. | 0.454136 | Structured | 0.529953 | Binding | 0.278 | 0.731 | 0.125 | -13.684 | Likely Pathogenic | 0.905 | Likely Pathogenic | Ambiguous | 0.241 | Likely Benign | 0.2854 | 0.0712 | -1.70 | Neutral | 0.995 | Probably Damaging | 0.979 | Probably Damaging | 3.85 | Benign | 0.00 | Affected | -1 | -2 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||||||||
| c.477C>G | I159M 2D AIThe SynGAP1 missense variant I159M is not reported 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 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 | 0.454136 | Structured | 0.529953 | Binding | 0.278 | 0.731 | 0.125 | -9.838 | Likely Pathogenic | 0.142 | Likely Benign | Likely Benign | 0.071 | Likely Benign | 0.0678 | 0.2500 | -0.48 | Neutral | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 3.89 | Benign | 0.00 | Affected | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||
| c.478C>A | L160M 2D AIThe SynGAP1 missense variant L160M is not 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, 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 because it yields a 2‑to‑2 split. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; the SGM Consensus is unavailable; and Foldetta, which combines FoldX‑MD and Rosetta stability calculations, has no reported output for this variant. Overall, the balance of evidence leans toward a pathogenic interpretation, but the single high‑accuracy benign prediction and the lack of a ClinVar assertion mean the variant’s clinical significance remains uncertain. This assessment does not contradict any existing ClinVar status, as none is available. Thus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.454136 | Structured | 0.526760 | Binding | 0.275 | 0.728 | 0.125 | -11.120 | Likely Pathogenic | 0.723 | Likely Pathogenic | Likely Benign | 0.097 | Likely Benign | 0.0837 | 0.3613 | -0.94 | Neutral | 0.877 | Possibly Damaging | 0.580 | Possibly Damaging | 3.85 | Benign | 0.00 | Affected | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||
| c.478C>G | L160V 2D AIThe SynGAP1 missense variant L160V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. three pathogenic) indicate that the variant is most likely benign. This conclusion is consistent with the lack of ClinVar evidence and gnomAD presence, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.454136 | Structured | 0.526760 | Binding | 0.275 | 0.728 | 0.125 | -12.506 | Likely Pathogenic | 0.729 | Likely Pathogenic | Likely Benign | 0.055 | Likely Benign | 0.1553 | 0.3319 | -1.44 | Neutral | 0.247 | Benign | 0.113 | Benign | 3.90 | Benign | 0.00 | Affected | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.479T>A | L160Q 2D AIThe SynGAP1 missense variant L160Q is not 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 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 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 | 0.454136 | Structured | 0.526760 | Binding | 0.275 | 0.728 | 0.125 | -16.626 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.227 | Likely Benign | 0.1248 | 0.1060 | -2.83 | Deleterious | 0.700 | Possibly Damaging | 0.483 | Possibly Damaging | 3.87 | Benign | 0.00 | Affected | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||
| c.479T>C | L160P 2D AIThe SynGAP1 missense variant L160P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a majority pathogenic vote (3 pathogenic vs. 1 benign) and is labeled “Likely Pathogenic.” AlphaMissense‑Optimized independently predicts pathogenicity. 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 pathogenic, and this assessment does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.454136 | Structured | 0.526760 | Binding | 0.275 | 0.728 | 0.125 | -15.939 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 0.283 | Likely Benign | 0.3589 | 0.1484 | -3.06 | Deleterious | 0.001 | Benign | 0.000 | Benign | 3.86 | Benign | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||
| c.479T>G | L160R 2D AIThe SynGAP1 missense variant L160R is not 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 did not provide a result, so its status is unavailable. 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 annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.454136 | Structured | 0.526760 | Binding | 0.275 | 0.728 | 0.125 | -14.539 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.190 | Likely Benign | 0.1482 | 0.0702 | -2.83 | Deleterious | 0.700 | Possibly Damaging | 0.483 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||
| c.481C>A | P161T 2D AIThe SynGAP1 missense variant P161T has no ClinVar entry and is not reported in gnomAD. Computational predictors fall into two groups: benign predictions come from 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, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy tools further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method that combines FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic effect, and this assessment is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.509769 | Disordered | 0.520000 | Binding | 0.256 | 0.713 | 0.375 | -8.759 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.153 | Likely Benign | 0.1891 | 0.5038 | -3.77 | Deleterious | 0.535 | Possibly Damaging | 0.310 | Benign | 3.92 | Benign | 0.00 | Affected | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||
| c.481C>G | P161A 2D AIThe SynGAP1 missense variant P161A is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls arise from PROVEAN, SIFT, ESM1b and AlphaMissense‑Default. When predictions are grouped by consensus, four tools predict benign and four predict pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Overall, the balance of evidence, especially the SGM Consensus and the majority of individual predictors, indicates that P161A 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 | -9.012 | Likely Pathogenic | 0.926 | Likely Pathogenic | Ambiguous | 0.079 | Likely Benign | 0.3600 | 0.4123 | -3.52 | Deleterious | 0.247 | Benign | 0.091 | Benign | 3.95 | Benign | 0.00 | Affected | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| c.481C>T | P161S 2D AIThe SynGAP1 missense variant P161S 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. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta 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 (none is available). 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 | -8.550 | Likely Pathogenic | 0.945 | Likely Pathogenic | Ambiguous | 0.085 | Likely Benign | 0.3628 | 0.4597 | -3.63 | Deleterious | 0.700 | Possibly Damaging | 0.383 | Benign | 3.94 | Benign | 0.00 | Affected | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||
| c.482C>A | P161H 2D AIThe SynGAP1 missense variant P161H 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 (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and 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. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple in silico predictors indicates that P161H 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 | 0.509769 | Disordered | 0.520000 | Binding | 0.256 | 0.713 | 0.375 | -12.103 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.291 | Likely Benign | 0.2060 | 0.4039 | -4.22 | Deleterious | 0.964 | Probably Damaging | 0.650 | Possibly Damaging | 3.89 | Benign | 0.00 | Affected | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1716 | 0.2900 | -4.16 | Deleterious | 0.700 | Possibly Damaging | 0.483 | Possibly Damaging | 3.93 | Benign | 0.00 | Affected | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.482C>T | P161L 2D AIThe SynGAP1 missense variant P161L is not 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 comprise PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus (SGM‑Consensus) derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN classifies the variant as Likely Pathogenic. AlphaMissense‑Optimized also predicts Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the majority of predictions (seven pathogenic vs. four benign) indicate that P161L 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 | 0.509769 | Disordered | 0.520000 | Binding | 0.256 | 0.713 | 0.375 | -12.159 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.236 | Likely Benign | 0.2424 | 0.5902 | -4.48 | Deleterious | 0.001 | Benign | 0.003 | Benign | 3.92 | Benign | 0.00 | Affected | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||
| c.484C>A | R162S 2D AIThe SynGAP1 missense variant R162S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). AlphaMissense‑Optimized is currently Uncertain, and no Foldetta stability result is available. Overall, the majority of high‑accuracy and consensus predictions indicate a benign impact. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.501700 | Disordered | 0.516348 | Binding | 0.315 | 0.692 | 0.250 | -1.395 | Likely Benign | 0.894 | Likely Pathogenic | Ambiguous | 0.191 | Likely Benign | 0.3080 | 0.4974 | -0.24 | Neutral | 0.487 | Possibly Damaging | 0.272 | Benign | 4.14 | Benign | 0.75 | Tolerated | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||
| c.484C>G | R162G 2D AIThe SynGAP1 missense variant R162G is listed in ClinVar (ID 2703066.0) with an uncertain significance status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta stability analysis is unavailable. Overall, the majority of predictions support a benign impact, and this is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.501700 | Disordered | 0.516348 | Binding | 0.315 | 0.692 | 0.250 | Uncertain | 1 | -6.985 | Likely Benign | 0.664 | Likely Pathogenic | Likely Benign | 0.190 | Likely Benign | 0.3562 | 0.4308 | -0.73 | Neutral | 0.487 | Possibly Damaging | 0.272 | Benign | 4.09 | Benign | 0.78 | Tolerated | 3.74 | 4 | -2 | -3 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||
| c.484C>T | R162C 2D AIThe SynGAP1 missense variant R162C is listed in ClinVar as Pathogenic and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, whereas tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive, and Foldetta stability analysis is unavailable. Overall, the available predictions are split evenly between benign and pathogenic, with no single method providing decisive evidence. Thus, the variant’s pathogenicity remains uncertain based on computational predictions, which contradicts the ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.516348 | Binding | 0.315 | 0.692 | 0.250 | Pathogenic | 2 | -8.157 | Likely Pathogenic | 0.787 | Likely Pathogenic | Ambiguous | 0.150 | Likely Benign | 0.3364 | 0.4292 | -2.05 | Neutral | 0.988 | Probably Damaging | 0.513 | Possibly Damaging | 4.00 | Benign | 0.11 | Tolerated | 3.74 | 4 | -4 | -3 | 7.0 | -53.05 | ||||||||||||||||||||||||||||||||
| c.485G>A | R162H 2D AIThe SynGAP1 missense variant R162H is listed in ClinVar with an uncertain significance and is present in the gnomAD database (variant ID 6‑33432782‑G‑A). Functional prediction tools cluster into two groups: benign calls are made by REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls come from polyPhen‑2 (HumDiv and HumVar) and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a benign verdict. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the preponderance of evidence points to a benign effect, which does not contradict the ClinVar uncertain classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.516348 | Binding | 0.315 | 0.692 | 0.250 | Uncertain | 1 | 6-33432782-G-A | 2 | 1.24e-6 | -9.730 | Likely Pathogenic | 0.480 | Ambiguous | Likely Benign | 0.167 | Likely Benign | 0.2981 | 0.2872 | -1.13 | Neutral | 0.957 | Probably Damaging | 0.513 | Possibly Damaging | 4.03 | Benign | 0.12 | Tolerated | 3.74 | 4 | 2 | 0 | 1.3 | -19.05 | |||||||||||||||||||||||||||||
| c.485G>C | R162P 2D AISynGAP1 missense variant R162P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool reports an uncertain result, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Foldetta, which combines FoldX‑MD and Rosetta stability outputs, has no available result for this variant. Consequently, the evidence is evenly divided: four tools support benign, four support pathogenic, and the remaining high‑accuracy methods provide no decisive signal. The variant is therefore not clearly benign or pathogenic based on current predictions, and this lack of consensus does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.516348 | Binding | 0.315 | 0.692 | 0.250 | -10.077 | Likely Pathogenic | 0.787 | Likely Pathogenic | Ambiguous | 0.241 | Likely Benign | 0.2192 | 0.5507 | -1.50 | Neutral | 0.910 | Possibly Damaging | 0.578 | Possibly Damaging | 4.03 | Benign | 0.30 | Tolerated | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||
| c.485G>T | R162L 2D AIThe SynGAP1 missense variant R162L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM, giving six concordant benign calls. Two tools predict a pathogenic effect: ESM1b and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta data are unavailable. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.516348 | Binding | 0.315 | 0.692 | 0.250 | -9.952 | Likely Pathogenic | 0.840 | Likely Pathogenic | Ambiguous | 0.219 | Likely Benign | 0.1888 | 0.5894 | -1.83 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.05 | Benign | 0.15 | Tolerated | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||||
| c.487T>A | F163I 2D AIThe SynGAP1 missense variant F163I is not 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. 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. Overall, the majority of evaluated tools (five pathogenic vs. three 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 is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.433034 | Structured | 0.513928 | Binding | 0.325 | 0.686 | 0.375 | -10.706 | Likely Pathogenic | 0.912 | Likely Pathogenic | Ambiguous | 0.175 | Likely Benign | 0.2114 | 0.2320 | -1.62 | Neutral | 0.981 | Probably Damaging | 0.966 | Probably Damaging | 4.12 | Benign | 0.03 | Affected | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||||||||
| c.487T>C | F163L 2D AIThe SynGAP1 missense variant F163L has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, whereas the SGM‑Consensus indicates a likely benign outcome; Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, and this assessment does not contradict the ClinVar status, which currently has no classification for F163L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.513928 | Binding | 0.325 | 0.686 | 0.375 | -6.380 | Likely Benign | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.193 | Likely Benign | 0.2191 | 0.3491 | -1.22 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 4.21 | Benign | 0.37 | Tolerated | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||
| c.487T>G | F163V 2D AIThe SynGAP1 missense variant F163V is not 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 polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict a pathogenic impact. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and therefore unavailable; Foldetta data are not provided. Overall, the majority of available predictions (five pathogenic vs. three benign) indicate that the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.433034 | Structured | 0.513928 | Binding | 0.325 | 0.686 | 0.375 | -12.580 | Likely Pathogenic | 0.927 | Likely Pathogenic | Ambiguous | 0.236 | Likely Benign | 0.2214 | 0.2547 | -2.06 | Neutral | 0.981 | Probably Damaging | 0.954 | Probably Damaging | 4.13 | Benign | 0.02 | Affected | -1 | -1 | 1.4 | -48.04 | ||||||||||||||||||||||||||||||||||||
| c.488T>A | F163Y 2D AIThe SynGAP1 missense variant F163Y is not 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, 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) and is therefore treated as unavailable. High‑accuracy methods show AlphaMissense‑Optimized as benign; Foldetta results are not provided, so its stability prediction is unavailable. Overall, the majority of available predictions (5 pathogenic vs. 4 benign) indicate 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. | 0.433034 | Structured | 0.513928 | Binding | 0.325 | 0.686 | 0.375 | -10.087 | Likely Pathogenic | 0.722 | Likely Pathogenic | Likely Benign | 0.125 | Likely Benign | 0.1529 | 0.2152 | -1.09 | Neutral | 0.981 | Probably Damaging | 0.931 | Probably Damaging | 4.03 | Benign | 0.04 | Affected | 7 | 3 | -4.1 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.488T>C | F163S 2D AIThe SynGAP1 missense variant F163S 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. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence indicates that F163S is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.433034 | Structured | 0.513928 | Binding | 0.325 | 0.686 | 0.375 | -13.338 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.273 | Likely Benign | 0.5240 | 0.0358 | Weaken | -2.64 | Deleterious | 0.995 | Probably Damaging | 0.979 | Probably Damaging | 4.05 | Benign | 0.00 | Affected | -3 | -2 | -3.6 | -60.10 | ||||||||||||||||||||||||||||||||||
| c.488T>G | F163C 2D AIThe SynGAP1 missense variant F163C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM. All other evaluated 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)—predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus indicates a likely pathogenic status. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of predictions, including the high‑accuracy tools, point 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 | 0.433034 | Structured | 0.513928 | Binding | 0.325 | 0.686 | 0.375 | -12.221 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.282 | Likely Benign | 0.2860 | 0.1232 | -2.99 | Deleterious | 0.999 | Probably Damaging | 0.990 | Probably Damaging | 4.01 | Benign | 0.00 | Affected | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||||||||
| c.489C>A | F163L 2D AIThe SynGAP1 missense variant F163L has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, whereas the SGM‑Consensus indicates a likely benign outcome; Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, and this assessment does not contradict the ClinVar status, which currently has no classification for F163L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.513928 | Binding | 0.325 | 0.686 | 0.375 | -6.380 | Likely Benign | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.190 | Likely Benign | 0.2191 | 0.3491 | -1.22 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 4.21 | Benign | 0.37 | Tolerated | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||
| c.489C>G | F163L 2D AIThe SynGAP1 missense variant F163L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, six tools favor a benign outcome versus four favoring pathogenicity, and the high‑accuracy predictions are conflicting. Thus, the variant is most likely benign based on the current consensus, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.513928 | Binding | 0.325 | 0.686 | 0.375 | -6.380 | Likely Benign | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.190 | Likely Benign | 0.2191 | 0.3491 | -1.22 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 4.21 | Benign | 0.37 | Tolerated | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||
| c.490C>G | R164G 2D AIThe SynGAP1 missense variant R164G has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split opinion: benign calls come from REVEL, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: the SGM‑Consensus remains Likely Pathogenic, AlphaMissense‑Optimized is inconclusive, and the Foldetta stability analysis is unavailable. Overall, the majority of evidence points toward a pathogenic impact. Because there is no ClinVar classification to oppose this, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.414856 | Structured | 0.512396 | Binding | 0.317 | 0.666 | 0.250 | -12.416 | Likely Pathogenic | 0.879 | Likely Pathogenic | Ambiguous | 0.190 | Likely Benign | 0.3657 | 0.3631 | -3.01 | Deleterious | 0.487 | Possibly Damaging | 0.272 | Benign | 3.77 | Benign | 0.00 | Affected | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||
| c.491G>A | R164Q 2D AISynGAP1 missense variant R164Q is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33432788‑G‑A). Functional prediction tools show mixed results: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions come from polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split; Foldetta results are not available. Overall, the balance of evidence slightly favors a benign interpretation, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.414856 | Structured | 0.512396 | Binding | 0.317 | 0.666 | 0.250 | Uncertain | 1 | 6-33432788-G-A | 2 | 1.24e-6 | -11.208 | Likely Pathogenic | 0.600 | Likely Pathogenic | Likely Benign | 0.184 | Likely Benign | 0.3607 | 0.2711 | -1.86 | Neutral | 0.957 | Probably Damaging | 0.342 | Benign | 3.82 | Benign | 0.00 | Affected | 3.74 | 4 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||||
| c.491G>C | R164P 2D AIThe SynGAP1 missense variant R164P is reported in gnomAD (ID 6‑33432788‑G‑C) but has no ClinVar entry. Functional prediction tools split in two groups: benign predictions come from REVEL and FATHMM, whereas pathogenic predictions 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, classifies the variant as Likely Pathogenic. AlphaMissense‑Optimized returns an Uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available output for this variant. Overall, the majority of high‑confidence tools predict pathogenicity, and this assessment does not contradict any ClinVar status (none is available). Therefore, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.414856 | Structured | 0.512396 | Binding | 0.317 | 0.666 | 0.250 | 6-33432788-G-C | 1 | 6.20e-7 | -12.792 | Likely Pathogenic | 0.898 | Likely Pathogenic | Ambiguous | 0.339 | Likely Benign | 0.2408 | 0.4730 | -3.42 | Deleterious | 0.910 | Possibly Damaging | 0.578 | Possibly Damaging | 3.77 | Benign | 0.00 | Affected | 3.74 | 4 | -2 | 0 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||
| c.491G>T | R164L 2D AIThe SynGAP1 missense variant R164L is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls arise from PROVEAN, SIFT, ESM1b and AlphaMissense‑Default. Grouping by consensus, four tools predict benign and four predict pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Taken together, the majority of evidence, including the SGM Consensus, points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for R164L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.414856 | Structured | 0.512396 | Binding | 0.317 | 0.666 | 0.250 | -10.794 | Likely Pathogenic | 0.910 | Likely Pathogenic | Ambiguous | 0.274 | Likely Benign | 0.2137 | 0.5154 | -3.37 | Deleterious | 0.001 | Benign | 0.003 | Benign | 3.80 | Benign | 0.00 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1003 | 0.3969 | -1.89 | Neutral | 0.567 | Possibly Damaging | 0.249 | Benign | 4.01 | Benign | 0.00 | Affected | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| c.493A>G | S165G 2D AIThe SynGAP1 missense variant S165G is not reported 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. Only SIFT predicts a pathogenic outcome, 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 interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable. Overall, the preponderance of evidence points to the variant being most likely benign, and this conclusion 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 | 0.429200 | Structured | 0.509123 | Binding | 0.324 | 0.644 | 0.250 | -7.691 | In-Between | 0.223 | Likely Benign | Likely Benign | 0.182 | Likely Benign | 0.2622 | 0.4441 | -1.17 | Neutral | 0.272 | Benign | 0.086 | Benign | 3.99 | Benign | 0.00 | Affected | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.493A>T | S165C 2D AIThe SynGAP1 missense variant S165C is not reported 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. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact for S165C, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.509123 | Binding | 0.324 | 0.644 | 0.250 | -8.425 | Likely Pathogenic | 0.367 | Ambiguous | Likely Benign | 0.304 | Likely Benign | 0.1306 | 0.5534 | -1.92 | Neutral | 0.938 | Possibly Damaging | 0.498 | Possibly Damaging | 3.94 | Benign | 0.00 | Affected | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||
| c.494G>A | S165N 2D AIThe SynGAP1 missense variant S165N is not reported 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, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and ESM1b. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also 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, as no ClinVar classification exists for S165N. 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 | -9.041 | Likely Pathogenic | 0.509 | Ambiguous | Likely Benign | 0.074 | Likely Benign | 0.1589 | 0.4862 | -0.49 | Neutral | 0.532 | Possibly Damaging | 0.229 | Benign | 4.03 | Benign | 0.00 | Affected | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||
| c.494G>C | S165T 2D AIThe SynGAP1 missense variant S165T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect. The variant is most likely benign, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.509123 | Binding | 0.324 | 0.644 | 0.250 | -6.952 | Likely Benign | 0.205 | Likely Benign | Likely Benign | 0.076 | Likely Benign | 0.1754 | 0.5779 | -0.94 | Neutral | 0.155 | Benign | 0.064 | Benign | 4.02 | Benign | 0.00 | Affected | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.494G>T | S165I 2D AISynGAP1 missense variant S165I has no ClinVar record and is absent from gnomAD. Individual prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains Likely Pathogenic; Foldetta stability analysis is unavailable. Overall, the majority of single‑tool predictions favor a benign effect, whereas the consensus score suggests pathogenicity. Consequently, the variant is most likely benign according to the bulk of evidence, 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 Pathogenic | 0.429200 | Structured | 0.509123 | Binding | 0.324 | 0.644 | 0.250 | -11.304 | Likely Pathogenic | 0.774 | Likely Pathogenic | Likely Benign | 0.259 | Likely Benign | 0.0943 | 0.5027 | -2.53 | Deleterious | 0.084 | Benign | 0.031 | Benign | 3.96 | Benign | 0.00 | Affected | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1003 | 0.3969 | -1.89 | Neutral | 0.567 | Possibly Damaging | 0.249 | Benign | 4.01 | Benign | 0.00 | Affected | 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 | 0.1003 | 0.3969 | -1.89 | Neutral | 0.567 | Possibly Damaging | 0.249 | Benign | 4.01 | Benign | 0.00 | Affected | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| c.496G>A | A166T 2D  AIThe SynGAP1 missense variant A166T is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess sequence conservation and structural impact (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the change as benign. No tool in the dataset predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign.” Foldetta results are not available. Overall, the consensus of all available predictions indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.505037 | Binding | 0.384 | 0.658 | 0.125 | -6.700 | Likely Benign | 0.169 | Likely Benign | Likely Benign | 0.115 | Likely Benign | 0.1420 | 0.5134 | -0.78 | Neutral | 0.399 | Benign | 0.273 | Benign | 4.10 | Benign | 0.31 | Tolerated | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.496G>C | A166P 2D  AIThe SynGAP1 missense variant A166P is not reported 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 for A166P, 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 | 0.425610 | Structured | 0.505037 | Binding | 0.384 | 0.658 | 0.125 | -9.665 | Likely Pathogenic | 0.273 | Likely Benign | Likely Benign | 0.172 | Likely Benign | 0.1861 | 0.3668 | -2.04 | Neutral | 0.877 | Possibly Damaging | 0.580 | Possibly Damaging | 3.99 | Benign | 0.02 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||
| c.496G>T | A166S 2D  AIThe SynGAP1 missense variant A166 S 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 outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.505037 | Binding | 0.384 | 0.658 | 0.125 | -6.008 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.080 | Likely Benign | 0.2286 | 0.4146 | -0.78 | Neutral | 0.399 | Benign | 0.212 | Benign | 4.07 | Benign | 0.05 | Affected | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||
| c.497C>A | A166D 2D  AIThe SynGAP1 missense variant A166D is not 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. The high‑accuracy consensus method SGM (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive, yielding a 2‑to‑2 split. AlphaMissense‑Optimized rates the variant as uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result for this change. Overall, the majority of tools predict a pathogenic impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely pathogenic based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.425610 | Structured | 0.505037 | Binding | 0.384 | 0.658 | 0.125 | -12.171 | Likely Pathogenic | 0.900 | Likely Pathogenic | Ambiguous | 0.144 | Likely Benign | 0.2031 | 0.2694 | -2.21 | Neutral | 0.877 | Possibly Damaging | 0.580 | Possibly Damaging | 4.02 | Benign | 0.01 | Affected | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||
| c.497C>G | A166G 2D AIThe SynGAP1 missense variant A166G 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 SIFT and ESM1b predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a majority‑benign vote and is reported as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.505037 | Binding | 0.384 | 0.658 | 0.125 | -8.188 | Likely Pathogenic | 0.215 | Likely Benign | Likely Benign | 0.101 | Likely Benign | 0.1665 | 0.3201 | -1.16 | Neutral | 0.399 | Benign | 0.212 | Benign | 4.02 | Benign | 0.03 | Affected | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.497C>T | A166V 2D AIThe SynGAP1 missense variant A166V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.505037 | Binding | 0.384 | 0.658 | 0.125 | -6.689 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.191 | Likely Benign | 0.1027 | 0.4281 | -1.09 | Neutral | 0.141 | Benign | 0.091 | Benign | 4.07 | Benign | 0.02 | Affected | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||
| c.499G>A | D167N 2D AIThe SynGAP1 missense variant D167N is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33432796‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic, two benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the available predictions, the variant is most likely benign; this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.502306 | Binding | 0.377 | 0.667 | 0.375 | 6-33432796-G-A | 3 | 1.86e-6 | -11.939 | Likely Pathogenic | 0.843 | Likely Pathogenic | Ambiguous | 0.097 | Likely Benign | 0.1222 | 0.7330 | -2.32 | Neutral | 0.141 | Benign | 0.123 | Benign | 3.96 | Benign | 0.00 | Affected | 3.74 | 4 | 1 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||
| c.499G>C | D167H 2D AIThe SynGAP1 missense variant D167H is not 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 | 0.429200 | Structured | 0.502306 | Binding | 0.377 | 0.667 | 0.375 | -12.606 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 0.338 | Likely Benign | 0.1478 | 0.7563 | -3.29 | Deleterious | 0.898 | Possibly Damaging | 0.557 | Possibly Damaging | 3.93 | Benign | 0.00 | Affected | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||
| c.499G>T | D167Y 2D AIThe SynGAP1 missense variant D167Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL and FATHMM, whereas the remaining eight predictors—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized—and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. No Foldetta stability analysis is available for this residue. Overall, the majority of evidence points to a pathogenic impact for D167Y, and this conclusion is not contradicted by any ClinVar annotation, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.429200 | Structured | 0.502306 | Binding | 0.377 | 0.667 | 0.375 | -14.228 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.414 | Likely Benign | 0.0493 | 0.6358 | -4.23 | Deleterious | 0.898 | Possibly Damaging | 0.557 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||
| c.500A>C | D167A 2D AIThe SynGAP1 D167A missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools split evenly: benign calls come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls come from PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Taken together, the preponderance of evidence, especially the SGM Consensus, points to a pathogenic effect. This conclusion is consistent with the absence of a ClinVar classification, so there is no contradiction with existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.429200 | Structured | 0.502306 | Binding | 0.377 | 0.667 | 0.375 | -13.473 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | 0.291 | Likely Benign | 0.3429 | 0.6549 | -3.61 | Deleterious | 0.141 | Benign | 0.056 | Benign | 3.97 | Benign | 0.00 | Affected | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||
| c.500A>G | D167G 2D AIThe SynGAP1 missense variant D167G is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those 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 Uncertain, while Foldetta (combining FoldX‑MD and Rosetta outputs) is not available for this variant. Overall, the majority of evidence points to a pathogenic impact. The prediction is consistent with the absence of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.429200 | Structured | 0.502306 | Binding | 0.377 | 0.667 | 0.375 | -11.806 | Likely Pathogenic | 0.898 | Likely Pathogenic | Ambiguous | 0.338 | Likely Benign | 0.3580 | 0.6750 | -3.20 | Deleterious | 0.141 | Benign | 0.091 | Benign | 3.93 | Benign | 0.00 | Affected | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||
| c.500A>T | D167V 2D AIThe SynGAP1 D167V variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic impact are 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 outcome: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic effect, 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 | 0.429200 | Structured | 0.502306 | Binding | 0.377 | 0.667 | 0.375 | -14.388 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.396 | Likely Benign | 0.0709 | 0.6905 | -4.03 | Deleterious | 0.535 | Possibly Damaging | 0.247 | Benign | 3.92 | Benign | 0.00 | Affected | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||
| c.501C>A | D167E 2D AIThe SynGAP1 D167E missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive because it receives two benign votes and two uncertain votes, yielding no clear majority. Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.502306 | Binding | 0.377 | 0.667 | 0.375 | -7.636 | In-Between | 0.516 | Ambiguous | Likely Benign | 0.067 | Likely Benign | 0.1392 | 0.7144 | -1.52 | Neutral | 0.063 | Benign | 0.062 | Benign | 4.07 | Benign | 0.00 | Affected | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.501C>G | D167E 2D AIThe SynGAP1 D167E missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive because it receives two benign votes and two uncertain votes, yielding no clear majority. Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.502306 | Binding | 0.377 | 0.667 | 0.375 | -7.636 | In-Between | 0.516 | Ambiguous | Likely Benign | 0.067 | Likely Benign | 0.1392 | 0.7144 | -1.52 | Neutral | 0.063 | Benign | 0.062 | Benign | 4.07 | Benign | 0.00 | Affected | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.502C>A | H168N 2D  AIThe SynGAP1 missense variant H168N is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. No tools predict pathogenicity. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | -4.764 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.081 | Likely Benign | 0.1516 | 0.2589 | -0.14 | Neutral | 0.016 | Benign | 0.015 | Benign | 4.29 | Benign | 0.60 | Tolerated | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||
| c.502C>G | H168D 2D  AIThe SynGAP1 missense variant H168D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only ESM1b predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign consensus, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This prediction is consistent with the lack of ClinVar annotation and does not contradict any existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | -8.519 | Likely Pathogenic | 0.481 | Ambiguous | Likely Benign | 0.131 | Likely Benign | 0.2365 | 0.2017 | -1.24 | Neutral | 0.016 | Benign | 0.021 | Benign | 4.24 | Benign | 0.08 | Tolerated | 1 | -1 | -0.3 | -22.05 | ||||||||||||||||||||||||||||||||||||
| c.502C>T | H168Y 2D  AIThe SynGAP1 missense variant H168Y is listed in ClinVar (ID 956914.0) as benign and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are SIFT and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | Benign | 1 | -8.914 | Likely Pathogenic | 0.264 | Likely Benign | Likely Benign | 0.065 | Likely Benign | 0.0695 | 0.4657 | -1.53 | Neutral | 0.192 | Benign | 0.062 | Benign | 4.18 | Benign | 0.01 | Affected | 4.32 | 3 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||
| c.503A>C | H168P 2D  AIThe SynGAP1 missense variant H168P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome, while ESM1b 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 for this variant. Taken together, the preponderance 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 | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | -7.686 | In-Between | 0.124 | Likely Benign | Likely Benign | 0.279 | Likely Benign | 0.2004 | 0.3960 | -1.66 | Neutral | 0.072 | Benign | 0.043 | Benign | 4.19 | Benign | 0.02 | Affected | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||
| c.503A>G | H168R 2D  AIThe SynGAP1 missense variant H168R is reported in gnomAD (ID 6‑33432800‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized all classify the change as benign, whereas SIFT predicts it to be pathogenic. 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 not available. Overall, the preponderance of evidence points to a benign impact. This conclusion does not contradict ClinVar, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | 6-33432800-A-G | 1 | 6.20e-7 | -7.334 | In-Between | 0.395 | Ambiguous | Likely Benign | 0.153 | Likely Benign | 0.1752 | 0.2499 | -1.08 | Neutral | 0.016 | Benign | 0.011 | Benign | 4.26 | Benign | 0.02 | Affected | 4.32 | 3 | 0 | 2 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||
| c.503A>T | H168L 2D  AIThe SynGAP1 H168L missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT 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, 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 | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | -7.936 | In-Between | 0.178 | Likely Benign | Likely Benign | 0.250 | Likely Benign | 0.0752 | 0.5602 | -2.36 | Neutral | 0.037 | Benign | 0.021 | Benign | 4.21 | Benign | 0.01 | Affected | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||
| c.504T>A | H168Q 2D  AIThe SynGAP1 missense variant H168Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar or gnomAD entries—there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | -5.177 | Likely Benign | 0.189 | Likely Benign | Likely Benign | 0.093 | Likely Benign | 0.1307 | 0.3873 | -0.85 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.31 | Benign | 0.02 | Affected | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||
| c.504T>G | H168Q 2D AIThe SynGAP1 missense variant H168Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar or gnomAD entries—there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | -5.177 | Likely Benign | 0.189 | Likely Benign | Likely Benign | 0.090 | Likely Benign | 0.1307 | 0.3873 | -0.85 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.31 | Benign | 0.02 | Affected | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||
| c.505G>A | D169N 2D AIThe SynGAP1 missense variant D169N is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split: six methods (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Optimized) predict a benign effect, while three (SIFT, ESM1b, AlphaMissense‑Default) predict pathogenicity. High‑accuracy assessments are mixed: AlphaMissense‑Optimized indicates benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive. No Foldetta stability data are available. Overall, the balance of evidence 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. | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | Uncertain | 1 | -10.713 | Likely Pathogenic | 0.761 | Likely Pathogenic | Likely Benign | 0.110 | Likely Benign | 0.1430 | 0.7391 | -2.04 | Neutral | 0.079 | Benign | 0.052 | Benign | 4.07 | Benign | 0.01 | Affected | 3.74 | 4 | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||
| c.505G>C | D169H 2D AIThe SynGAP1 D169H variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the majority of computational evidence points toward a pathogenic impact, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | -12.048 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | 0.181 | Likely Benign | 0.1791 | 0.7624 | -2.83 | Deleterious | 0.651 | Possibly Damaging | 0.417 | Benign | 4.03 | Benign | 0.00 | Affected | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||
| c.505G>T | D169Y 2D AIThe SynGAP1 missense variant D169Y is not 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 are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Pathogenic. AlphaMissense‑Optimized returns an uncertain result, and no Foldetta (FoldX‑MD/Rosetta) stability data are available. Based on the overall pattern of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | -13.524 | Likely Pathogenic | 0.933 | Likely Pathogenic | Ambiguous | 0.282 | Likely Benign | 0.0571 | 0.6896 | -3.71 | Deleterious | 0.651 | Possibly Damaging | 0.347 | Benign | 4.01 | Benign | 0.00 | Affected | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||
| c.506A>C | D169A 2D AIThe SynGAP1 D169A missense variant is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls arise from PROVEAN, SIFT, ESM1b and AlphaMissense‑Default. Grouping by consensus, the benign set includes REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; the pathogenic set includes PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta predictions are unavailable. Overall, the balance of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | -11.065 | Likely Pathogenic | 0.874 | Likely Pathogenic | Ambiguous | 0.159 | Likely Benign | 0.4012 | 0.6809 | -3.15 | Deleterious | 0.018 | Benign | 0.025 | Benign | 4.10 | Benign | 0.01 | Affected | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||
| c.506A>G | D169G 2D AIThe SynGAP1 missense variant D169G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a tie (2 pathogenic vs 2 benign) and is therefore unavailable; Foldetta results are not provided. Overall, the majority of standard predictors lean toward a benign classification, and this is consistent with the lack of ClinVar evidence. 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. | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | -9.853 | Likely Pathogenic | 0.820 | Likely Pathogenic | Ambiguous | 0.186 | Likely Benign | 0.3907 | 0.6560 | -2.44 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.04 | Benign | 0.01 | Affected | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||||||||
| c.506A>T | D169V 2D AIThe SynGAP1 D169V missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls arise from PROVEAN, SIFT, ESM1b and AlphaMissense‑Default. When predictions are grouped by consensus, four tools predict benign and four predict pathogenic. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized returns an uncertain result, whereas 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 residue. Overall, the balance of evidence, particularly the SGM Consensus and the pathogenic calls from multiple independent predictors, indicates that D169V 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 | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | -12.395 | Likely Pathogenic | 0.925 | Likely Pathogenic | Ambiguous | 0.243 | Likely Benign | 0.0895 | 0.7166 | -3.77 | Deleterious | 0.380 | Benign | 0.193 | Benign | 4.03 | Benign | 0.00 | Affected | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||
| c.507C>A | D169E 2D AIThe SynGAP1 missense variant D169E is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | -4.571 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.030 | Likely Benign | 0.1636 | 0.7316 | -1.31 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.23 | Benign | 0.42 | Tolerated | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.507C>G | D169E 2D AIThe SynGAP1 missense variant D169E is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | -4.571 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.029 | Likely Benign | 0.1636 | 0.7316 | -1.31 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.23 | Benign | 0.42 | Tolerated | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.508C>G | R170G 2D AIThe SynGAP1 missense variant R170G is not reported in ClinVar and has no entries in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as likely pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic impact for R170G, 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 | 0.480142 | Structured | 0.492928 | Uncertain | 0.406 | 0.661 | 0.250 | -10.092 | Likely Pathogenic | 0.902 | Likely Pathogenic | Ambiguous | 0.196 | Likely Benign | 0.3285 | 0.3004 | -3.19 | Deleterious | 0.664 | Possibly Damaging | 0.137 | Benign | 3.88 | Benign | 0.00 | Affected | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||
| c.508C>T | R170W 2D AIThe SynGAP1 missense variant R170W is listed in ClinVar (ID 1310195.0) with an “Uncertain” status 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 indicates it is likely pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.480142 | Structured | 0.492928 | Uncertain | 0.406 | 0.661 | 0.250 | Uncertain | 2 | -11.660 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.241 | Likely Benign | 0.1026 | 0.3469 | -4.28 | Deleterious | 0.999 | Probably Damaging | 0.849 | Possibly Damaging | 3.84 | Benign | 0.00 | Affected | 3.74 | 4 | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||
| c.509G>A | R170Q 2D AISynGAP1 missense variant R170Q is listed in ClinVar as Pathogenic and is not reported in gnomAD. Computational predictors show a split: benign calls come from REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls come from polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is Uncertain, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive; Foldetta stability analysis is unavailable. Thus, no single method or high‑accuracy consensus strongly supports pathogenicity. The variant is most likely benign according to the current computational evidence, which contradicts the ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.480142 | Structured | 0.492928 | Uncertain | 0.406 | 0.661 | 0.250 | Pathogenic/Likely path. | 6 | -9.021 | Likely Pathogenic | 0.798 | Likely Pathogenic | Ambiguous | 0.221 | Likely Benign | 0.2524 | 0.2299 | -2.31 | Neutral | 0.947 | Possibly Damaging | 0.342 | Benign | 3.91 | Benign | 0.00 | Affected | 3.74 | 4 | 1 | 1 | 1.0 | -28.06 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.509G>C | R170P 2D AIThe SynGAP1 missense variant R170P is not 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 score (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that R170P 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 | 0.480142 | Structured | 0.492928 | Uncertain | 0.406 | 0.661 | 0.250 | -9.687 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.386 | Likely Benign | 0.1967 | 0.3989 | -3.96 | Deleterious | 0.966 | Probably Damaging | 0.599 | Possibly Damaging | 3.86 | Benign | 0.00 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||
| c.509G>T | R170L 2D AIThe SynGAP1 missense variant R170L has no ClinVar entry and is not reported in gnomAD. In silico predictors fall into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy tools further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote) also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of pathogenic predictions, including the high‑accuracy consensus, suggests that R170L is most likely pathogenic. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.480142 | Structured | 0.492928 | Uncertain | 0.406 | 0.661 | 0.250 | -8.649 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.319 | Likely Benign | 0.1561 | 0.4310 | -4.02 | Deleterious | 0.798 | Possibly Damaging | 0.319 | Benign | 3.87 | Benign | 0.00 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||
| c.511G>A | A171T 2D AIThe SynGAP1 missense variant A171T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only SIFT predicts pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of tools, including the high‑accuracy methods, points to a benign impact. This prediction does not contradict any ClinVar annotation, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.492272 | Uncertain | 0.358 | 0.652 | 0.375 | -2.388 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.019 | Likely Benign | 0.1075 | 0.5763 | -0.51 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.25 | Benign | 0.03 | Affected | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.511G>C | A171P 2D AIThe SynGAP1 missense variant A171P 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 likely benign. Foldetta results are unavailable for this variant. Overall, the majority of computational 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 | 0.562014 | Disordered | 0.492272 | Uncertain | 0.358 | 0.652 | 0.375 | -5.071 | Likely Benign | 0.569 | Likely Pathogenic | Likely Benign | 0.160 | Likely Benign | 0.1630 | 0.3938 | -1.42 | Neutral | 0.396 | Benign | 0.099 | Benign | 4.14 | Benign | 0.02 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||
| c.511G>T | A171S 2D AIThe SynGAP1 missense variant A171S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.492272 | Uncertain | 0.358 | 0.652 | 0.375 | -0.011 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.054 | Likely Benign | 0.2221 | 0.4383 | 0.40 | Neutral | 0.002 | Benign | 0.001 | Benign | 4.33 | Benign | 0.91 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||
| c.512C>A | A171D 2D AIThe SynGAP1 missense variant A171D is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments therefore lean toward a benign interpretation: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus is benign, and Foldetta data are missing. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.492272 | Uncertain | 0.358 | 0.652 | 0.375 | -6.977 | Likely Benign | 0.908 | Likely Pathogenic | Ambiguous | 0.144 | Likely Benign | 0.1634 | 0.2462 | -1.45 | Neutral | 0.244 | Benign | 0.037 | Benign | 4.15 | Benign | 0.01 | Affected | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||
| c.512C>G | A171G 2D AIThe SynGAP1 missense variant A171G is not reported 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 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 | 0.562014 | Disordered | 0.492272 | Uncertain | 0.358 | 0.652 | 0.375 | -4.019 | Likely Benign | 0.301 | Likely Benign | Likely Benign | 0.050 | Likely Benign | 0.1767 | 0.3278 | -1.08 | Neutral | 0.063 | Benign | 0.026 | Benign | 4.14 | Benign | 0.05 | Affected | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.512C>T | A171V 2D AIThe SynGAP1 missense variant A171V is catalogued in gnomAD (ID 6‑33435154‑C‑T) but has no ClinVar entry. Functional 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, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact for A171V, 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 | 0.562014 | Disordered | 0.492272 | Uncertain | 0.358 | 0.652 | 0.375 | 6-33435154-C-T | 1 | 6.20e-7 | -6.437 | Likely Benign | 0.434 | Ambiguous | Likely Benign | 0.052 | Likely Benign | 0.0766 | 0.4897 | -1.65 | Neutral | 0.118 | Benign | 0.026 | Benign | 4.15 | Benign | 0.03 | Affected | 3.74 | 4 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||
| c.514C>G | R172G 2D AIThe SynGAP1 R172G missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Computational predictions are split: benign calls come from REVEL, polyPhen‑2 HumVar, ESM1b, and FATHMM, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy consensus tools are inconclusive: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a 2‑vs‑2 split, and Foldetta results are unavailable. Consequently, the variant is neither clearly benign nor pathogenic according to current predictions, and there is no ClinVar annotation to contradict this ambiguous assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.525368 | Disordered | 0.491688 | Uncertain | 0.411 | 0.651 | 0.375 | -6.685 | Likely Benign | 0.811 | Likely Pathogenic | Ambiguous | 0.175 | Likely Benign | 0.2991 | 0.3169 | -2.69 | Deleterious | 0.789 | Possibly Damaging | 0.253 | Benign | 3.98 | Benign | 0.02 | Affected | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||
| c.514C>T | R172W 2D AIThe SynGAP1 missense variant R172W is listed in ClinVar (ID 996892.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33435156‑C‑T). Prediction tools that agree on a benign effect include REVEL and FATHMM. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic.” AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. High‑accuracy assessments therefore indicate a likely pathogenic outcome (SGM‑Consensus) with no definitive stabilizing‑folding evidence. Overall, the majority of computational predictions support a pathogenic classification, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.525368 | Disordered | 0.491688 | Uncertain | 0.411 | 0.651 | 0.375 | Uncertain | 2 | 6-33435156-C-T | 9 | 5.58e-6 | -10.258 | Likely Pathogenic | 0.878 | Likely Pathogenic | Ambiguous | 0.228 | Likely Benign | 0.1071 | 0.4065 | -3.61 | Deleterious | 0.997 | Probably Damaging | 0.803 | Possibly Damaging | 3.95 | Benign | 0.00 | Affected | 3.61 | 5 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||
| c.515G>A | R172Q 2D AISynGAP1 missense variant R172Q is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33435157‑G‑A). Functional prediction tools that agree on benign impact include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are polyPhen‑2 HumDiv and SIFT, while ESM1b and AlphaMissense‑Default are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also returns 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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.525368 | Disordered | 0.491688 | Uncertain | 0.411 | 0.651 | 0.375 | Uncertain | 1 | 6-33435157-G-A | 3 | 1.86e-6 | -7.245 | In-Between | 0.465 | Ambiguous | Likely Benign | 0.135 | Likely Benign | 0.2254 | 0.2532 | -1.72 | Neutral | 0.804 | Possibly Damaging | 0.091 | Benign | 4.04 | Benign | 0.04 | Affected | 3.61 | 5 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||||
| c.515G>C | R172P 2D AIThe SynGAP1 missense variant R172P has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, while Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.525368 | Disordered | 0.491688 | Uncertain | 0.411 | 0.651 | 0.375 | -8.059 | Likely Pathogenic | 0.889 | Likely Pathogenic | Ambiguous | 0.227 | Likely Benign | 0.1864 | 0.4312 | -3.16 | Deleterious | 0.929 | Possibly Damaging | 0.519 | Possibly Damaging | 3.99 | Benign | 0.01 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||
| c.515G>T | R172L 2D AIThe SynGAP1 missense variant R172L is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls arise from PROVEAN, SIFT, ESM1b and AlphaMissense‑Default. Grouping by consensus, four tools predict benign and four predict pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Taken together, the majority of evidence, including the SGM Consensus, points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.525368 | Disordered | 0.491688 | Uncertain | 0.411 | 0.651 | 0.375 | -8.201 | Likely Pathogenic | 0.797 | Likely Pathogenic | Ambiguous | 0.131 | Likely Benign | 0.1423 | 0.4729 | -3.09 | Deleterious | 0.276 | Benign | 0.103 | Benign | 3.99 | Benign | 0.02 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||
| c.517C>A | L173M 2D AIThe SynGAP1 missense variant L173M is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Two tools—AlphaMissense‑Default and ESM1b—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields two benign and two uncertain calls, and Foldetta data are unavailable. Overall, the balance of evidence favors a benign classification, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.534167 | Disordered | 0.491566 | Uncertain | 0.390 | 0.631 | 0.375 | -7.149 | In-Between | 0.534 | Ambiguous | Likely Benign | 0.129 | Likely Benign | 0.0648 | 0.3123 | -0.61 | Neutral | 0.940 | Possibly Damaging | 0.564 | Possibly Damaging | 3.96 | Benign | 0.20 | Tolerated | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||
| c.517C>G | L173V 2D AIThe SynGAP1 missense variant L173V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Only ESM1b predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority vote. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.534167 | Disordered | 0.491566 | Uncertain | 0.390 | 0.631 | 0.375 | -8.320 | Likely Pathogenic | 0.495 | Ambiguous | Likely Benign | 0.100 | Likely Benign | 0.1343 | 0.3217 | -0.95 | Neutral | 0.131 | Benign | 0.058 | Benign | 4.05 | Benign | 0.22 | Tolerated | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.518T>A | L173Q 2D AIThe SynGAP1 missense variant L173Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Only AlphaMissense‑Default predicts a pathogenic outcome, while AlphaMissense‑Optimized is uncertain. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple in silico predictors and the SGM‑Consensus indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.534167 | Disordered | 0.491566 | Uncertain | 0.390 | 0.631 | 0.375 | -5.605 | Likely Benign | 0.850 | Likely Pathogenic | Ambiguous | 0.133 | Likely Benign | 0.1028 | 0.0919 | -1.72 | Neutral | 0.022 | Benign | 0.022 | Benign | 3.94 | Benign | 0.08 | Tolerated | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||
| c.518T>C | L173P 2D AIThe SynGAP1 missense variant L173P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, whereas tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑to‑2 split; Foldetta results are not available. Consequently, the computational evidence is evenly divided, providing no clear advantage for either benign or pathogenic classification. The variant is therefore most likely inconclusive based on current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.534167 | Disordered | 0.491566 | Uncertain | 0.390 | 0.631 | 0.375 | -8.758 | Likely Pathogenic | 0.918 | Likely Pathogenic | Ambiguous | 0.135 | Likely Benign | 0.3318 | 0.1382 | -2.38 | Neutral | 0.838 | Possibly Damaging | 0.466 | Possibly Damaging | 3.92 | Benign | 0.15 | Tolerated | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||
| c.518T>G | L173R 2D AIThe SynGAP1 missense variant L173R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of consensus tools lean toward a benign interpretation, and there is no ClinVar evidence to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.534167 | Disordered | 0.491566 | Uncertain | 0.390 | 0.631 | 0.375 | -9.524 | Likely Pathogenic | 0.904 | Likely Pathogenic | Ambiguous | 0.119 | Likely Benign | 0.1258 | 0.0761 | -1.63 | Neutral | 0.561 | Possibly Damaging | 0.178 | Benign | 3.95 | Benign | 0.08 | Tolerated | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||
| c.520A>C | M174L 2D  AIThe SynGAP1 missense variant M174L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Taken together, the majority of evidence points to a benign impact for M174L. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.485854 | Uncertain | 0.373 | 0.620 | 0.375 | -5.839 | Likely Benign | 0.608 | Likely Pathogenic | Likely Benign | 0.192 | Likely Benign | 0.1335 | 0.4545 | -0.82 | Neutral | 0.055 | Benign | 0.011 | Benign | 4.21 | Benign | 0.46 | Tolerated | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||
| c.520A>G | M174V 2D  AIThe SynGAP1 missense variant M174V is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID: 6‑33435162‑A‑G). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM; pathogenic predictions come from SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and no Foldetta stability data are available. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a 2‑vs‑2 split and is therefore inconclusive. With five benign versus three pathogenic calls and no contradictory ClinVar evidence, 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. | 0.661982 | Disordered | 0.485854 | Uncertain | 0.373 | 0.620 | 0.375 | 6-33435162-A-G | 2 | 1.24e-6 | -8.604 | Likely Pathogenic | 0.897 | Likely Pathogenic | Ambiguous | 0.108 | Likely Benign | 0.2866 | 0.3841 | -1.76 | Neutral | 0.213 | Benign | 0.067 | Benign | 4.12 | Benign | 0.04 | Affected | 3.61 | 5 | 1 | 2 | 2.3 | -32.06 | |||||||||||||||||||||||||||||||
| c.520A>T | M174L 2D AIThe SynGAP1 missense variant M174L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Taken together, the majority of evidence points to a benign impact for M174L. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.485854 | Uncertain | 0.373 | 0.620 | 0.375 | -5.839 | Likely Benign | 0.608 | Likely Pathogenic | Likely Benign | 0.192 | Likely Benign | 0.1335 | 0.4545 | -0.82 | Neutral | 0.055 | Benign | 0.011 | Benign | 4.21 | Benign | 0.46 | Tolerated | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||
| c.521T>A | M174K 2D  AIThe SynGAP1 missense variant M174K 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, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic, and AlphaMissense‑Optimized independently predicts it as Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence from high‑accuracy predictors and the consensus score points to a pathogenic classification. This assessment is not contradicted by ClinVar, which currently contains no entry for M174K. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.661982 | Disordered | 0.485854 | Uncertain | 0.373 | 0.620 | 0.375 | -9.542 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.325 | Likely Benign | 0.1373 | 0.0688 | -3.21 | Deleterious | 0.002 | Benign | 0.002 | Benign | 4.06 | Benign | 0.01 | Affected | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||
| c.521T>C | M174T 2D  AIThe SynGAP1 missense variant M174T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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 impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote) also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.661982 | Disordered | 0.485854 | Uncertain | 0.373 | 0.620 | 0.375 | -9.174 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.286 | Likely Benign | 0.1949 | 0.2334 | -3.12 | Deleterious | 0.244 | Benign | 0.049 | Benign | 4.08 | Benign | 0.01 | Affected | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||||||||
| c.521T>G | M174R 2D  AIThe SynGAP1 missense variant M174R is not reported in ClinVar and is absent from gnomAD. Computational assessment shows a split in predictions: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar), and FATHMM, whereas pathogenic calls arise from PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy tools further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote) also indicates Likely Pathogenic. Foldetta results are unavailable, so no additional stability evidence is provided. Overall, the preponderance of evidence points to a pathogenic effect; 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 | 0.661982 | Disordered | 0.485854 | Uncertain | 0.373 | 0.620 | 0.375 | -9.114 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.308 | Likely Benign | 0.1545 | 0.1037 | -3.15 | Deleterious | 0.139 | Benign | 0.039 | Benign | 4.05 | Benign | 0.01 | Affected | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||
| c.522G>A | M174I 2D  AIThe SynGAP1 missense variant M174I is listed in gnomAD (ID 6‑33435164‑G‑A) but has no ClinVar record. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; pathogenic predictions come from ESM1b and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2) and Foldetta results are unavailable. Overall, six tools predict benign while only two predict pathogenic, and the only high‑accuracy pathogenic call is from AlphaMissense‑Optimized. Thus, the variant is most likely benign based on the preponderance of evidence, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.661982 | Disordered | 0.485854 | Uncertain | 0.373 | 0.620 | 0.375 | 6-33435164-G-A | 4 | 2.48e-6 | -8.732 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.120 | Likely Benign | 0.1191 | 0.3469 | -1.63 | Neutral | 0.213 | Benign | 0.067 | Benign | 4.10 | Benign | 0.07 | Tolerated | 3.61 | 5 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||
| c.522G>C | M174I 2D AIThe SynGAP1 missense variant M174I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. High‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs 2 benign), and Foldetta’s stability assessment is unavailable. Overall, the majority of standard predictors favor a benign outcome, and the high‑accuracy predictions do not override this trend. Thus, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar reporting. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.661982 | Disordered | 0.485854 | Uncertain | 0.373 | 0.620 | 0.375 | -8.732 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.120 | Likely Benign | 0.1191 | 0.3469 | -1.63 | Neutral | 0.213 | Benign | 0.067 | Benign | 4.10 | Benign | 0.07 | Tolerated | 3.61 | 5 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||
| c.522G>T | M174I 2D AIThe SynGAP1 missense variant M174I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. High‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta data are unavailable. Overall, the majority of standard predictors indicate a benign impact, while the single high‑accuracy tool suggests pathogenicity but is not supported by consensus or folding‑stability evidence. Thus, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.661982 | Disordered | 0.485854 | Uncertain | 0.373 | 0.620 | 0.375 | -8.732 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.120 | Likely Benign | 0.1191 | 0.3469 | -1.63 | Neutral | 0.213 | Benign | 0.067 | Benign | 4.10 | Benign | 0.07 | Tolerated | 3.61 | 5 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||
| c.523C>A | Q175K 2D AIThe SynGAP1 missense variant Q175K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Only AlphaMissense‑Default predicts a pathogenic outcome, while AlphaMissense‑Optimized is uncertain. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support this: AlphaMissense‑Optimized remains uncertain, SGM‑Consensus is benign, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for Q175K, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.474689 | Uncertain | 0.367 | 0.618 | 0.375 | -5.908 | Likely Benign | 0.826 | Likely Pathogenic | Ambiguous | 0.202 | Likely Benign | 0.1655 | 0.3723 | -0.89 | Neutral | 0.118 | Benign | 0.039 | Benign | 4.18 | Benign | 0.37 | Tolerated | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||
| c.523C>G | Q175E 2D AIThe SynGAP1 missense variant Q175E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a benign bias: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, whereas ESM1b predicts it to be pathogenic. AlphaMissense‑Default remains uncertain. High‑accuracy assessment further supports a benign outcome: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta stability analysis is unavailable. Consequently, the overall evidence points to a benign effect for Q175E. This conclusion is consistent with the absence of a ClinVar assertion, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.653063 | Disordered | 0.474689 | Uncertain | 0.367 | 0.618 | 0.375 | -11.035 | Likely Pathogenic | 0.502 | Ambiguous | Likely Benign | 0.149 | Likely Benign | 0.1351 | 0.2028 | -0.68 | Neutral | 0.118 | Benign | 0.039 | Benign | 4.17 | Benign | 0.40 | Tolerated | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||||
| c.524A>C | Q175P 2D AIThe SynGAP1 missense variant Q175P is reported in gnomAD (ID 6‑33435166‑A‑C) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all score the substitution as benign. The consensus from the SGM framework, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as likely benign. High‑accuracy predictors corroborate this assessment: AlphaMissense‑Optimized predicts a benign outcome, and the SGM‑Consensus (majority vote) confirms a likely benign status. No high‑accuracy folding‑stability analysis (Foldetta) is available for this residue, so stability effects remain unassessed. Overall, the collective evidence points to a benign impact for Q175P, and this conclusion is consistent with the absence of a pathogenic ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.474689 | Uncertain | 0.367 | 0.618 | 0.375 | 6-33435166-A-C | 1 | 6.20e-7 | -6.995 | Likely Benign | 0.432 | Ambiguous | Likely Benign | 0.211 | Likely Benign | 0.2075 | 0.4584 | 1.55 | Neutral | 0.396 | Benign | 0.188 | Benign | 4.20 | Benign | 1.00 | Tolerated | 3.61 | 5 | -1 | 0 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||
| c.524A>G | Q175R 2D AIThe SynGAP1 missense variant Q175R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The only tool that predicts a pathogenic outcome is AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus remains likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.474689 | Uncertain | 0.367 | 0.618 | 0.375 | -5.785 | Likely Benign | 0.789 | Likely Pathogenic | Ambiguous | 0.194 | Likely Benign | 0.1485 | 0.1352 | -1.29 | Neutral | 0.012 | Benign | 0.006 | Benign | 4.14 | Benign | 0.26 | Tolerated | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||
| c.524A>T | Q175L 2D AIThe SynGAP1 missense variant Q175L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, seven tools favor benign while two favor pathogenic, with no ClinVar evidence to contradict this. Thus, the variant is most likely benign based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.653063 | Disordered | 0.474689 | Uncertain | 0.367 | 0.618 | 0.375 | -8.699 | Likely Pathogenic | 0.579 | Likely Pathogenic | Likely Benign | 0.188 | Likely Benign | 0.0647 | 0.5109 | -2.46 | Neutral | 0.118 | Benign | 0.039 | Benign | 4.10 | Benign | 0.14 | Tolerated | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||||||||
| c.525A>C | Q175H 2D AIThe SynGAP1 missense variant Q175H has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are unavailable. Overall, the balance of evidence favors a benign classification, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.474689 | Uncertain | 0.367 | 0.618 | 0.375 | -6.635 | Likely Benign | 0.824 | Likely Pathogenic | Ambiguous | 0.185 | Likely Benign | 0.1273 | 0.3411 | -1.52 | Neutral | 0.875 | Possibly Damaging | 0.459 | Possibly Damaging | 4.09 | Benign | 0.10 | Tolerated | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.525A>T | Q175H 2D AIThe SynGAP1 missense variant Q175H has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; no Foldetta stability data are available. Overall, the balance of evidence favors a benign classification, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.474689 | Uncertain | 0.367 | 0.618 | 0.375 | -6.635 | Likely Benign | 0.824 | Likely Pathogenic | Ambiguous | 0.185 | Likely Benign | 0.1273 | 0.3411 | -1.52 | Neutral | 0.875 | Possibly Damaging | 0.459 | Possibly Damaging | 4.09 | Benign | 0.10 | Tolerated | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||
| c.526A>C | S176R 2D AIThe SynGAP1 missense variant S176R is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM, whereas polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains likely benign; Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, and this assessment does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | Uncertain | 1 | -6.492 | Likely Benign | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.247 | Likely Benign | 0.0697 | 0.3160 | 0.94 | Neutral | 0.718 | Possibly Damaging | 0.168 | Benign | 4.16 | Benign | 0.87 | Tolerated | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||
| c.526A>G | S176G 2D AIThe SynGAP1 missense variant S176G is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33435168‑A‑G). Consensus among most in silico predictors is benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized all report a benign effect. No tool predicts pathogenicity. Two predictors are inconclusive: ESM1b and AlphaMissense‑Default, which are grouped under uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) remains uncertain, and Foldetta stability analysis is unavailable. Overall, the computational evidence overwhelmingly favors a benign impact, which does not contradict the ClinVar uncertain classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | Uncertain | 1 | 6-33435168-A-G | 1 | 6.20e-7 | -7.541 | In-Between | 0.360 | Ambiguous | Likely Benign | 0.066 | Likely Benign | 0.2361 | 0.3414 | -1.08 | Neutral | 0.131 | Benign | 0.039 | Benign | 4.08 | Benign | 0.22 | Tolerated | 3.54 | 6 | 0 | 1 | 0.4 | -30.03 | |||||||||||||||||||||||||||||
| c.526A>T | S176C 2D AIThe SynGAP1 missense variant S176C is not reported in ClinVar 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) also yields benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence from both conventional and high‑accuracy tools 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. | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | -9.785 | Likely Pathogenic | 0.529 | Ambiguous | Likely Benign | 0.143 | Likely Benign | 0.0823 | 0.5153 | -1.88 | Neutral | 0.983 | Probably Damaging | 0.436 | Benign | 4.02 | Benign | 0.02 | Affected | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||
| c.527G>A | S176N 2D AIThe SynGAP1 missense variant S176N is catalogued in gnomAD (ID 6‑33435169‑G‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none reported). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | 6-33435169-G-A | 1 | 6.20e-7 | -6.286 | Likely Benign | 0.594 | Likely Pathogenic | Likely Benign | 0.070 | Likely Benign | 0.0996 | 0.3930 | -0.56 | Neutral | 0.421 | Benign | 0.080 | Benign | 4.10 | Benign | 0.22 | Tolerated | 3.54 | 6 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||
| c.527G>C | S176T 2D AIThe SynGAP1 missense variant S176T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | -3.682 | Likely Benign | 0.351 | Ambiguous | Likely Benign | 0.045 | Likely Benign | 0.1103 | 0.4979 | -0.73 | Neutral | 0.421 | Benign | 0.054 | Benign | 4.09 | Benign | 0.19 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.527G>T | S176I 2D AIThe SynGAP1 missense variant S176I is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a 2‑vs‑2 split, and Foldetta results are not available. Overall, the majority of evidence (six benign predictions versus two pathogenic) supports a benign classification. This conclusion does not contradict ClinVar, as the variant has no ClinVar entry. Thus, the variant is most likely benign based on current predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | -10.247 | Likely Pathogenic | 0.903 | Likely Pathogenic | Ambiguous | 0.152 | Likely Benign | 0.0790 | 0.5290 | -2.03 | Neutral | 0.002 | Benign | 0.003 | Benign | 4.04 | Benign | 0.06 | Tolerated | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||
| c.528C>A | S176R 2D AIThe SynGAP1 missense variant S176R has no ClinVar record and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (majority vote) all classify the change as benign or likely benign. In contrast, polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized predict a pathogenic impact. High‑accuracy assessments are mixed: AlphaMissense‑Optimized reports a pathogenic outcome, whereas the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect; Foldetta data are unavailable. Overall, the majority of predictions support a benign interpretation, and there is no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | -6.492 | Likely Benign | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.230 | Likely Benign | 0.0697 | 0.3160 | 0.94 | Neutral | 0.718 | Possibly Damaging | 0.168 | Benign | 4.16 | Benign | 0.87 | Tolerated | 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 | 0.0697 | 0.3160 | 0.94 | Neutral | 0.718 | Possibly Damaging | 0.168 | Benign | 4.16 | Benign | 0.87 | Tolerated | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||
| c.529T>A | F177I 2D AIThe SynGAP1 missense variant F177I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that predict a pathogenic effect are ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. three pathogenic) suggest a benign impact, though the presence of pathogenic signals from high‑accuracy tools introduces uncertainty. The variant is most likely benign based on the current evidence, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.461817 | Uncertain | 0.357 | 0.598 | 0.500 | -10.208 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.148 | Likely Benign | 0.2282 | 0.3299 | -0.60 | Neutral | 0.131 | Benign | 0.058 | Benign | 4.18 | Benign | 0.11 | Tolerated | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||||||||
| c.529T>C | F177L 2D AIThe SynGAP1 missense variant F177L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are AlphaMissense‑Default and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, while the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence (seven benign predictions versus two pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.461817 | Uncertain | 0.357 | 0.598 | 0.500 | -5.564 | Likely Benign | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.184 | Likely Benign | 0.2376 | 0.4280 | 0.24 | Neutral | 0.022 | Benign | 0.022 | Benign | 4.41 | Benign | 1.00 | Tolerated | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||
| c.529T>G | F177V 2D AIThe SynGAP1 missense variant F177V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that predict a pathogenic effect are ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of standard predictors favor a benign outcome, but the optimized AlphaMissense model and ESM1b suggest potential pathogenicity. Thus, the variant is most likely benign based on the collective evidence, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.461817 | Uncertain | 0.357 | 0.598 | 0.500 | -11.582 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 0.188 | Likely Benign | 0.2454 | 0.3526 | -1.26 | Neutral | 0.028 | Benign | 0.009 | Benign | 4.18 | Benign | 0.06 | Tolerated | -1 | -1 | 1.4 | -48.04 | ||||||||||||||||||||||||||||||||||||
| c.530T>A | F177Y 2D AIThe SynGAP1 missense variant F177Y is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2). Foldetta, a protein‑folding stability method, has no available output for this variant. Overall, the majority of consensus tools lean toward a benign interpretation, and there is no ClinVar record to contradict this assessment. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.461817 | Uncertain | 0.357 | 0.598 | 0.500 | -9.643 | Likely Pathogenic | 0.932 | Likely Pathogenic | Ambiguous | 0.138 | Likely Benign | 0.1511 | 0.2756 | -1.17 | Neutral | 0.818 | Possibly Damaging | 0.201 | Benign | 4.08 | Benign | 0.07 | Tolerated | 7 | 3 | -4.1 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.530T>C | F177S 2D AIThe SynGAP1 missense variant F177S is not 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 are PROVEAN, polyPhen‑2 HumDiv, 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 also predicts Pathogenic, while the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic impact, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.505461 | Disordered | 0.461817 | Uncertain | 0.357 | 0.598 | 0.500 | -10.283 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.282 | Likely Benign | 0.5034 | 0.1049 | Weaken | -2.58 | Deleterious | 0.596 | Possibly Damaging | 0.203 | Benign | 4.11 | Benign | 0.01 | Affected | -3 | -2 | -3.6 | -60.10 | ||||||||||||||||||||||||||||||||||
| c.530T>G | F177C 2D AIThe SynGAP1 missense variant F177C is not 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 predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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. Overall, the majority of high‑confidence predictors (six pathogenic vs three benign) 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. | 0.505461 | Disordered | 0.461817 | Uncertain | 0.357 | 0.598 | 0.500 | -11.487 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.241 | Likely Benign | 0.2797 | 0.2539 | -2.20 | Neutral | 0.983 | Probably Damaging | 0.635 | Possibly Damaging | 4.07 | Benign | 0.01 | Affected | -4 | -2 | -0.3 | -44.04 | ||||||||||||||||||||||||||||||||||||
| c.531T>A | F177L 2D AIThe SynGAP1 missense variant F177L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are AlphaMissense‑Default and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, while the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence (seven benign predictions versus two pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.461817 | Uncertain | 0.357 | 0.598 | 0.500 | -5.564 | Likely Benign | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.173 | Likely Benign | 0.2376 | 0.4280 | 0.24 | Neutral | 0.022 | Benign | 0.022 | Benign | 4.41 | Benign | 1.00 | Tolerated | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||
| c.531T>G | F177L 2D AIThe SynGAP1 missense variant F177L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are AlphaMissense‑Default and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, while the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence (seven benign predictions versus two pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.461817 | Uncertain | 0.357 | 0.598 | 0.500 | -5.564 | Likely Benign | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.173 | Likely Benign | 0.2376 | 0.4280 | 0.24 | Neutral | 0.022 | Benign | 0.022 | Benign | 4.41 | Benign | 1.00 | Tolerated | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||
| c.532A>C | K178Q 2D AIThe SynGAP1 K178Q missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default all classify the variant as damaging. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect. 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 | 0.497853 | Structured | 0.455271 | Uncertain | 0.354 | 0.622 | 0.375 | -9.779 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.197 | Likely Benign | 0.5170 | 0.1216 | Weaken | -2.57 | Deleterious | 0.971 | Probably Damaging | 0.598 | Possibly Damaging | 3.88 | Benign | 0.01 | Affected | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||||||
| c.532A>G | K178E 2D AIThe SynGAP1 missense variant K178E 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 assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.497853 | Structured | 0.455271 | Uncertain | 0.354 | 0.622 | 0.375 | -13.695 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.205 | Likely Benign | 0.4659 | 0.0952 | -2.63 | Deleterious | 0.905 | Possibly Damaging | 0.393 | Benign | 3.90 | Benign | 0.01 | Affected | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||||
| c.533A>C | K178T 2D AIThe SynGAP1 missense variant K178T is not reported in ClinVar and is absent from gnomAD. Computational predictors show a split: benign calls come from REVEL, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic calls arise from PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus agrees. Foldetta, a protein‑folding stability method that combines FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.497853 | Structured | 0.455271 | Uncertain | 0.354 | 0.622 | 0.375 | -13.359 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.249 | Likely Benign | 0.2631 | 0.2788 | -3.95 | Deleterious | 0.759 | Possibly Damaging | 0.306 | Benign | 3.86 | Benign | 0.01 | Affected | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||
| c.533A>G | K178R 2D AIThe SynGAP1 missense variant K178R is reported in gnomAD (ID 6‑33435175‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, while the consensus score from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus also indicates likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for K178R, and this conclusion is not contradicted by any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.497853 | Structured | 0.455271 | Uncertain | 0.354 | 0.622 | 0.375 | 6-33435175-A-G | 1 | 6.20e-7 | -4.398 | Likely Benign | 0.281 | Likely Benign | Likely Benign | 0.117 | Likely Benign | 0.5403 | 0.1131 | Weaken | -1.62 | Neutral | 0.905 | Possibly Damaging | 0.393 | Benign | 3.98 | Benign | 0.14 | Tolerated | 3.54 | 6 | 2 | 3 | -0.6 | 28.01 | |||||||||||||||||||||||||||||
| c.533A>T | K178M 2D AIThe SynGAP1 missense variant K178M 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 (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. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.497853 | Structured | 0.455271 | Uncertain | 0.354 | 0.622 | 0.375 | -13.585 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.287 | Likely Benign | 0.1486 | 0.3607 | -3.95 | Deleterious | 0.992 | Probably Damaging | 0.751 | Possibly Damaging | 3.83 | Benign | 0.00 | Affected | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||
| c.534G>C | K178N 2D AIThe SynGAP1 missense variant K178N 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 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, and PROVEAN)—all predict it to be pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus reports Likely Pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Based on the preponderance of pathogenic predictions, K178N 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 | 0.497853 | Structured | 0.455271 | Uncertain | 0.354 | 0.622 | 0.375 | -12.137 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.131 | Likely Benign | 0.4503 | 0.1321 | -3.32 | Deleterious | 0.971 | Probably Damaging | 0.598 | Possibly Damaging | 3.86 | Benign | 0.01 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||
| c.534G>T | K178N 2D AIThe SynGAP1 missense variant K178N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM, while 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)—all 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 indicates it is likely pathogenic, and Foldetta’s protein‑folding stability analysis is unavailable. Based on the preponderance of pathogenic predictions and the high‑accuracy tools’ results, the variant is most likely pathogenic; this conclusion is not contradicted by any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.497853 | Structured | 0.455271 | Uncertain | 0.354 | 0.622 | 0.375 | -12.137 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.131 | Likely Benign | 0.4503 | 0.1321 | -3.32 | Deleterious | 0.971 | Probably Damaging | 0.598 | Possibly Damaging | 3.86 | Benign | 0.01 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||
| c.535G>A | E179K 2D  AIThe SynGAP1 missense variant E179K is not 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. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑accuracy predictors (five pathogenic vs. four benign) indicate a pathogenic impact. No ClinVar entry contradicts this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.517562 | Disordered | 0.448169 | Uncertain | 0.329 | 0.635 | 0.500 | -11.305 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.174 | Likely Benign | 0.2867 | 0.7695 | -2.32 | Neutral | 0.596 | Possibly Damaging | 0.202 | Benign | 4.03 | Benign | 0.02 | Affected | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||
| c.535G>C | E179Q 2D  AIThe SynGAP1 missense variant E179Q has no ClinVar record (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Computational predictions are split: benign calls come from REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls come from polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy consensus tools are inconclusive: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a tie, and Foldetta results are unavailable. Consequently, the variant is neither clearly benign nor pathogenic based on current predictions, and there is no ClinVar status to contradict this ambiguous assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.517562 | Disordered | 0.448169 | Uncertain | 0.329 | 0.635 | 0.500 | -10.388 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.123 | Likely Benign | 0.1674 | 0.7383 | -1.82 | Neutral | 0.818 | Possibly Damaging | 0.419 | Benign | 3.99 | Benign | 0.02 | Affected | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||
| c.536A>C | E179A 2D  AISynGAP1 E179A is not reported in ClinVar and has no entry in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM; pathogenic predictions come from PROVEAN, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is Uncertain, SGM‑Consensus is Likely Pathogenic, and Foldetta data are unavailable. Overall, the majority of individual predictors lean benign, yet the consensus and high‑accuracy tools indicate pathogenicity, leaving the variant’s effect ambiguous. The predictions do not contradict ClinVar status, which has no entry for this variant. Based on the aggregate predictions, the variant is most likely benign, although the SGM‑Consensus and high‑accuracy tools raise a pathogenic signal, making the overall assessment inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.517562 | Disordered | 0.448169 | Uncertain | 0.329 | 0.635 | 0.500 | -9.862 | Likely Pathogenic | 0.955 | Likely Pathogenic | Ambiguous | 0.124 | Likely Benign | 0.4465 | 0.7186 | -3.61 | Deleterious | 0.131 | Benign | 0.079 | Benign | 4.01 | Benign | 0.09 | Tolerated | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||
| c.536A>G | E179G 2D  AIThe SynGAP1 missense variant E179G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Among the available in‑silico predictors, six tools (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM) unanimously predict a benign effect, whereas two tools (PROVEAN and AlphaMissense‑Default) predict pathogenicity. High‑accuracy predictors give no definitive verdict: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign votes); and Foldetta results are unavailable. Consequently, the overall evidence leans toward a benign interpretation, with no conflict with the lack of ClinVar annotation. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.517562 | Disordered | 0.448169 | Uncertain | 0.329 | 0.635 | 0.500 | -6.527 | Likely Benign | 0.949 | Likely Pathogenic | Ambiguous | 0.158 | Likely Benign | 0.3273 | 0.6425 | -4.24 | Deleterious | 0.001 | Benign | 0.004 | Benign | 3.97 | Benign | 0.09 | Tolerated | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||
| c.536A>T | E179V 2D  AIThe SynGAP1 missense variant E179V 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 | 0.517562 | Disordered | 0.448169 | Uncertain | 0.329 | 0.635 | 0.500 | -10.930 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.190 | Likely Benign | 0.1077 | 0.7864 | -4.34 | Deleterious | 0.596 | Possibly Damaging | 0.328 | Benign | 3.94 | Benign | 0.01 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||
| c.537G>C | E179D 2D  AIThe SynGAP1 missense variant E179D is not 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, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. Two tools—ESM1b and AlphaMissense‑Optimized—return uncertain results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is uncertain, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority vote, and Foldetta data are unavailable. Overall, the balance of evidence (four benign vs. three pathogenic predictions, with a benign consensus from high‑accuracy methods) indicates that the variant is most likely benign. 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. | 0.517562 | Disordered | 0.448169 | Uncertain | 0.329 | 0.635 | 0.500 | -7.741 | In-Between | 0.929 | Likely Pathogenic | Ambiguous | 0.145 | Likely Benign | 0.2327 | 0.5011 | -1.91 | Neutral | 0.596 | Possibly Damaging | 0.142 | Benign | 3.97 | Benign | 0.05 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.537G>T | E179D 2D AIThe SynGAP1 missense variant E179D is not 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, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. Two tools—ESM1b and AlphaMissense‑Optimized—return uncertain results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is uncertain, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority vote, and Foldetta data are unavailable. Overall, the balance of evidence (four benign vs. three pathogenic predictions, with a benign consensus from high‑accuracy methods) 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. | 0.517562 | Disordered | 0.448169 | Uncertain | 0.329 | 0.635 | 0.500 | -7.741 | In-Between | 0.929 | Likely Pathogenic | Ambiguous | 0.145 | Likely Benign | 0.2327 | 0.5011 | -1.91 | Neutral | 0.596 | Possibly Damaging | 0.142 | Benign | 3.97 | Benign | 0.05 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.538T>A | S180T 2D AIThe SynGAP1 missense variant S180T is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. three pathogenic) support a benign classification. This consensus does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Thus, the variant is most likely benign based on current predictive evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.509769 | Disordered | 0.442877 | Uncertain | 0.320 | 0.616 | 0.500 | -9.851 | Likely Pathogenic | 0.669 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | 0.1238 | 0.5171 | -2.07 | Neutral | 0.057 | Benign | 0.020 | Benign | 3.86 | Benign | 0.02 | Affected | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.538T>C | S180P 2D AIThe SynGAP1 missense variant S180P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM‑Consensus as Likely Pathogenic; the Foldetta protein‑folding stability analysis is unavailable. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.509769 | Disordered | 0.442877 | Uncertain | 0.320 | 0.616 | 0.500 | -14.574 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.225 | Likely Benign | 0.1916 | 0.4735 | -3.19 | Deleterious | 0.917 | Possibly Damaging | 0.446 | Benign | 3.81 | Benign | 0.01 | Affected | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.538T>G | S180A 2D AIThe SynGAP1 missense variant S180A is not 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 predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority (2 benign vs. 1 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that the S180A variant is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.509769 | Disordered | 0.442877 | Uncertain | 0.320 | 0.616 | 0.500 | -10.413 | Likely Pathogenic | 0.559 | Ambiguous | Likely Benign | 0.095 | Likely Benign | 0.5003 | 0.3788 | Weaken | -1.94 | Neutral | 0.390 | Benign | 0.079 | Benign | 3.90 | Benign | 0.04 | Affected | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||
| c.539C>T | S180L 2D AIThe SynGAP1 missense variant S180L is not 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 are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus (SGM‑Consensus) derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a “Likely Pathogenic” classification. AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.509769 | Disordered | 0.442877 | Uncertain | 0.320 | 0.616 | 0.500 | -12.967 | Likely Pathogenic | 0.955 | Likely Pathogenic | Ambiguous | 0.250 | Likely Benign | 0.0885 | 0.5550 | -3.80 | Deleterious | 0.608 | Possibly Damaging | 0.202 | Benign | 3.84 | Benign | 0.00 | Affected | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||||||||
| c.541C>A | H181N 2D AIThe SynGAP1 missense variant H181N is not reported 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, 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). Foldetta results are unavailable. Overall, the preponderance of evidence indicates that H181N is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.439530 | Uncertain | 0.294 | 0.616 | 0.500 | -10.315 | Likely Pathogenic | 0.526 | Ambiguous | Likely Benign | 0.090 | Likely Benign | 0.1335 | 0.1839 | -1.50 | Neutral | 0.421 | Benign | 0.107 | Benign | 4.18 | Benign | 0.05 | Affected | 2 | 1 | -0.3 | -23.04 | ||||||||||||||||||||||||||||||||||||
| c.541C>G | H181D 2D AIThe SynGAP1 missense variant H181D has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split opinion: benign calls come from REVEL, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: the SGM‑Consensus is pathogenic, AlphaMissense‑Optimized remains uncertain, and the Foldetta stability analysis is unavailable. Overall, the majority of evidence points toward a pathogenic impact. Because there is no ClinVar classification to oppose this, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.505461 | Disordered | 0.439530 | Uncertain | 0.294 | 0.616 | 0.500 | -15.380 | Likely Pathogenic | 0.901 | Likely Pathogenic | Ambiguous | 0.260 | Likely Benign | 0.2157 | 0.1255 | -2.93 | Deleterious | 0.596 | Possibly Damaging | 0.107 | Benign | 4.17 | Benign | 0.02 | Affected | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||
| c.541C>T | H181Y 2D AIThe SynGAP1 missense variant H181Y is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33435183‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and ESM1b. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors a benign outcome. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for H181Y, and this conclusion does not contradict the ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.439530 | Uncertain | 0.294 | 0.616 | 0.500 | 6-33435183-C-T | 2 | 1.24e-6 | -9.477 | Likely Pathogenic | 0.551 | Ambiguous | Likely Benign | 0.161 | Likely Benign | 0.0588 | 0.3875 | -2.36 | Neutral | 0.818 | Possibly Damaging | 0.255 | Benign | 4.13 | Benign | 0.02 | Affected | 3.54 | 6 | 2 | 0 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||
| c.542A>C | H181P 2D AISynGAP1 H181P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign calls come from REVEL, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates majority votes from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts a benign effect, whereas the SGM‑Consensus indicates pathogenicity; Foldetta stability analysis is unavailable. Overall, the majority of evidence points toward a pathogenic effect, 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 | 0.505461 | Disordered | 0.439530 | Uncertain | 0.294 | 0.616 | 0.500 | -13.151 | Likely Pathogenic | 0.737 | Likely Pathogenic | Likely Benign | 0.236 | Likely Benign | 0.1783 | 0.3169 | -3.27 | Deleterious | 0.940 | Possibly Damaging | 0.360 | Benign | 4.14 | Benign | 0.04 | Affected | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||
| c.542A>G | H181R 2D AIThe SynGAP1 missense variant H181R is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus likewise indicates Likely Benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.439530 | Uncertain | 0.294 | 0.616 | 0.500 | -3.668 | Likely Benign | 0.521 | Ambiguous | Likely Benign | 0.174 | Likely Benign | 0.1585 | 0.1782 | -0.11 | Neutral | 0.818 | Possibly Damaging | 0.188 | Benign | 4.35 | Benign | 1.00 | Tolerated | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||
| c.542A>T | H181L 2D AIThe SynGAP1 H181L variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leans pathogenic (2 pathogenic vs 1 benign). Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the majority of standard predictors classify the variant as benign, and there is no ClinVar entry to contradict this assessment. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.439530 | Uncertain | 0.294 | 0.616 | 0.500 | -11.014 | Likely Pathogenic | 0.561 | Ambiguous | Likely Benign | 0.212 | Likely Benign | 0.0734 | 0.4395 | -3.51 | Deleterious | 0.267 | Benign | 0.039 | Benign | 4.17 | Benign | 0.04 | Affected | -2 | -3 | 7.0 | -23.98 | ||||||||||||||||||||||||||||||||||||
| c.543C>A | H181Q 2D AIThe SynGAP1 missense variant H181Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic, two benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools therefore give a benign prediction from AlphaMissense‑Optimized, an inconclusive SGM Consensus, and no Foldetta data. Overall, the majority of predictions (six benign vs. three pathogenic) indicate that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.439530 | Uncertain | 0.294 | 0.616 | 0.500 | -9.577 | Likely Pathogenic | 0.692 | Likely Pathogenic | Likely Benign | 0.125 | Likely Benign | 0.1241 | 0.2835 | -1.45 | Neutral | 0.940 | Possibly Damaging | 0.360 | Benign | 4.19 | Benign | 0.09 | Tolerated | 3 | 0 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||||
| c.543C>G | H181Q 2D AIThe SynGAP1 H181Q missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs two benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools therefore give a benign prediction from AlphaMissense‑Optimized, an inconclusive SGM Consensus, and an unavailable Foldetta result. Overall, the majority of predictions (six benign vs three pathogenic) indicate that the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.439530 | Uncertain | 0.294 | 0.616 | 0.500 | -9.577 | Likely Pathogenic | 0.692 | Likely Pathogenic | Likely Benign | 0.125 | Likely Benign | 0.1241 | 0.2835 | -1.45 | Neutral | 0.940 | Possibly Damaging | 0.360 | Benign | 4.19 | Benign | 0.09 | Tolerated | 3 | 0 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||||
| c.544T>A | S182T 2D AIThe SynGAP1 missense variant S182T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, the majority of available predictions (five benign vs three pathogenic) suggest a benign impact. This consensus does not contradict any ClinVar annotation, as no ClinVar entry exists for this variant. Thus, based on current computational evidence, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.436016 | Uncertain | 0.368 | 0.619 | 0.625 | -11.247 | Likely Pathogenic | 0.857 | Likely Pathogenic | Ambiguous | 0.128 | Likely Benign | 0.1624 | 0.5657 | -2.29 | Neutral | 0.231 | Benign | 0.081 | Benign | 3.68 | Benign | 0.00 | Affected | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.544T>C | S182P 2D AIThe SynGAP1 missense variant S182P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority of the four high‑accuracy tools) also indicates pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.501700 | Disordered | 0.436016 | Uncertain | 0.368 | 0.619 | 0.625 | -13.362 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.279 | Likely Benign | 0.2438 | 0.5030 | -3.71 | Deleterious | 0.838 | Possibly Damaging | 0.367 | Benign | 3.67 | Benign | 0.00 | Affected | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.544T>G | S182A 2D AIThe SynGAP1 missense variant S182A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, the majority of standard predictors lean toward a benign impact, and no ClinVar evidence contradicts this assessment. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.436016 | Uncertain | 0.368 | 0.619 | 0.625 | -9.417 | Likely Pathogenic | 0.838 | Likely Pathogenic | Ambiguous | 0.113 | Likely Benign | 0.5466 | 0.4660 | Weaken | -2.26 | Neutral | 0.001 | Benign | 0.005 | Benign | 3.70 | Benign | 0.00 | Affected | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0656 | 0.5158 | -4.40 | Deleterious | 0.940 | Possibly Damaging | 0.564 | Possibly Damaging | 3.64 | Benign | 0.00 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||
| c.545C>G | S182C 2D AIThe SynGAP1 missense variant S182C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all classify the variant as damaging. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, while the SGM‑Consensus (majority vote) remains pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple in silico 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 | 0.501700 | Disordered | 0.436016 | Uncertain | 0.368 | 0.619 | 0.625 | -12.707 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 0.216 | Likely Benign | 0.1179 | 0.5800 | -3.14 | Deleterious | 0.983 | Probably Damaging | 0.635 | Possibly Damaging | 3.63 | Benign | 0.00 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0597 | 0.5482 | -4.30 | Deleterious | 0.838 | Possibly Damaging | 0.466 | Possibly Damaging | 3.64 | Benign | 0.00 | Affected | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||
| c.547C>A | H183N 2D AIThe SynGAP1 H183N missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, tools that predict a pathogenic impact are PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote) also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the majority of predictions, including the high‑accuracy tools, point to a pathogenic effect, 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 | 0.476583 | Structured | 0.432952 | Uncertain | 0.421 | 0.622 | 0.500 | -12.028 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.188 | Likely Benign | 0.1714 | 0.2589 | -4.97 | Deleterious | 0.012 | Benign | 0.006 | Benign | 3.81 | Benign | 0.01 | Affected | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||
| c.547C>G | H183D 2D AIThe SynGAP1 missense variant H183D is not 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 comprise PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Pathogenic, and AlphaMissense‑Optimized independently predicts Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the majority of predictions (seven pathogenic vs. four benign) indicate a pathogenic impact. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for H183D. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.476583 | Structured | 0.432952 | Uncertain | 0.421 | 0.622 | 0.500 | -18.626 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.311 | Likely Benign | 0.2620 | 0.1817 | -6.55 | Deleterious | 0.421 | Benign | 0.107 | Benign | 3.81 | Benign | 0.01 | Affected | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||
| c.547C>T | H183Y 2D AIThe SynGAP1 H183Y missense variant 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 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 | 0.476583 | Structured | 0.432952 | Uncertain | 0.421 | 0.622 | 0.500 | -9.481 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.250 | Likely Benign | 0.0831 | 0.4406 | -4.48 | Deleterious | 0.818 | Possibly Damaging | 0.255 | Benign | 3.77 | Benign | 0.00 | Affected | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||
| c.548A>C | H183P 2D AIThe SynGAP1 missense variant H183P 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, 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 also predicts Pathogenic, while the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic impact, and this conclusion does not contradict any existing ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.476583 | Structured | 0.432952 | Uncertain | 0.421 | 0.622 | 0.500 | -18.527 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.410 | Likely Benign | 0.2143 | 0.3712 | -7.18 | Deleterious | 0.838 | Possibly Damaging | 0.276 | Benign | 3.79 | Benign | 0.01 | Affected | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||
| c.548A>G | H183R 2D AIThe SynGAP1 H183R missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus (majority vote) also pathogenic; Foldetta stability analysis is unavailable. Based on the majority of computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.476583 | Structured | 0.432952 | Uncertain | 0.421 | 0.622 | 0.500 | -10.937 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.368 | Likely Benign | 0.1915 | 0.2249 | -5.43 | Deleterious | 0.596 | Possibly Damaging | 0.142 | Benign | 3.90 | Benign | 0.13 | Tolerated | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||
| c.548A>T | H183L 2D AIThe SynGAP1 missense variant H183L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Pathogenic” verdict (3 pathogenic vs. 1 benign votes). AlphaMissense‑Optimized alone also predicts pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact, 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 | 0.476583 | Structured | 0.432952 | Uncertain | 0.421 | 0.622 | 0.500 | -12.898 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.325 | Likely Benign | 0.0911 | 0.5304 | -8.12 | Deleterious | 0.421 | Benign | 0.058 | Benign | 3.79 | Benign | 0.01 | Affected | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||
| c.549T>A | H183Q 2D AIThe SynGAP1 missense variant H183Q is not 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 pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic effect, 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 | 0.432952 | Uncertain | 0.421 | 0.622 | 0.500 | -10.383 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.223 | Likely Benign | 0.1470 | 0.3623 | -5.43 | Deleterious | 0.838 | Possibly Damaging | 0.276 | Benign | 3.88 | Benign | 0.01 | Affected | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||
| c.549T>G | H183Q 2D AIThe SynGAP1 missense variant H183Q is not 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 pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic effect, 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 | 0.432952 | Uncertain | 0.421 | 0.622 | 0.500 | -10.383 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.223 | Likely Benign | 0.1470 | 0.3623 | -5.43 | Deleterious | 0.838 | Possibly Damaging | 0.276 | Benign | 3.88 | Benign | 0.01 | Affected | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||
| c.550G>A | E184K 2D AIThe SynGAP1 missense variant E184K is not 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, 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 majority of computational evidence indicates that E184K 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 | 0.557691 | Disordered | 0.431514 | Uncertain | 0.348 | 0.622 | 0.625 | -14.037 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.289 | Likely Benign | 0.2890 | 0.8227 | -3.31 | Deleterious | 0.970 | Probably Damaging | 0.681 | Possibly Damaging | 3.50 | Benign | 0.00 | Affected | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||
| c.550G>C | E184Q 2D AIThe SynGAP1 missense variant E184Q is not 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, 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, so it does not influence the overall assessment. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.557691 | Disordered | 0.431514 | Uncertain | 0.348 | 0.622 | 0.625 | -11.927 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.210 | Likely Benign | 0.1688 | 0.7914 | -2.55 | Deleterious | 0.990 | Probably Damaging | 0.815 | Possibly Damaging | 3.47 | Benign | 0.00 | Affected | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||
| c.551A>C | E184A 2D AIThe SynGAP1 missense variant E184A has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic impact are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (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 supports a pathogenic effect for E184A. This prediction is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.557691 | Disordered | 0.431514 | Uncertain | 0.348 | 0.622 | 0.625 | -11.486 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.338 | Likely Benign | 0.4419 | 0.7381 | -4.98 | Deleterious | 0.868 | Possibly Damaging | 0.344 | Benign | 3.48 | Benign | 0.00 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||
| c.551A>G | E184G 2D AIThe SynGAP1 missense variant E184G is not 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, 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 from both general and high‑accuracy predictors indicates that E184G 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 | 0.557691 | Disordered | 0.431514 | Uncertain | 0.348 | 0.622 | 0.625 | -10.725 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.353 | Likely Benign | 0.3281 | 0.6534 | -5.52 | Deleterious | 0.970 | Probably Damaging | 0.607 | Possibly Damaging | 3.45 | Benign | 0.00 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||
| c.551A>T | E184V 2D AIThe SynGAP1 missense variant E184V 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 scores the variant as pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability analysis is available for this variant. Overall, the preponderance of evidence indicates that E184V 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 | 0.557691 | Disordered | 0.431514 | Uncertain | 0.348 | 0.622 | 0.625 | -13.119 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.371 | Likely Benign | 0.0995 | 0.8511 | -5.72 | Deleterious | 0.997 | Probably Damaging | 0.879 | Possibly Damaging | 3.44 | Benign | 0.00 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||
| c.552G>C | E184D 2D AIThe SynGAP1 E184D 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. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence (six pathogenic vs. three benign predictions) indicates that the variant is most likely pathogenic, 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. | 0.557691 | Disordered | 0.431514 | Uncertain | 0.348 | 0.622 | 0.625 | -6.753 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.195 | Likely Benign | 0.2249 | 0.5394 | -2.55 | Deleterious | 0.930 | Possibly Damaging | 0.584 | Possibly Damaging | 3.52 | Benign | 0.00 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.552G>T | E184D 2D AIThe SynGAP1 E184D 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. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence (six pathogenic vs. three benign predictions) indicates that the variant is most likely pathogenic, 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. | 0.557691 | Disordered | 0.431514 | Uncertain | 0.348 | 0.622 | 0.625 | -6.753 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.195 | Likely Benign | 0.2249 | 0.5394 | -2.55 | Deleterious | 0.930 | Possibly Damaging | 0.584 | Possibly Damaging | 3.52 | Benign | 0.00 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.553T>A | S185T 2D AIThe SynGAP1 missense variant S185T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, while Foldetta (combining FoldX‑MD and Rosetta outputs) is not available for this variant. Overall, the majority of evidence points to a pathogenic impact. The variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.545602 | Disordered | 0.430485 | Uncertain | 0.365 | 0.623 | 0.500 | -10.943 | Likely Pathogenic | 0.903 | Likely Pathogenic | Ambiguous | 0.186 | Likely Benign | 0.1484 | 0.6236 | -2.54 | Deleterious | 0.596 | Possibly Damaging | 0.142 | Benign | 3.60 | Benign | 0.00 | Affected | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.553T>C | S185P 2D AIThe SynGAP1 missense variant S185P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the S185P variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.545602 | Disordered | 0.430485 | Uncertain | 0.365 | 0.623 | 0.500 | -15.129 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.285 | Likely Benign | 0.2156 | 0.5242 | -4.02 | Deleterious | 0.940 | Possibly Damaging | 0.462 | Possibly Damaging | 3.56 | Benign | 0.00 | Affected | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.553T>G | S185A 2D AIThe SynGAP1 missense variant S185A is not 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, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome. AlphaMissense‑Optimized is uncertain, and no Foldetta stability result is available. High‑accuracy assessments therefore show a likely pathogenic consensus from SGM‑Consensus, with no contradictory evidence from ClinVar or population databases. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar status (none reported). 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 | -11.839 | Likely Pathogenic | 0.868 | Likely Pathogenic | Ambiguous | 0.203 | Likely Benign | 0.5147 | 0.4472 | Weaken | -2.57 | Deleterious | 0.231 | Benign | 0.107 | Benign | 3.65 | Benign | 0.00 | Affected | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||
| 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 | 0.0736 | 0.5439 | -4.93 | Deleterious | 0.718 | Possibly Damaging | 0.178 | Benign | 3.56 | Benign | 0.00 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||
| c.554C>G | S185C 2D AIThe SynGAP1 missense variant S185C has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, while the majority of other in silico predictors (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 indicate a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (derived from the same set of predictors) also reports 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; this conclusion is not contradicted by any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.545602 | Disordered | 0.430485 | Uncertain | 0.365 | 0.623 | 0.500 | -10.612 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.266 | Likely Benign | 0.0989 | 0.6000 | -3.96 | Deleterious | 0.983 | Probably Damaging | 0.635 | Possibly Damaging | 3.54 | Benign | 0.00 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0628 | 0.5563 | -5.03 | Deleterious | 0.838 | Possibly Damaging | 0.466 | Possibly Damaging | 3.55 | Benign | 0.00 | Affected | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||
| c.556T>A | L186M 2D AIThe SynGAP1 missense variant L186M is not 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 are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool rates the variant as uncertain, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (5 pathogenic vs. 3 benign) suggest 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. | 0.458154 | Structured | 0.428613 | Uncertain | 0.397 | 0.617 | 0.500 | -11.783 | Likely Pathogenic | 0.933 | Likely Pathogenic | Ambiguous | 0.146 | Likely Benign | 0.0671 | 0.3396 | -1.58 | Neutral | 0.952 | Possibly Damaging | 0.694 | Possibly Damaging | 3.50 | Benign | 0.00 | Affected | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||
| c.556T>G | L186V 2D AIThe SynGAP1 missense variant L186V is not 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. High‑accuracy assessments are mixed: AlphaMissense‑Optimized predicts pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields no clear majority and is therefore unavailable; Foldetta results are also unavailable. Overall, the majority of available predictions (five pathogenic vs. four benign) indicate a pathogenic effect. There is no ClinVar entry to contradict this assessment, so 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. | 0.458154 | Structured | 0.428613 | Uncertain | 0.397 | 0.617 | 0.500 | -9.385 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.090 | Likely Benign | 0.1419 | 0.3665 | -2.27 | Neutral | 0.734 | Possibly Damaging | 0.185 | Benign | 3.60 | Benign | 0.00 | Affected | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.557T>C | L186S 2D  AIThe SynGAP1 missense variant L186S is not 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). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a deleterious effect, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels the variant 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 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 | 0.458154 | Structured | 0.428613 | Uncertain | 0.397 | 0.617 | 0.500 | -13.906 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.250 | Likely Benign | 0.3214 | 0.0808 | -4.73 | Deleterious | 0.952 | Possibly Damaging | 0.601 | Possibly Damaging | 3.51 | Benign | 0.00 | Affected | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0539 | 0.3138 | -4.78 | Deleterious | 0.996 | Probably Damaging | 0.819 | Possibly Damaging | 3.46 | Benign | 0.00 | Affected | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||||||||
| c.558G>C | L186F 2D AIThe SynGAP1 missense variant L186F is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), and FATHMM. In contrast, tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote) also indicates likely pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a pathogenic effect, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.458154 | Structured | 0.428613 | Uncertain | 0.397 | 0.617 | 0.500 | Uncertain | 1 | -11.861 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.132 | Likely Benign | 0.0524 | 0.3177 | -3.03 | Deleterious | 0.009 | Benign | 0.012 | Benign | 3.50 | Benign | 0.00 | Affected | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||
| c.558G>T | L186F 2D AIThe SynGAP1 missense variant L186F has no ClinVar entry (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “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 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 | 0.458154 | Structured | 0.428613 | Uncertain | 0.397 | 0.617 | 0.500 | -11.861 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.132 | Likely Benign | 0.0524 | 0.3177 | -3.03 | Deleterious | 0.009 | Benign | 0.012 | Benign | 3.50 | Benign | 0.00 | Affected | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||
| c.559C>A | L187M 2D AIThe SynGAP1 missense variant L187M is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM. Those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, which would assess protein‑folding stability, has no available output for this variant. Overall, the majority of predictions (five pathogenic vs. three benign) lean toward pathogenicity, 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. | 0.465241 | Structured | 0.428046 | Uncertain | 0.367 | 0.625 | 0.375 | -8.814 | Likely Pathogenic | 0.954 | Likely Pathogenic | Ambiguous | 0.136 | Likely Benign | 0.0848 | 0.3613 | -1.35 | Neutral | 0.971 | Probably Damaging | 0.641 | Possibly Damaging | 3.72 | Benign | 0.02 | Affected | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||
| c.559C>G | L187V 2D AIThe SynGAP1 missense variant L187V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign). High‑accuracy AlphaMissense‑Optimized predicts pathogenic, while Foldetta (combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the majority of standard predictors lean toward a benign classification, but the single high‑accuracy tool indicates pathogenicity. Thus, the variant is most likely benign based on the collective evidence, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.465241 | Structured | 0.428046 | Uncertain | 0.367 | 0.625 | 0.375 | -10.543 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.136 | Likely Benign | 0.1525 | 0.3509 | -2.24 | Neutral | 0.437 | Benign | 0.079 | Benign | 3.81 | Benign | 0.02 | Affected | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.560T>A | L187Q 2D AIThe SynGAP1 missense variant L187Q is not 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, 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, 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 predictors points to a pathogenic effect for the SynGAP1 L187Q variant, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.465241 | Structured | 0.428046 | Uncertain | 0.367 | 0.625 | 0.375 | -13.063 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.322 | Likely Benign | 0.1251 | 0.1060 | -4.31 | Deleterious | 0.917 | Possibly Damaging | 0.548 | Possibly Damaging | 3.72 | Benign | 0.00 | Affected | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||
| c.560T>C | L187P 2D AIThe SynGAP1 missense variant L187P is listed in gnomAD (ID 6‑33435202‑T‑C) but has no ClinVar entry. Functional prediction tools split in two groups: benign predictions come from 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 indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus classifies the variant as Likely Pathogenic. No Foldetta stability result is available, so it does not influence the overall assessment. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently reports no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.465241 | Structured | 0.428046 | Uncertain | 0.367 | 0.625 | 0.375 | 6-33435202-T-C | 1 | 6.20e-7 | -13.192 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.320 | Likely Benign | 0.3604 | 0.1484 | -5.17 | Deleterious | 0.917 | Possibly Damaging | 0.548 | Possibly Damaging | 3.70 | Benign | 0.01 | Affected | 3.47 | 9 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||
| c.560T>G | L187R 2D AIThe SynGAP1 missense variant L187R is not 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). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a deleterious effect, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels the variant 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 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 | 0.465241 | Structured | 0.428046 | Uncertain | 0.367 | 0.625 | 0.375 | -14.118 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.332 | Likely Benign | 0.1481 | 0.0702 | -4.38 | Deleterious | 0.917 | Possibly Damaging | 0.467 | Possibly Damaging | 3.72 | Benign | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0916 | 0.4236 | -3.82 | Deleterious | 0.985 | Probably Damaging | 0.767 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||
| c.562A>G | S188G 2D AIThe SynGAP1 missense variant S188G is not 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 are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus (SGM‑Consensus) derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN is “Likely Pathogenic.” AlphaMissense‑Optimized returns an uncertain result, and Foldetta (which would combine FoldX‑MD and Rosetta outputs) has no available data for this variant. Based on the overall distribution of predictions, the variant is most likely pathogenic; this assessment does not contradict any ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.490133 | Structured | 0.428502 | Uncertain | 0.298 | 0.603 | 0.500 | -10.113 | Likely Pathogenic | 0.919 | Likely Pathogenic | Ambiguous | 0.123 | Likely Benign | 0.3045 | 0.5542 | -3.10 | Deleterious | 0.882 | Possibly Damaging | 0.404 | Benign | 3.91 | Benign | 0.00 | Affected | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.562A>T | S188C 2D AIThe SynGAP1 missense variant S188C 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 | 0.490133 | Structured | 0.428502 | Uncertain | 0.298 | 0.603 | 0.500 | -8.670 | Likely Pathogenic | 0.849 | Likely Pathogenic | Ambiguous | 0.111 | Likely Benign | 0.1007 | 0.6737 | -2.96 | Deleterious | 0.999 | Probably Damaging | 0.956 | Probably Damaging | 3.87 | Benign | 0.00 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.563G>A | S188N 2D AIThe SynGAP1 missense variant S188N is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of available predictions (five benign vs three pathogenic) suggest 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. | 0.490133 | Structured | 0.428502 | Uncertain | 0.298 | 0.603 | 0.500 | -10.307 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.095 | Likely Benign | 0.1420 | 0.5658 | -2.34 | Neutral | 0.259 | Benign | 0.048 | Benign | 3.92 | Benign | 0.01 | Affected | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||
| c.563G>C | S188T 2D AIThe SynGAP1 missense variant S188T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Uncertain predictions come from ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows that the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans benign (two benign versus one pathogenic vote). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact; this conclusion does not contradict any ClinVar annotation, as none exists for S188T. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.490133 | Structured | 0.428502 | Uncertain | 0.298 | 0.603 | 0.500 | -7.906 | In-Between | 0.801 | Likely Pathogenic | Ambiguous | 0.124 | Likely Benign | 0.1491 | 0.7492 | -1.97 | Neutral | 0.948 | Possibly Damaging | 0.484 | Possibly Damaging | 3.92 | Benign | 0.13 | Tolerated | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.563G>T | S188I 2D AIThe SynGAP1 missense variant S188I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM, while 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, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus also pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for S188I, 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 | 0.490133 | Structured | 0.428502 | Uncertain | 0.298 | 0.603 | 0.500 | -12.133 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.205 | Likely Benign | 0.0878 | 0.6335 | -3.98 | Deleterious | 0.995 | Probably Damaging | 0.880 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0916 | 0.4236 | -3.82 | Deleterious | 0.985 | Probably Damaging | 0.767 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 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 | 0.0916 | 0.4236 | -3.82 | Deleterious | 0.985 | Probably Damaging | 0.767 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||
| c.565C>A | P189T 2D AISynGAP1 missense variant P189T is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect comprise PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority‑vote method) reports it as likely pathogenic; Foldetta 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 | 0.497853 | Structured | 0.428590 | Uncertain | 0.331 | 0.602 | 0.250 | -8.622 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.265 | Likely Benign | 0.1603 | 0.6392 | -5.26 | Deleterious | 0.384 | Benign | 0.177 | Benign | 4.05 | Benign | 0.05 | Affected | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||
| c.565C>G | P189A 2D AIThe SynGAP1 missense variant P189A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (two pathogenic, two benign), and Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs. four benign) and the pathogenic call from AlphaMissense‑Optimized suggest that the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.497853 | Structured | 0.428590 | Uncertain | 0.331 | 0.602 | 0.250 | -4.998 | Likely Benign | 0.974 | Likely Pathogenic | Likely Pathogenic | 0.211 | Likely Benign | 0.3719 | 0.6209 | -5.46 | Deleterious | 0.941 | Possibly Damaging | 0.607 | Possibly Damaging | 4.07 | Benign | 0.07 | Tolerated | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||
| c.565C>T | P189S 2D AIThe SynGAP1 missense variant P189S is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized; ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors pathogenicity (2 pathogenic vs. 1 benign). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of computational evidence indicates a pathogenic effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.497853 | Structured | 0.428590 | Uncertain | 0.331 | 0.602 | 0.250 | -7.191 | In-Between | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.211 | Likely Benign | 0.3626 | 0.6460 | -5.23 | Deleterious | 0.941 | Possibly Damaging | 0.531 | Possibly Damaging | 4.09 | Benign | 0.15 | Tolerated | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||
| c.566C>A | P189H 2D AIThe SynGAP1 missense variant P189H is not 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, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: 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 majority of computational evidence indicates that P189H 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 | 0.497853 | Structured | 0.428590 | Uncertain | 0.331 | 0.602 | 0.250 | -9.633 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.298 | Likely Benign | 0.1620 | 0.5327 | -6.49 | Deleterious | 0.999 | Probably Damaging | 0.936 | Probably Damaging | 4.00 | Benign | 0.00 | Affected | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||
| 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 | 0.1363 | 0.3894 | -6.45 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.05 | Benign | 0.01 | Affected | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.566C>T | P189L 2D AIThe SynGAP1 missense variant P189L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM. In contrast, a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all indicate likely pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. Foldetta results are unavailable for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic classification, with no ClinVar record to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.497853 | Structured | 0.428590 | Uncertain | 0.331 | 0.602 | 0.250 | -10.132 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.290 | Likely Benign | 0.2283 | 0.7378 | -7.28 | Deleterious | 0.991 | Probably Damaging | 0.781 | Possibly Damaging | 4.04 | Benign | 0.17 | Tolerated | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0809 | 0.4059 | -2.92 | Deleterious | 0.917 | Possibly Damaging | 0.446 | Benign | 4.07 | Benign | 0.04 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||
| c.568A>G | S190G 2D AIThe SynGAP1 missense variant S190G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the consensus of all available predictions is that the variant is most likely benign, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -5.440 | Likely Benign | 0.321 | Likely Benign | Likely Benign | 0.048 | Likely Benign | 0.2780 | 0.4765 | -1.26 | Neutral | 0.243 | Benign | 0.079 | Benign | 4.11 | Benign | 0.19 | Tolerated | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.568A>T | S190C 2D AIThe SynGAP1 missense variant S190C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -6.696 | Likely Benign | 0.617 | Likely Pathogenic | Likely Benign | 0.107 | Likely Benign | 0.0937 | 0.6667 | -2.04 | Neutral | 0.992 | Probably Damaging | 0.707 | Possibly Damaging | 4.01 | Benign | 0.23 | Tolerated | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.569G>A | S190N 2D AIThe SynGAP1 missense variant S190N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM, while polyPhen‑2 HumDiv and AlphaMissense‑Default predict a pathogenic outcome. The remaining tools, ESM1b and AlphaMissense‑Optimized, are uncertain. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized is uncertain; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) resolves to benign (two benign votes versus one pathogenic and one uncertain); and Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -7.497 | In-Between | 0.838 | Likely Pathogenic | Ambiguous | 0.160 | Likely Benign | 0.1119 | 0.5285 | -1.73 | Neutral | 0.759 | Possibly Damaging | 0.202 | Benign | 4.06 | Benign | 0.08 | Tolerated | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||
| c.569G>C | S190T 2D AIThe SynGAP1 missense variant S190T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus confirms Likely Benign, and Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -6.870 | Likely Benign | 0.408 | Ambiguous | Likely Benign | 0.114 | Likely Benign | 0.1294 | 0.6920 | -1.31 | Neutral | 0.608 | Possibly Damaging | 0.108 | Benign | 4.08 | Benign | 0.20 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.569G>T | S190I 2D AIThe SynGAP1 missense variant S190I is not 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 are PROVEAN, polyPhen‑2 HumDiv, 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. AlphaMissense‑Optimized returns an Uncertain result. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Overall, the majority of evidence points to a pathogenic impact, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -9.868 | Likely Pathogenic | 0.954 | Likely Pathogenic | Ambiguous | 0.316 | Likely Benign | 0.0769 | 0.5963 | -3.39 | Deleterious | 0.845 | Possibly Damaging | 0.368 | Benign | 4.03 | Benign | 0.03 | Affected | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0809 | 0.4059 | -2.92 | Deleterious | 0.917 | Possibly Damaging | 0.446 | Benign | 4.07 | Benign | 0.04 | Affected | 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 | 0.0809 | 0.4059 | -2.92 | Deleterious | 0.917 | Possibly Damaging | 0.446 | Benign | 4.07 | Benign | 0.04 | Affected | 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 | 0.0973 | 0.4344 | -3.82 | Deleterious | 0.838 | Possibly Damaging | 0.367 | Benign | 3.78 | Benign | 0.01 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||
| c.571A>G | S191G 2D AIThe SynGAP1 missense variant S191G is not 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, also leans toward benign (two benign versus two uncertain). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that S191G is most likely benign, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -7.161 | In-Between | 0.506 | Ambiguous | Likely Benign | 0.173 | Likely Benign | 0.2893 | 0.5335 | -2.43 | Neutral | 0.131 | Benign | 0.058 | Benign | 3.77 | Benign | 0.03 | Affected | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||||
| c.571A>T | S191C 2D AIThe SynGAP1 missense variant S191C is not 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. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic)—leans pathogenic. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of tools and the SGM Consensus predict a pathogenic impact, so the variant is most likely pathogenic, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -7.009 | In-Between | 0.709 | Likely Pathogenic | Likely Benign | 0.288 | Likely Benign | 0.1064 | 0.7134 | -3.39 | Deleterious | 0.983 | Probably Damaging | 0.635 | Possibly Damaging | 3.73 | Benign | 0.00 | Affected | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||
| c.572G>A | S191N 2D AIThe SynGAP1 missense variant S191N is not 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, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. Two tools report an uncertain outcome: 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 toward benign (2 benign vs. 1 pathogenic). AlphaMissense‑Optimized remains uncertain, and Foldetta folding‑stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact for S191N, and this conclusion does not contradict any ClinVar annotation, 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 | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -7.887 | In-Between | 0.830 | Likely Pathogenic | Ambiguous | 0.148 | Likely Benign | 0.1366 | 0.5898 | -2.21 | Neutral | 0.596 | Possibly Damaging | 0.260 | Benign | 3.78 | Benign | 0.03 | Affected | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||
| c.572G>C | S191T 2D AIThe SynGAP1 missense variant S191T is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools overwhelmingly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score benign, while the majority‑vote SGM‑Consensus also classifies it as likely benign. Only SIFT predicts a pathogenic outcome, and ESM1b remains uncertain. High‑accuracy assessments corroborate the benign consensus: AlphaMissense‑Optimized returns a benign prediction and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports likely benign. Foldetta stability analysis is not available for this variant. Overall, the preponderance of evidence supports a benign classification, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -7.315 | In-Between | 0.319 | Likely Benign | Likely Benign | 0.150 | Likely Benign | 0.1466 | 0.7405 | -2.34 | Neutral | 0.231 | Benign | 0.081 | Benign | 3.81 | Benign | 0.03 | Affected | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.572G>T | S191I 2D AIThe SynGAP1 missense variant S191I 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 opinion: benign predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), and FATHMM, while pathogenic predictions arise from PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. When the predictions are grouped by consensus, four tools favor benign and four favor pathogenic. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized returns an uncertain result, whereas 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. Taken together, the majority of evidence, including the SGM Consensus, points to a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -11.271 | Likely Pathogenic | 0.927 | Likely Pathogenic | Ambiguous | 0.283 | Likely Benign | 0.0954 | 0.6842 | -4.51 | Deleterious | 0.421 | Benign | 0.086 | Benign | 3.76 | Benign | 0.00 | Affected | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0973 | 0.4344 | -3.82 | Deleterious | 0.838 | Possibly Damaging | 0.367 | Benign | 3.78 | Benign | 0.01 | Affected | 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 | 0.0973 | 0.4344 | -3.82 | Deleterious | 0.838 | Possibly Damaging | 0.367 | Benign | 3.78 | Benign | 0.01 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||
| c.574G>A | A192T 2D AIThe SynGAP1 missense variant A192T has no ClinVar record (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome (2 benign vs. 1 pathogenic, 1 uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM Consensus remains benign; Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.422041 | Structured | 0.428195 | Uncertain | 0.321 | 0.589 | 0.125 | -7.562 | In-Between | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.089 | Likely Benign | 0.1148 | 0.5343 | -2.46 | Neutral | 0.978 | Probably Damaging | 0.714 | Possibly Damaging | 3.96 | Benign | 0.34 | Tolerated | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||
| c.574G>C | A192P 2D AIThe SynGAP1 missense variant A192P is not 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 both general and high‑accuracy prediction tools 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 | 0.422041 | Structured | 0.428195 | Uncertain | 0.321 | 0.589 | 0.125 | -9.795 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.245 | Likely Benign | 0.1658 | 0.3719 | -3.35 | Deleterious | 0.999 | Probably Damaging | 0.946 | Probably Damaging | 3.90 | Benign | 0.02 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||
| c.574G>T | A192S 2D AIThe SynGAP1 missense variant A192S is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default; ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.422041 | Structured | 0.428195 | Uncertain | 0.321 | 0.589 | 0.125 | -7.969 | In-Between | 0.757 | Likely Pathogenic | Likely Benign | 0.118 | Likely Benign | 0.2365 | 0.3764 | -2.01 | Neutral | 0.633 | Possibly Damaging | 0.171 | Benign | 3.98 | Benign | 0.12 | Tolerated | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||
| 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 | 0.0939 | 0.1628 | -3.52 | Deleterious | 0.997 | Probably Damaging | 0.888 | Possibly Damaging | 3.93 | Benign | 0.01 | Affected | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||||||||
| c.575C>G | A192G 2D AIThe SynGAP1 missense variant A192G is not 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, and AlphaMissense‑Default all indicate pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. AlphaMissense‑Optimized returns an uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available prediction for this variant. Overall, the preponderance of evidence from multiple in silico tools points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.422041 | Structured | 0.428195 | Uncertain | 0.321 | 0.589 | 0.125 | -9.003 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | 0.133 | Likely Benign | 0.2081 | 0.2857 | -3.00 | Deleterious | 0.989 | Probably Damaging | 0.621 | Possibly Damaging | 3.91 | Benign | 0.02 | Affected | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.575C>T | A192V 2D AIThe SynGAP1 missense variant A192V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. ESM1b remains uncertain. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic majority (2 pathogenic vs. 1 benign, 1 uncertain). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that A192V is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.422041 | Structured | 0.428195 | Uncertain | 0.321 | 0.589 | 0.125 | -7.464 | In-Between | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.172 | Likely Benign | 0.0904 | 0.5066 | -2.66 | Deleterious | 0.996 | Probably Damaging | 0.877 | Possibly Damaging | 4.01 | Benign | 0.11 | Tolerated | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||
| c.577G>A | A193T 2D AIThe SynGAP1 missense variant A193T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.428386 | Uncertain | 0.310 | 0.577 | 0.125 | -4.973 | Likely Benign | 0.789 | Likely Pathogenic | Ambiguous | 0.208 | Likely Benign | 0.1452 | 0.7231 | -1.36 | Neutral | 0.990 | Probably Damaging | 0.815 | Possibly Damaging | 4.07 | Benign | 0.21 | Tolerated | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.577G>C | A193P 2D AIThe SynGAP1 missense variant A193P 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, while the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized model classifies the variant as pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic), also yields a pathogenic consensus. 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 indicates that A193P is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.428386 | Uncertain | 0.310 | 0.577 | 0.125 | -7.293 | In-Between | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.267 | Likely Benign | 0.1855 | 0.5601 | -2.70 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 3.99 | Benign | 0.05 | Affected | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||||||||
| c.577G>T | A193S 2D AIThe SynGAP1 missense variant A193S is not reported 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 remains uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is 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 available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.428386 | Uncertain | 0.310 | 0.577 | 0.125 | -2.408 | Likely Benign | 0.533 | Ambiguous | Likely Benign | 0.180 | Likely Benign | 0.2595 | 0.5852 | -1.62 | Neutral | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 4.04 | Benign | 0.04 | Affected | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||
| c.578C>A | A193D 2D AIThe SynGAP1 missense variant A193D 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, while the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized model classifies the variant as pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic), also yields a pathogenic consensus. 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 A193D is most likely pathogenic, 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. | 0.429200 | Structured | 0.428386 | Uncertain | 0.310 | 0.577 | 0.125 | -7.488 | In-Between | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.217 | Likely Benign | 0.1688 | 0.1835 | -3.46 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 3.99 | Benign | 0.01 | Affected | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||
| c.578C>G | A193G 2D AIThe SynGAP1 missense variant A193G is not 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, while 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 from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, more tools predict pathogenicity (5) than benignity (3), and no ClinVar evidence contradicts this assessment. Therefore, 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. | 0.429200 | Structured | 0.428386 | Uncertain | 0.310 | 0.577 | 0.125 | -4.822 | Likely Benign | 0.835 | Likely Pathogenic | Ambiguous | 0.136 | Likely Benign | 0.2283 | 0.4999 | -2.61 | Deleterious | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 4.00 | Benign | 0.01 | Affected | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.578C>T | A193V 2D AIThe SynGAP1 A193V missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.428386 | Uncertain | 0.310 | 0.577 | 0.125 | -3.548 | Likely Benign | 0.744 | Likely Pathogenic | Likely Benign | 0.177 | Likely Benign | 0.1169 | 0.6775 | 0.52 | Neutral | 0.767 | Possibly Damaging | 0.344 | Benign | 4.30 | Benign | 1.00 | Tolerated | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||
| c.580G>A | E194K 2D AIThe SynGAP1 missense variant E194K 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, which aggregates the majority vote from 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 also indicates Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.418646 | Structured | 0.430723 | Uncertain | 0.346 | 0.551 | 0.125 | -13.294 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.259 | Likely Benign | 0.2231 | 0.5152 | -2.53 | Deleterious | 0.734 | Possibly Damaging | 0.321 | Benign | 4.04 | Benign | 0.01 | Affected | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||
| c.580G>C | E194Q 2D AIThe SynGAP1 missense variant E194Q is not 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 and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool rates the variant as uncertain, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, more evidence supports a pathogenic classification (5 pathogenic vs. 3 benign predictions). Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.418646 | Structured | 0.430723 | Uncertain | 0.346 | 0.551 | 0.125 | -8.902 | Likely Pathogenic | 0.955 | Likely Pathogenic | Ambiguous | 0.140 | Likely Benign | 0.1043 | 0.4954 | -1.97 | Neutral | 0.849 | Possibly Damaging | 0.478 | Possibly Damaging | 4.00 | Benign | 0.02 | Affected | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||
| c.581A>C | E194A 2D AIThe SynGAP1 missense variant E194A is not 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, and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. The high‑accuracy assessment shows AlphaMissense‑Optimized predicts pathogenicity. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic), also indicates pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions—including the high‑accuracy tools—suggest that E194A is likely pathogenic, 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. | 0.418646 | Structured | 0.430723 | Uncertain | 0.346 | 0.551 | 0.125 | -7.101 | In-Between | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.235 | Likely Benign | 0.4331 | 0.5079 | -3.75 | Deleterious | 0.009 | Benign | 0.012 | Benign | 3.99 | Benign | 0.01 | Affected | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||
| c.581A>G | E194G 2D AIThe SynGAP1 missense variant E194G is not 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. The Foldetta protein‑folding stability analysis is unavailable 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 | 0.418646 | Structured | 0.430723 | Uncertain | 0.346 | 0.551 | 0.125 | -9.136 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.316 | Likely Benign | 0.3633 | 0.4616 | -4.47 | Deleterious | 0.580 | Possibly Damaging | 0.196 | Benign | 3.96 | Benign | 0.01 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||
| c.581A>T | E194V 2D AIThe SynGAP1 missense variant E194V 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 the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. No Foldetta stability analysis is available for this variant. Overall, the preponderance of computational evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.418646 | Structured | 0.430723 | Uncertain | 0.346 | 0.551 | 0.125 | -10.261 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.284 | Likely Benign | 0.0623 | 0.5469 | -4.67 | Deleterious | 0.580 | Possibly Damaging | 0.254 | Benign | 3.94 | Benign | 0.00 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||
| c.582G>C | E194D 2D AIThe SynGAP1 missense variant E194D is not reported 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 “Likely Benign.” AlphaMissense‑Optimized is uncertain, and 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 | 0.418646 | Structured | 0.430723 | Uncertain | 0.346 | 0.551 | 0.125 | -6.310 | Likely Benign | 0.883 | Likely Pathogenic | Ambiguous | 0.079 | Likely Benign | 0.1969 | 0.2779 | -2.07 | Neutral | 0.849 | Possibly Damaging | 0.301 | Benign | 4.01 | Benign | 0.04 | Affected | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.582G>T | E194D 2D AIThe SynGAP1 missense variant E194D is not reported 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, PROVEAN) yields a “Likely Benign” classification, while AlphaMissense‑Optimized is uncertain. Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.418646 | Structured | 0.430723 | Uncertain | 0.346 | 0.551 | 0.125 | -6.310 | Likely Benign | 0.883 | Likely Pathogenic | Ambiguous | 0.079 | Likely Benign | 0.1969 | 0.2779 | -2.07 | Neutral | 0.849 | Possibly Damaging | 0.301 | Benign | 4.01 | Benign | 0.04 | Affected | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.583G>A | A195T 2D AIThe SynGAP1 missense variant A195T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The remaining tools, ESM1b and AlphaMissense‑Optimized, return uncertain results. High‑accuracy assessment shows that the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans benign (2 benign vs. 1 pathogenic, 1 uncertain). Foldetta, which would provide a protein‑folding stability estimate, has no available output for this variant. Overall, the preponderance of evidence indicates that A195T is most likely benign, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.346032 | Structured | 0.430388 | Uncertain | 0.363 | 0.533 | 0.125 | -7.060 | In-Between | 0.883 | Likely Pathogenic | Ambiguous | 0.085 | Likely Benign | 0.0937 | 0.6006 | -2.09 | Neutral | 0.970 | Probably Damaging | 0.681 | Possibly Damaging | 4.08 | Benign | 0.14 | Tolerated | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||
| c.583G>C | A195P 2D AIThe SynGAP1 missense variant A195P is listed in ClinVar as Pathogenic (ClinVar ID 375527.0) and is not reported in gnomAD. 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, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “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 supports a pathogenic 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 Pathogenic | 0.346032 | Structured | 0.430388 | Uncertain | 0.363 | 0.533 | 0.125 | Likely Pathogenic | 1 | -9.715 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.152 | Likely Benign | 0.1403 | 0.4402 | -3.03 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.00 | Benign | 0.04 | Affected | 3.54 | 6 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||
| c.583G>T | A195S 2D AIThe SynGAP1 missense variant A195S is listed in gnomAD (6‑33435225‑G‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority of the four high‑accuracy predictors) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the available predictions points to a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.346032 | Structured | 0.430388 | Uncertain | 0.363 | 0.533 | 0.125 | 6-33435225-G-T | 1 | 6.20e-7 | -4.936 | Likely Benign | 0.618 | Likely Pathogenic | Likely Benign | 0.078 | Likely Benign | 0.1846 | 0.4427 | -1.13 | Neutral | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 4.10 | Benign | 0.08 | Tolerated | 3.54 | 6 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| 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 | 0.0855 | 0.1877 | -3.20 | Deleterious | 0.997 | Probably Damaging | 0.879 | Possibly Damaging | 4.12 | Benign | 0.02 | Affected | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||||||||
| c.584C>G | A195G 2D AIThe SynGAP1 missense variant A195G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and FATHMM, while those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. Two tools give uncertain results: 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 (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic)—favors a pathogenic outcome. Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic impact for A195G, 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. | 0.346032 | Structured | 0.430388 | Uncertain | 0.363 | 0.533 | 0.125 | -7.186 | In-Between | 0.907 | Likely Pathogenic | Ambiguous | 0.146 | Likely Benign | 0.1694 | 0.3388 | -2.64 | Deleterious | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 4.01 | Benign | 0.05 | Affected | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.584C>T | A195V 2D AIThe SynGAP1 missense variant A195V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN and AlphaMissense‑Default. High‑accuracy methods give no definitive verdict: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs. 2 benign votes), and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.346032 | Structured | 0.430388 | Uncertain | 0.363 | 0.533 | 0.125 | -5.830 | Likely Benign | 0.924 | Likely Pathogenic | Ambiguous | 0.210 | Likely Benign | 0.0782 | 0.5560 | -2.63 | Deleterious | 0.384 | Benign | 0.070 | Benign | 4.05 | Benign | 0.12 | Tolerated | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||
| c.586T>A | L196M 2D AIThe SynGAP1 missense variant L196M is not 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 predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool rates the variant as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result. Overall, more tools predict pathogenicity (5) than benignity (3), and the high‑accuracy predictions do not overturn this trend. 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. | 0.284882 | Structured | 0.429452 | Uncertain | 0.489 | 0.521 | 0.125 | -8.957 | Likely Pathogenic | 0.902 | Likely Pathogenic | Ambiguous | 0.094 | Likely Benign | 0.0689 | 0.2786 | -1.48 | Neutral | 0.971 | Probably Damaging | 0.691 | Possibly Damaging | 3.64 | Benign | 0.01 | Affected | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||
| c.586T>G | L196V 2D AIThe SynGAP1 missense variant L196V is not reported 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, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, the majority of evidence (five benign vs three pathogenic) points to a benign impact. 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. | 0.284882 | Structured | 0.429452 | Uncertain | 0.489 | 0.521 | 0.125 | -8.702 | Likely Pathogenic | 0.898 | Likely Pathogenic | Ambiguous | 0.106 | Likely Benign | 0.1436 | 0.2850 | -2.31 | Neutral | 0.243 | Benign | 0.097 | Benign | 3.71 | Benign | 0.01 | Affected | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.587T>C | L196S 2D AIThe SynGAP1 missense variant L196S is not 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 comprise PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is Likely Pathogenic, while Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.284882 | Structured | 0.429452 | Uncertain | 0.489 | 0.521 | 0.125 | -9.987 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.353 | Likely Benign | 0.3473 | 0.0736 | -4.75 | Deleterious | 0.437 | Benign | 0.186 | Benign | 3.65 | Benign | 0.00 | Affected | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||||||||
| 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 | 0.0551 | 0.2718 | -4.91 | Deleterious | 0.992 | Probably Damaging | 0.869 | Possibly Damaging | 3.58 | Benign | 0.00 | Affected | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||||||||
| c.588G>C | L196F 2D AIThe SynGAP1 missense variant L196F is not 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 pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.284882 | Structured | 0.429452 | Uncertain | 0.489 | 0.521 | 0.125 | -10.245 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.177 | Likely Benign | 0.0557 | 0.2756 | -3.17 | Deleterious | 0.917 | Possibly Damaging | 0.502 | Possibly Damaging | 3.64 | Benign | 0.01 | Affected | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||
| c.588G>T | L196F 2D AIThe SynGAP1 missense variant L196F is not 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 | 0.284882 | Structured | 0.429452 | Uncertain | 0.489 | 0.521 | 0.125 | -10.245 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.177 | Likely Benign | 0.0557 | 0.2756 | -3.17 | Deleterious | 0.917 | Possibly Damaging | 0.502 | Possibly Damaging | 3.64 | Benign | 0.01 | Affected | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||
| c.589G>A | E197K 2D AIThe SynGAP1 missense variant E197K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, whereas pathogenic calls arise from PROVEAN, SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized. Grouping by consensus, the majority of high‑confidence predictors (AlphaMissense‑Optimized, SGM‑Consensus, PROVEAN, SIFT, ESM1b) indicate pathogenicity, while a minority (REVEL, polyPhen‑2, FATHMM) suggest benign impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN, is classified as Likely Pathogenic. AlphaMissense‑Optimized also predicts Pathogenic. Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for E197K, and this assessment does not conflict with ClinVar, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.349426 | Structured | 0.431896 | Uncertain | 0.452 | 0.492 | 0.125 | -11.045 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.198 | Likely Benign | 0.1824 | 0.5890 | -2.50 | Deleterious | 0.118 | Benign | 0.037 | Benign | 4.09 | Benign | 0.02 | Affected | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||
| c.589G>C | E197Q 2D AIThe SynGAP1 E197Q variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and therefore reports a likely benign outcome. AlphaMissense‑Optimized also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.349426 | Structured | 0.431896 | Uncertain | 0.452 | 0.492 | 0.125 | -6.347 | Likely Benign | 0.723 | Likely Pathogenic | Likely Benign | 0.145 | Likely Benign | 0.0867 | 0.5228 | -1.75 | Neutral | 0.396 | Benign | 0.067 | Benign | 4.05 | Benign | 0.02 | Affected | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||
| c.590A>C | E197A 2D AIThe SynGAP1 E197A 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. Two tools give uncertain results: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows that the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, while AlphaMissense‑Optimized remains uncertain and Foldetta (which would combine FoldX‑MD and Rosetta outputs) has no available result. Overall, the balance of evidence—including the pathogenic majority in the high‑accuracy consensus—suggests that the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.349426 | Structured | 0.431896 | Uncertain | 0.452 | 0.492 | 0.125 | -7.956 | In-Between | 0.787 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | 0.3134 | 0.5290 | -3.56 | Deleterious | 0.055 | Benign | 0.016 | Benign | 4.06 | Benign | 0.02 | Affected | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||
| c.590A>G | E197G 2D AIThe SynGAP1 missense variant E197G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign impact include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict pathogenicity are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Pathogenic, while AlphaMissense‑Optimized remains benign; Foldetta results are unavailable. Overall, the majority of individual predictors lean toward pathogenicity, and the SGM‑Consensus supports this view. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.349426 | Structured | 0.431896 | Uncertain | 0.452 | 0.492 | 0.125 | -8.480 | Likely Pathogenic | 0.749 | Likely Pathogenic | Likely Benign | 0.165 | Likely Benign | 0.2638 | 0.4615 | -3.13 | Deleterious | 0.118 | Benign | 0.037 | Benign | 4.03 | Benign | 0.01 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||
| c.590A>T | E197V 2D AIThe SynGAP1 missense variant E197V 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 opinion: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls arise from PROVEAN, SIFT, ESM1b and AlphaMissense‑Default. When predictions are grouped by consensus, four tools predict benign and four predict pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Taken together, the preponderance of evidence from both general and high‑accuracy predictors indicates that E197V is most likely pathogenic, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.349426 | Structured | 0.431896 | Uncertain | 0.452 | 0.492 | 0.125 | -9.023 | Likely Pathogenic | 0.932 | Likely Pathogenic | Ambiguous | 0.247 | Likely Benign | 0.0490 | 0.6024 | -4.51 | Deleterious | 0.396 | Benign | 0.099 | Benign | 4.01 | Benign | 0.00 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||
| c.591G>C | E197D 2D AIThe SynGAP1 missense variant E197D is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Overall, the consensus of all available predictions strongly supports a benign classification, and this is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.349426 | Structured | 0.431896 | Uncertain | 0.452 | 0.492 | 0.125 | 0.784 | Likely Benign | 0.130 | Likely Benign | Likely Benign | 0.066 | Likely Benign | 0.1579 | 0.3345 | 1.81 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.66 | Benign | 1.00 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.591G>T | E197D 2D AIThe SynGAP1 missense variant E197D is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions strongly supports a benign classification, and this is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.349426 | Structured | 0.431896 | Uncertain | 0.452 | 0.492 | 0.125 | 0.784 | Likely Benign | 0.130 | Likely Benign | Likely Benign | 0.066 | Likely Benign | 0.1579 | 0.3345 | 1.81 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.66 | Benign | 1.00 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.592C>A | L198I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L198I 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, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Uncertain or inconclusive results come from AlphaMissense‑Default, FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.444081 | Structured | 0.431715 | Uncertain | 0.572 | 0.485 | 0.125 | -10.411 | Likely Pathogenic | 0.563 | Ambiguous | Likely Benign | 0.234 | Likely Benign | 0.0921 | 0.3307 | 0.59 | Ambiguous | 0.1 | 0.70 | Ambiguous | 0.65 | Ambiguous | 0.10 | Likely Benign | -1.72 | Neutral | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 3.43 | Benign | 0.00 | Affected | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||
| c.592C>G | L198V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L198V variant has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, 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, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled Likely Pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (3 pathogenic vs. 1 benign) indicates pathogenicity; Foldetta remains uncertain. Overall, the majority of evaluated tools predict a pathogenic impact, and this is not contradicted by any ClinVar annotation (none exists). Thus, the variant is most likely pathogenic based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.444081 | Structured | 0.431715 | Uncertain | 0.572 | 0.485 | 0.125 | -9.343 | Likely Pathogenic | 0.747 | Likely Pathogenic | Likely Benign | 0.265 | Likely Benign | 0.1520 | 0.3017 | 1.10 | Ambiguous | 0.2 | 1.24 | Ambiguous | 1.17 | Ambiguous | 0.34 | Likely Benign | -2.54 | Deleterious | 0.990 | Probably Damaging | 0.675 | Possibly Damaging | 3.44 | Benign | 0.00 | Affected | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||
| c.592C>T | L198F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L198F has no ClinVar entry and is absent from gnomAD. Functional prediction tools split into two consensus groups: benign predictions come from REVEL, Rosetta, premPS, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments are mixed: AlphaMissense‑Optimized and Foldetta report uncertain results, whereas the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect. No evidence from ClinVar contradicts these findings. Overall, the preponderance of pathogenic predictions and the SGM‑Consensus designation suggest that the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.444081 | Structured | 0.431715 | Uncertain | 0.572 | 0.485 | 0.125 | -10.602 | Likely Pathogenic | 0.930 | Likely Pathogenic | Ambiguous | 0.282 | Likely Benign | 0.0586 | 0.3112 | 1.03 | Ambiguous | 0.2 | 0.27 | Likely Benign | 0.65 | Ambiguous | 0.00 | Likely Benign | -3.33 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 3.39 | Benign | 0.00 | Affected | 2 | 0 | -1.0 | 34.02 | ||||||||||||||||||||||||||
| c.593T>A | L198H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L198H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for L198H. 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 | 0.444081 | Structured | 0.431715 | Uncertain | 0.572 | 0.485 | 0.125 | -15.650 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.419 | Likely Benign | 0.1057 | 0.0519 | 1.09 | Ambiguous | 0.2 | 1.04 | Ambiguous | 1.07 | Ambiguous | 0.74 | Ambiguous | -5.91 | Deleterious | 0.999 | Probably Damaging | 0.936 | Probably Damaging | 3.33 | Benign | 0.00 | Affected | -2 | -3 | -7.0 | 23.98 | ||||||||||||||||||||||||||
| c.593T>C | L198P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L198P has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and FATHMM, while pathogenic predictions 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 show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points toward a deleterious effect. Thus, 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 | 0.444081 | Structured | 0.431715 | Uncertain | 0.572 | 0.485 | 0.125 | -12.250 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.491 | Likely Benign | 0.3882 | 0.1582 | 1.55 | Ambiguous | 0.3 | 0.40 | Likely Benign | 0.98 | Ambiguous | 0.65 | Ambiguous | -5.87 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 3.33 | Benign | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||
| c.593T>G | L198R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L198R is not 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 a 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). Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence from multiple in‑silico predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.444081 | Structured | 0.431715 | Uncertain | 0.572 | 0.485 | 0.125 | -15.992 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.410 | Likely Benign | 0.1180 | 0.0719 | 0.74 | Ambiguous | 0.2 | 1.56 | Ambiguous | 1.15 | Ambiguous | 0.69 | Ambiguous | -4.98 | Deleterious | 0.982 | Probably Damaging | 0.648 | Possibly Damaging | 3.34 | Benign | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||
| c.595A>C | N199H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N199H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No predictions are missing or inconclusive. Overall, the majority of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which contains no pathogenic assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | -6.387 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.064 | Likely Benign | 0.0879 | 0.5635 | 0.17 | Likely Benign | 0.1 | 0.15 | Likely Benign | 0.16 | Likely Benign | 0.20 | Likely Benign | -1.99 | Neutral | 0.952 | Possibly Damaging | 0.496 | Possibly Damaging | 4.17 | Benign | 0.08 | Tolerated | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||
| c.595A>G | N199D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N199D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach a consensus classify the variant as benign: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. The only inconclusive results come from ESM1b and Rosetta, which are treated as unavailable. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a benign outcome. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | -7.874 | In-Between | 0.338 | Likely Benign | Likely Benign | 0.028 | Likely Benign | 0.1516 | 0.3514 | -0.14 | Likely Benign | 0.1 | -0.67 | Ambiguous | -0.41 | Likely Benign | 0.13 | Likely Benign | -1.41 | Neutral | 0.276 | Benign | 0.062 | Benign | 4.22 | Benign | 0.35 | Tolerated | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||
| c.595A>T | N199Y 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant N199Y 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, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 (HumVar), FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from SIFT, PROVEAN, polyPhen‑2 (HumDiv), and ESM1b. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates benign stability. Overall, the majority of conventional tools (8 benign vs. 4 pathogenic) favor a benign effect, and this interpretation does not conflict with the absence of ClinVar annotation. Therefore, the variant is most likely benign based on the current predictive evidence, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | -8.575 | Likely Pathogenic | 0.391 | Ambiguous | Likely Benign | 0.097 | Likely Benign | 0.0389 | 0.5630 | -0.06 | Likely Benign | 0.1 | 0.14 | Likely Benign | 0.04 | Likely Benign | 0.20 | Likely Benign | -3.12 | Deleterious | 0.952 | Possibly Damaging | 0.395 | Benign | 4.15 | Benign | 0.04 | Affected | -2 | -2 | 2.2 | 49.07 | ||||||||||||||||||||||||||
| c.596A>C | N199T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N199T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify it as benign or likely benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM Consensus predicts likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | -4.123 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.025 | Likely Benign | 0.0862 | 0.6186 | 0.16 | Likely Benign | 0.2 | -0.10 | Likely Benign | 0.03 | Likely Benign | -0.04 | Likely Benign | -0.82 | Neutral | 0.002 | Benign | 0.003 | Benign | 4.24 | Benign | 0.10 | Tolerated | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||
| c.596A>G | N199S 2D  AIThe SynGAP1 missense variant N199S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). All available in‑silico predictors classify the variant as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts pathogenicity. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote) indicates likely benign; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Overall, the variant is most likely benign, and this prediction does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | -0.268 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.040 | Likely Benign | 0.2601 | 0.6023 | 0.08 | Likely Benign | 0.4 | -0.08 | Likely Benign | 0.00 | Likely Benign | -0.44 | Likely Benign | 0.09 | Neutral | 0.160 | Benign | 0.045 | Benign | 4.36 | Benign | 0.57 | Tolerated | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||
| c.596A>T | N199I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N199I is not 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, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields an equal split of benign and pathogenic calls. Overall, the majority of evidence points to a benign impact. 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. | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | -8.299 | Likely Pathogenic | 0.328 | Likely Benign | Likely Benign | 0.066 | Likely Benign | 0.0450 | 0.6009 | 0.27 | Likely Benign | 0.1 | -0.11 | Likely Benign | 0.08 | Likely Benign | 0.20 | Likely Benign | -3.27 | Deleterious | 0.316 | Benign | 0.045 | Benign | 4.16 | Benign | 0.01 | Affected | -2 | -3 | 8.0 | -0.94 | ||||||||||||||||||||||||||
| c.597C>A | N199K 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant N199K is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized all classify the substitution as benign. Only ESM1b and AlphaMissense‑Default predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the preponderance of evidence supports a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | Uncertain | 1 | -8.198 | Likely Pathogenic | 0.686 | Likely Pathogenic | Likely Benign | 0.024 | Likely Benign | 0.1399 | 0.5218 | -0.19 | Likely Benign | 0.1 | 0.03 | Likely Benign | -0.08 | Likely Benign | 0.33 | Likely Benign | -1.48 | Neutral | 0.276 | Benign | 0.083 | Benign | 4.27 | Benign | 0.13 | Tolerated | 3.47 | 9 | 1 | 0 | -0.4 | 14.07 | 207.8 | 21.5 | -0.1 | 1.5 | 0.1 | 0.0 | X | Uncertain | Asn199, located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by a positively charged lysine. On the protein surface, both the carboxamide group of Asn199 and the amino group of Lys199 side chains can form hydrogen bonds with the backbone carbonyl groups of residues (e.g., Ala249) at the end of an α helix (res. Ala236-Lys251). However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||||
| c.597C>G | N199K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N199K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign impact. Overall, the majority of evidence (10 benign vs. 2 pathogenic) supports a benign classification. This consensus does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | -8.198 | Likely Pathogenic | 0.686 | Likely Pathogenic | Likely Benign | 0.024 | Likely Benign | 0.1399 | 0.5218 | -0.19 | Likely Benign | 0.1 | 0.03 | Likely Benign | -0.08 | Likely Benign | 0.33 | Likely Benign | -1.48 | Neutral | 0.276 | Benign | 0.083 | Benign | 4.27 | Benign | 0.13 | Tolerated | 3.47 | 9 | 1 | 0 | -0.4 | 14.07 | 207.8 | 21.5 | -0.1 | 1.5 | 0.1 | 0.0 | X | Uncertain | Asn199, located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by a positively charged lysine. On the protein surface, both the carboxamide group of Asn199 and the amino group of Lys199 side chains can form hydrogen bonds with the backbone carbonyl groups of residues (e.g., Ala249) at the end of an α helix (res. Ala236-Lys251). However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||||||
| c.598T>A | L200M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L200M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a benign outcome. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM‑Consensus, derived from the four high‑confidence predictors, is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Taken together, the overwhelming majority of evidence supports a benign classification for L200M, and this conclusion is consistent with the absence of a ClinVar entry. Thus, the variant is most likely benign, and this assessment does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.366687 | Structured | 0.428168 | Uncertain | 0.687 | 0.453 | 0.125 | -4.107 | Likely Benign | 0.215 | Likely Benign | Likely Benign | 0.139 | Likely Benign | 0.0751 | 0.3511 | 0.08 | Likely Benign | 0.1 | 0.41 | Likely Benign | 0.25 | Likely Benign | -0.25 | Likely Benign | 0.47 | Neutral | 0.997 | Probably Damaging | 0.960 | Probably Damaging | 4.11 | Benign | 0.31 | Tolerated | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||
| c.598T>G | L200V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L200V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic outcome are FoldX, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and the Foldetta stability assessment. Uncertain results come from Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as pathogenic. Overall, the majority of evidence points to a benign effect; there is no ClinVar annotation to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.366687 | Structured | 0.428168 | Uncertain | 0.687 | 0.453 | 0.125 | -6.917 | Likely Benign | 0.213 | Likely Benign | Likely Benign | 0.098 | Likely Benign | 0.1593 | 0.3607 | 2.15 | Destabilizing | 0.2 | 1.85 | Ambiguous | 2.00 | Destabilizing | 0.92 | Ambiguous | -1.07 | Neutral | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 4.09 | Benign | 0.24 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.599T>C | L200S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L200S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Those that predict a pathogenic effect comprise FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 vs 2). High‑accuracy methods give a pathogenic signal from Foldetta (protein‑folding stability analysis) while AlphaMissense‑Optimized is uncertain and thus not considered evidence. Overall, the majority of available predictions (10 pathogenic vs 4 benign) indicate a pathogenic impact. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.366687 | Structured | 0.428168 | Uncertain | 0.687 | 0.453 | 0.125 | -10.755 | Likely Pathogenic | 0.807 | Likely Pathogenic | Ambiguous | 0.141 | Likely Benign | 0.3279 | 0.0575 | 2.72 | Destabilizing | 0.1 | 3.38 | Destabilizing | 3.05 | Destabilizing | 1.43 | Destabilizing | -1.96 | Neutral | 0.970 | Probably Damaging | 0.683 | Possibly Damaging | 4.05 | Benign | 0.06 | Tolerated | -3 | -2 | -4.6 | -26.08 | ||||||||||||||||||||||||||
| 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 | 0.200 | Likely Benign | 0.0627 | 0.2893 | 2.90 | Destabilizing | 1.0 | 1.95 | Ambiguous | 2.43 | Destabilizing | 1.20 | Destabilizing | -2.93 | Deleterious | 0.999 | Probably Damaging | 0.970 | Probably Damaging | 3.98 | Benign | 0.02 | Affected | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||
| c.600G>C | L200F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L200F is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33435242‑G‑C). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Predictions that are inconclusive are FoldX, Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.366687 | Structured | 0.428168 | Uncertain | 0.687 | 0.453 | 0.125 | Uncertain | 1 | 6-33435242-G-C | 2 | 1.24e-6 | -7.606 | In-Between | 0.592 | Likely Pathogenic | Likely Benign | 0.094 | Likely Benign | 0.0640 | 0.3120 | 1.00 | Ambiguous | 0.5 | 1.45 | Ambiguous | 1.23 | Ambiguous | 0.43 | Likely Benign | -1.97 | Neutral | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.02 | Benign | 0.17 | Tolerated | 3.46 | 9 | 2 | 0 | -1.0 | 34.02 | 250.4 | -15.1 | 0.6 | 0.2 | 0.5 | 0.0 | X | Uncertain | Leu200, a hydrophobic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another hydrophobic residue, phenylalanine. Both the phenyl group of Phe200 and the branched iso-butyl hydrocarbon sidechain of Leu200 occupy an inward hydrophobic niche (e.g., Leu246, Val222, Phe231) during the simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||||
| c.600G>T | L200F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L200F missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, ESM1b, Foldetta) returned uncertain results and are not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (benign)—is benign; Foldetta remains uncertain and is treated as unavailable. Overall, the balance of evidence (six benign vs. three pathogenic predictions, with a benign consensus from high‑accuracy methods) indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.366687 | Structured | 0.428168 | Uncertain | 0.687 | 0.453 | 0.125 | -7.606 | In-Between | 0.592 | Likely Pathogenic | Likely Benign | 0.094 | Likely Benign | 0.0640 | 0.3120 | 1.00 | Ambiguous | 0.5 | 1.45 | Ambiguous | 1.23 | Ambiguous | 0.43 | Likely Benign | -1.97 | Neutral | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.02 | Benign | 0.17 | Tolerated | 3.46 | 9 | 2 | 0 | -1.0 | 34.02 | 250.4 | -15.1 | 0.6 | 0.2 | 0.5 | 0.0 | X | Uncertain | Leu200, a hydrophobic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another hydrophobic residue, phenylalanine. Both the phenyl group of Phe200 and the branched iso-butyl hydrocarbon sidechain of Leu200 occupy an inward hydrophobic niche (e.g., Leu246, Val222, Phe231) during the simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||||||
| c.601G>A | D201N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The remaining tools—Rosetta, Foldetta, ESM1b, and AlphaMissense‑Default—return uncertain results and are treated as unavailable for pathogenicity inference. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is unavailable because two of the four inputs are uncertain. Foldetta also yields an uncertain result and is unavailable. Overall, the preponderance of evidence points to a benign impact for D201N, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | -7.686 | In-Between | 0.525 | Ambiguous | Likely Benign | 0.160 | Likely Benign | 0.0911 | 0.5413 | 0.31 | Likely Benign | 0.0 | 1.21 | Ambiguous | 0.76 | Ambiguous | -0.10 | Likely Benign | -2.36 | Neutral | 0.996 | Probably Damaging | 0.877 | Possibly Damaging | 4.08 | Benign | 0.13 | Tolerated | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||
| c.601G>C | D201H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201H missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM. Those that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. 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 as uncertain. Overall, the majority of available predictions (seven pathogenic vs. three benign) indicate that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | -8.595 | Likely Pathogenic | 0.862 | Likely Pathogenic | Ambiguous | 0.284 | Likely Benign | 0.1152 | 0.5838 | 0.68 | Ambiguous | 0.2 | 1.43 | Ambiguous | 1.06 | Ambiguous | 0.44 | Likely Benign | -3.45 | Deleterious | 1.000 | Probably Damaging | 0.960 | Probably Damaging | 4.04 | Benign | 0.03 | Affected | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||
| c.601G>T | D201Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201Y missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, premPS, and FATHMM. Those that predict a pathogenic effect comprise SGM Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and Rosetta. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; SGM Consensus predicts likely pathogenic; Foldetta is uncertain. Because the majority of consensus and individual predictors (seven pathogenic vs four benign) lean toward a damaging outcome, the variant is most likely pathogenic. This assessment is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | -10.916 | Likely Pathogenic | 0.892 | Likely Pathogenic | Ambiguous | 0.334 | Likely Benign | 0.0431 | 0.5371 | 0.28 | Likely Benign | 0.2 | 2.39 | Destabilizing | 1.34 | Ambiguous | 0.31 | Likely Benign | -4.93 | Deleterious | 1.000 | Probably Damaging | 0.960 | Probably Damaging | 4.02 | Benign | 0.02 | Affected | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||
| c.602A>C | D201A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201A variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM, whereas a pathogenic consensus is reached by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Uncertain or unavailable results come from Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) leans toward pathogenic, and Foldetta remains inconclusive. Overall, the majority of standard tools favor a benign classification, but the high‑accuracy consensus indicates a pathogenic signal, leaving the variant’s impact uncertain. The predictions do not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | -7.793 | In-Between | 0.769 | Likely Pathogenic | Likely Benign | 0.261 | Likely Benign | 0.3177 | 0.5050 | 0.45 | Likely Benign | 0.1 | 1.86 | Ambiguous | 1.16 | Ambiguous | 0.23 | Likely Benign | -3.81 | Deleterious | 0.989 | Probably Damaging | 0.828 | Possibly Damaging | 4.11 | Benign | 0.09 | Tolerated | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||
| c.602A>G | D201G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201G missense change is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the balance of evidence favors a pathogenic interpretation, with no ClinVar annotation to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | -7.744 | In-Between | 0.603 | Likely Pathogenic | Likely Benign | 0.289 | Likely Benign | 0.3268 | 0.5047 | 0.71 | Ambiguous | 0.0 | 2.64 | Destabilizing | 1.68 | Ambiguous | 0.24 | Likely Benign | -3.03 | Deleterious | 0.996 | Probably Damaging | 0.877 | Possibly Damaging | 4.09 | Benign | 0.39 | Tolerated | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||
| c.602A>T | D201V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, while those that predict a pathogenic impact are SGM‑Consensus (Likely Pathogenic), Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain. With the majority of tools indicating pathogenicity and no ClinVar record 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 | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | -10.283 | Likely Pathogenic | 0.906 | Likely Pathogenic | Ambiguous | 0.305 | Likely Benign | 0.0572 | 0.5207 | 0.87 | Ambiguous | 0.1 | 2.18 | Destabilizing | 1.53 | Ambiguous | 0.31 | Likely Benign | -5.01 | Deleterious | 0.999 | Probably Damaging | 0.946 | Probably Damaging | 4.04 | Benign | 0.02 | Affected | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||
| c.603T>A | D201E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201E missense variant (ClinVar ID 3004688.0) is classified as **Benign** in ClinVar and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while Rosetta, Foldetta, and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as **Benign**, the SGM‑Consensus as **Likely Benign**, and Foldetta as **Uncertain**. Taken together, the overwhelming majority of evidence points to a benign impact, and this conclusion aligns with the ClinVar designation. Thus, the variant is most likely benign, with no contradiction to its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | Benign | 1 | -2.640 | Likely Benign | 0.406 | Ambiguous | Likely Benign | 0.165 | Likely Benign | 0.1069 | 0.5505 | 0.42 | Likely Benign | 0.2 | 1.99 | Ambiguous | 1.21 | Ambiguous | 0.23 | Likely Benign | -0.69 | Neutral | 0.633 | Possibly Damaging | 0.108 | Benign | 4.30 | Benign | 1.00 | Tolerated | 3.46 | 9 | 3 | 2 | 0.0 | 14.03 | 258.7 | -24.8 | 0.9 | 0.1 | -0.3 | 0.2 | X | Uncertain | Asp201, an acidic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another acidic residue, glutamate. The carboxylate groups of both Asp201 and Glu201 side chains form hydrogen bonds with the hydroxyl group of Ser221 in the simulations. Due to its shorter side chain, Asp201 can also hydrogen bond with the backbone amide groups of neighboring loop residues Ser204 and Asp203. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||||||
| c.603T>G | D201E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201E missense variant (gnomAD ID 6‑33435245‑T‑G) is listed in ClinVar with an uncertain significance. Across a broad panel of in silico predictors, the majority indicate a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all score benign. Only polyPhen‑2 HumDiv predicts pathogenicity, while Rosetta, Foldetta, and AlphaMissense‑Default remain inconclusive. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to “likely benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta is inconclusive. Taken together, the preponderance of evidence points to a benign impact, which does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | Conflicting | 2 | 6-33435245-T-G | 20 | 1.24e-5 | -2.640 | Likely Benign | 0.406 | Ambiguous | Likely Benign | 0.165 | Likely Benign | 0.1069 | 0.5505 | 0.42 | Likely Benign | 0.2 | 1.99 | Ambiguous | 1.21 | Ambiguous | 0.23 | Likely Benign | -0.69 | Neutral | 0.633 | Possibly Damaging | 0.108 | Benign | 4.30 | Benign | 1.00 | Tolerated | 3.46 | 9 | 3 | 2 | 0.0 | 14.03 | 258.7 | -24.8 | 0.9 | 0.1 | -0.3 | 0.2 | X | Uncertain | Asp201, an acidic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another acidic residue, glutamate. The carboxylate groups of both Asp201 and Glu201 side chains form hydrogen bonds with the hydroxyl group of Ser221 in the simulations. Due to its shorter side chain, Asp201 can also hydrogen bond with the backbone amide groups of neighboring loop residues Ser204 and Asp203. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||
| c.604G>A | E202K 2D AIThe SynGAP1 E202K missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Rosetta and Foldetta give uncertain results. High‑accuracy methods give mixed evidence: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta’s stability assessment is uncertain. Overall, more tools (7 vs. 5) predict pathogenicity, and the high‑accuracy consensus leans toward pathogenic. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.363090 | Structured | 0.429450 | Uncertain | 0.712 | 0.415 | 0.125 | -9.011 | Likely Pathogenic | 0.678 | Likely Pathogenic | Likely Benign | 0.231 | Likely Benign | 0.1963 | 0.6885 | -0.24 | Likely Benign | 0.3 | -0.76 | Ambiguous | -0.50 | Ambiguous | 0.10 | Likely Benign | -2.55 | Deleterious | 0.982 | Probably Damaging | 0.679 | Possibly Damaging | 4.07 | Benign | 0.03 | Affected | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||
| c.604G>C | E202Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E202Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar) and SIFT. Two tools, ESM1b and AlphaMissense‑Default, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta 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 effect. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.363090 | Structured | 0.429450 | Uncertain | 0.712 | 0.415 | 0.125 | -7.129 | In-Between | 0.456 | Ambiguous | Likely Benign | 0.175 | Likely Benign | 0.0949 | 0.6792 | -0.16 | Likely Benign | 0.0 | 0.23 | Likely Benign | 0.04 | Likely Benign | -0.13 | Likely Benign | -1.39 | Neutral | 0.995 | Probably Damaging | 0.747 | Possibly Damaging | 4.07 | Benign | 0.02 | Affected | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||
| c.605A>C | E202A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E202A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools (AlphaMissense‑Default and ESM1b) return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive and therefore unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.363090 | Structured | 0.429450 | Uncertain | 0.712 | 0.415 | 0.125 | -7.222 | In-Between | 0.538 | Ambiguous | Likely Benign | 0.220 | Likely Benign | 0.3903 | 0.6468 | 0.13 | Likely Benign | 0.0 | 0.14 | Likely Benign | 0.14 | Likely Benign | 0.19 | Likely Benign | -4.05 | Deleterious | 0.948 | Possibly Damaging | 0.484 | Possibly Damaging | 4.02 | Benign | 0.02 | Affected | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||
| c.605A>G | E202G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E202G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM. Those that predict a pathogenic impact are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Tools with uncertain or inconclusive results are Rosetta, AlphaMissense‑Default, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) leans toward pathogenic (2 pathogenic, 1 benign, 1 uncertain). Foldetta remains uncertain. Overall, the majority of standard prediction tools suggest a benign effect, and this conclusion does not contradict the lack of ClinVar reporting. Thus, the variant is most likely benign based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.363090 | Structured | 0.429450 | Uncertain | 0.712 | 0.415 | 0.125 | -8.310 | Likely Pathogenic | 0.495 | Ambiguous | Likely Benign | 0.259 | Likely Benign | 0.3061 | 0.5405 | 0.37 | Likely Benign | 0.0 | 0.74 | Ambiguous | 0.56 | Ambiguous | 0.27 | Likely Benign | -4.70 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 4.01 | Benign | 0.07 | Tolerated | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||
| c.605A>T | E202V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E202V missense variant has no ClinVar record and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are SIFT, PROVEAN, polyPhen‑2 HumDiv, ESM1b, 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 benign. Because the majority of tools (8 benign vs. 5 pathogenic) lean toward a benign outcome, the variant is most likely benign, although the SGM Consensus suggests pathogenicity. 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 | PH | 0.363090 | Structured | 0.429450 | Uncertain | 0.712 | 0.415 | 0.125 | -8.990 | Likely Pathogenic | 0.783 | Likely Pathogenic | Likely Benign | 0.270 | Likely Benign | 0.0525 | 0.7007 | 0.48 | Likely Benign | 0.0 | 0.34 | Likely Benign | 0.41 | Likely Benign | 0.12 | Likely Benign | -4.81 | Deleterious | 0.649 | Possibly Damaging | 0.259 | Benign | 3.96 | Benign | 0.01 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.606A>C | E202D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E202D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The high‑accuracy methods give a consistent benign verdict: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Rosetta alone is uncertain, but this inconclusive result does not alter the overall benign consensus. Based on the aggregate predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.363090 | Structured | 0.429450 | Uncertain | 0.712 | 0.415 | 0.125 | -5.646 | Likely Benign | 0.169 | Likely Benign | Likely Benign | 0.065 | Likely Benign | 0.1606 | 0.4051 | 0.35 | Likely Benign | 0.1 | 0.53 | Ambiguous | 0.44 | Likely Benign | 0.19 | Likely Benign | -1.82 | Neutral | 0.982 | Probably Damaging | 0.581 | Possibly Damaging | 4.02 | Benign | 0.04 | Affected | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.606A>T | E202D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E202D missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, and the SGM‑Consensus score. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized returns a benign prediction; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign effect. Taken together, the majority of evidence points to a benign impact, and this conclusion does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.363090 | Structured | 0.429450 | Uncertain | 0.712 | 0.415 | 0.125 | -5.646 | Likely Benign | 0.169 | Likely Benign | Likely Benign | 0.065 | Likely Benign | 0.1606 | 0.4051 | 0.35 | Likely Benign | 0.1 | 0.53 | Ambiguous | 0.44 | Likely Benign | 0.19 | Likely Benign | -1.82 | Neutral | 0.982 | Probably Damaging | 0.581 | Possibly Damaging | 4.02 | Benign | 0.04 | Affected | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.607G>A | D203N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D203N is reported in gnomAD (variant ID 6-33435249‑G‑A) and has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar; ESM1b is uncertain. The high‑accuracy consensus methods give a consistent benign signal: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. No prediction or folding stability result is missing or inconclusive. Based on the aggregate evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.314870 | Structured | 0.427620 | Uncertain | 0.740 | 0.407 | 0.125 | 6-33435249-G-A | 1 | 6.20e-7 | -7.465 | In-Between | 0.159 | Likely Benign | Likely Benign | 0.121 | Likely Benign | 0.0800 | 0.4296 | -0.19 | Likely Benign | 0.1 | -0.12 | Likely Benign | -0.16 | Likely Benign | -0.03 | Likely Benign | -2.26 | Neutral | 0.970 | Probably Damaging | 0.749 | Possibly Damaging | 4.06 | Benign | 0.06 | Tolerated | 3.44 | 10 | 1 | 2 | 0.0 | -0.98 | ||||||||||||||||||||
| c.607G>C | D203H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203H missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as benign. No prediction or folding result is missing or inconclusive. Overall, the predictions are mixed, but the two high‑accuracy tools favor a benign outcome, giving a slight bias toward benign. Thus, the variant is most likely benign, and this assessment does not contradict the ClinVar status (which is currently unreported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.314870 | Structured | 0.427620 | Uncertain | 0.740 | 0.407 | 0.125 | -9.130 | Likely Pathogenic | 0.593 | Likely Pathogenic | Likely Benign | 0.218 | Likely Benign | 0.0962 | 0.4815 | 0.00 | Likely Benign | 0.1 | 0.18 | Likely Benign | 0.09 | Likely Benign | -0.04 | Likely Benign | -3.28 | Deleterious | 0.999 | Probably Damaging | 0.936 | Probably Damaging | 3.98 | Benign | 0.02 | Affected | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||
| c.607G>T | D203Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203Y missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as benign. No prediction or folding result is missing or inconclusive. Overall, the majority of individual tools lean toward benign, and two of the three high‑accuracy methods also predict benign, so the variant is most likely benign. 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 | PH | 0.314870 | Structured | 0.427620 | Uncertain | 0.740 | 0.407 | 0.125 | -11.651 | Likely Pathogenic | 0.597 | Likely Pathogenic | Likely Benign | 0.260 | Likely Benign | 0.0382 | 0.4436 | -0.36 | Likely Benign | 0.0 | 0.09 | Likely Benign | -0.14 | Likely Benign | 0.05 | Likely Benign | -4.38 | Deleterious | 0.999 | Probably Damaging | 0.936 | Probably Damaging | 3.96 | Benign | 0.01 | Affected | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||
| c.608A>C | D203A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. All available predictions and stability analyses point to a benign impact. Therefore, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.314870 | Structured | 0.427620 | Uncertain | 0.740 | 0.407 | 0.125 | -6.807 | Likely Benign | 0.373 | Ambiguous | Likely Benign | 0.174 | Likely Benign | 0.2527 | 0.4128 | 0.07 | Likely Benign | 0.1 | 0.49 | Likely Benign | 0.28 | Likely Benign | 0.12 | Likely Benign | -3.34 | Deleterious | 0.941 | Possibly Damaging | 0.607 | Possibly Damaging | 4.05 | Benign | 0.17 | Tolerated | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||
| c.608A>G | D203G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, FoldX, premPS, ESM1b, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. 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) resolves to benign (two benign vs. one pathogenic, one uncertain); and Foldetta also predicts benign. No prediction or folding stability result is missing or inconclusive. Overall, the majority of evidence supports a benign effect, and this is consistent with the lack of any ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.314870 | Structured | 0.427620 | Uncertain | 0.740 | 0.407 | 0.125 | -6.332 | Likely Benign | 0.350 | Ambiguous | Likely Benign | 0.231 | Likely Benign | 0.2708 | 0.4312 | 0.07 | Likely Benign | 0.1 | 0.72 | Ambiguous | 0.40 | Likely Benign | 0.03 | Likely Benign | -3.42 | Deleterious | 0.990 | Probably Damaging | 0.681 | Possibly Damaging | 4.01 | Benign | 0.04 | Affected | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||
| c.608A>T | D203V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools and the SGM Consensus lean toward a pathogenic interpretation, whereas two high‑accuracy methods (AlphaMissense‑Optimized and Foldetta) suggest benign. Because ClinVar contains no entry for this variant, there is no contradiction between the predictions and existing clinical annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.314870 | Structured | 0.427620 | Uncertain | 0.740 | 0.407 | 0.125 | -10.660 | Likely Pathogenic | 0.523 | Ambiguous | Likely Benign | 0.289 | Likely Benign | 0.0534 | 0.4084 | 0.32 | Likely Benign | 0.0 | 0.44 | Likely Benign | 0.38 | Likely Benign | 0.05 | Likely Benign | -4.07 | Deleterious | 0.991 | Probably Damaging | 0.781 | Possibly Damaging | 3.98 | Benign | 0.02 | Affected | -2 | -3 | 7.7 | -15.96 | ||||||||||||||||||||||||||
| c.609T>A | D203E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203E missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two PolyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta)—all uniformly classify the variant as benign. No prediction or folding‑stability result is missing or inconclusive. Based on the consensus of the majority of tools and the unanimous high‑accuracy predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.314870 | Structured | 0.427620 | Uncertain | 0.740 | 0.407 | 0.125 | -4.067 | Likely Benign | 0.201 | Likely Benign | Likely Benign | 0.152 | Likely Benign | 0.0975 | 0.4189 | 0.10 | Likely Benign | 0.0 | 0.08 | Likely Benign | 0.09 | Likely Benign | -0.07 | Likely Benign | -0.93 | Neutral | 0.990 | Probably Damaging | 0.675 | Possibly Damaging | 4.15 | Benign | 0.81 | Tolerated | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||
| c.609T>G | D203E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203E missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two PolyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta)—all uniformly classify the variant as benign. No prediction or folding‑stability result is missing or inconclusive. Based on the consensus of the majority of tools and the unanimous high‑accuracy predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.314870 | Structured | 0.427620 | Uncertain | 0.740 | 0.407 | 0.125 | -4.067 | Likely Benign | 0.201 | Likely Benign | Likely Benign | 0.152 | Likely Benign | 0.0975 | 0.4189 | 0.10 | Likely Benign | 0.0 | 0.08 | Likely Benign | 0.09 | Likely Benign | -0.07 | Likely Benign | -0.93 | Neutral | 0.990 | Probably Damaging | 0.675 | Possibly Damaging | 4.15 | Benign | 0.81 | Tolerated | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||
| c.610T>A | S204T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S204T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. Only polyPhen‑2 HumDiv predicts a pathogenic effect. Stability‑based methods (FoldX, Rosetta, Foldetta, premPS) are inconclusive, providing no definitive evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Taken together, the majority of reliable predictors classify S204T as benign, and this conclusion does not contradict the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.268042 | Structured | 0.420667 | Uncertain | 0.816 | 0.405 | 0.125 | -4.164 | Likely Benign | 0.167 | Likely Benign | Likely Benign | 0.104 | Likely Benign | 0.0857 | 0.5063 | 0.75 | Ambiguous | 0.1 | 1.19 | Ambiguous | 0.97 | Ambiguous | -0.52 | Ambiguous | 0.55 | Neutral | 0.462 | Possibly Damaging | 0.173 | Benign | 4.19 | Benign | 1.00 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| c.610T>C | S204P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S204P variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and polyPhen‑2 HumVar, whereas a separate group predicts a pathogenic effect: FoldX, Rosetta, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. The remaining tools (premPS) are inconclusive and are not counted in either group. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain (treated as unavailable), the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie and therefore unavailable, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Overall, the majority of consensus predictions lean toward pathogenicity, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.268042 | Structured | 0.420667 | Uncertain | 0.816 | 0.405 | 0.125 | -8.855 | Likely Pathogenic | 0.820 | Likely Pathogenic | Ambiguous | 0.137 | Likely Benign | 0.1430 | 0.4815 | 3.71 | Destabilizing | 0.4 | 4.61 | Destabilizing | 4.16 | Destabilizing | 0.61 | Ambiguous | -1.28 | Neutral | 0.808 | Possibly Damaging | 0.382 | Benign | 4.13 | Benign | 0.12 | Tolerated | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||
| c.610T>G | S204A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S204A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from Rosetta, Foldetta, and premPS, which are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as Uncertain. Overall, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.268042 | Structured | 0.420667 | Uncertain | 0.816 | 0.405 | 0.125 | -3.330 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.091 | Likely Benign | 0.3706 | 0.3495 | -0.09 | Likely Benign | 0.0 | -1.17 | Ambiguous | -0.63 | Ambiguous | -0.83 | Ambiguous | 0.65 | Neutral | 0.004 | Benign | 0.004 | Benign | 4.28 | Benign | 0.27 | Tolerated | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||
| 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 | 0.170 | Likely Benign | 0.0452 | 0.5625 | 8.99 | Destabilizing | 3.8 | 5.20 | Destabilizing | 7.10 | Destabilizing | -0.03 | Likely Benign | -0.96 | Neutral | 0.978 | Probably Damaging | 0.694 | Possibly Damaging | 4.14 | Benign | 0.03 | Affected | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||
| c.611C>G | S204C 2D 3DClick to see structure in 3D Viewer AISynGAP1 S204C is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, Foldetta, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect. FoldX and Rosetta individually report uncertain stability changes. Overall, the majority of computational evidence supports a benign effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.268042 | Structured | 0.420667 | Uncertain | 0.816 | 0.405 | 0.125 | Uncertain | 1 | -6.613 | Likely Benign | 0.127 | Likely Benign | Likely Benign | 0.148 | Likely Benign | 0.0665 | 0.5237 | 0.65 | Ambiguous | 0.4 | -1.13 | Ambiguous | -0.24 | Likely Benign | 0.10 | Likely Benign | -0.64 | Neutral | 0.978 | Probably Damaging | 0.753 | Possibly Damaging | 4.13 | Benign | 0.05 | Affected | 3.44 | 10 | 0 | -1 | 3.3 | 16.06 | 223.6 | -13.8 | 0.6 | 0.3 | 0.0 | 0.2 | X | Uncertain | The hydroxyl-containing Ser204, located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by the thiol-containing cysteine. In the WT simulations, Ser204 simultaneously forms hydrogen bonds with the backbone carbonyl of Asp201 and the hydroxyl group of Thr224, helping to stabilize the two anti-parallel β strands (res. Ile205-Lys207 and Cys219-Thr223) at the end of the β sheet. Since the thiol group of cysteine forms weaker hydrogen bonds than the hydroxyl group of serine, Cys204 does not maintain the hydrogen bond network as stably as Ser204 in the variant simulations. However, because the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||||||
| 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 | 0.161 | Likely Benign | 0.0468 | 0.5764 | 7.35 | Destabilizing | 6.1 | 4.21 | Destabilizing | 5.78 | Destabilizing | -0.09 | Likely Benign | -0.88 | Neutral | 0.978 | Probably Damaging | 0.694 | Possibly Damaging | 4.16 | Benign | 0.03 | Affected | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||
| c.613A>C | I205L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I205L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the variant as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM Consensus predicts likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. No contradictory evidence exists. Based on the collective predictions, the variant is most likely benign, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.264545 | Structured | 0.409933 | Uncertain | 0.821 | 0.414 | 0.125 | -5.474 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.112 | Likely Benign | 0.0682 | 0.2702 | 0.07 | Likely Benign | 0.2 | 0.02 | Likely Benign | 0.05 | Likely Benign | 0.30 | Likely Benign | -0.86 | Neutral | 0.004 | Benign | 0.012 | Benign | 4.17 | Benign | 0.34 | Tolerated | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||
| c.613A>G | I205V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I205V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the variant as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM Consensus predicts likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Based on the consensus of all available predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.264545 | Structured | 0.409933 | Uncertain | 0.821 | 0.414 | 0.125 | -2.232 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.113 | Likely Benign | 0.0897 | 0.2791 | 0.45 | Likely Benign | 0.0 | -0.18 | Likely Benign | 0.14 | Likely Benign | 0.11 | Likely Benign | -0.11 | Neutral | 0.001 | Benign | 0.007 | Benign | 4.20 | Benign | 0.84 | Tolerated | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||
| c.613A>T | I205F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I205F missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, FoldX, PROVEAN, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, FATHMM, and polyPhen‑2 HumVar all classify it as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. Uncertain results from Foldetta, premPS, ESM1b, and Rosetta are treated as unavailable. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, while Foldetta remains uncertain. Overall, the consensus of the majority of tools indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.264545 | Structured | 0.409933 | Uncertain | 0.821 | 0.414 | 0.125 | -7.913 | In-Between | 0.271 | Likely Benign | Likely Benign | 0.113 | Likely Benign | 0.0461 | 0.2205 | 0.30 | Likely Benign | 0.3 | 0.89 | Ambiguous | 0.60 | Ambiguous | 0.52 | Ambiguous | -1.80 | Neutral | 0.838 | Possibly Damaging | 0.368 | Benign | 4.08 | Benign | 0.10 | Tolerated | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||
| c.614T>A | I205N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I205N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and ESM1b. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. No evidence from these tools contradicts the lack of ClinVar annotation. Overall, the majority of predictions (five pathogenic vs. four benign) and the pathogenic SGM Consensus suggest the variant is most likely pathogenic, with no ClinVar status to conflict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.264545 | Structured | 0.409933 | Uncertain | 0.821 | 0.414 | 0.125 | -10.928 | Likely Pathogenic | 0.552 | Ambiguous | Likely Benign | 0.138 | Likely Benign | 0.0802 | 0.0212 | 0.66 | Ambiguous | 0.1 | 1.16 | Ambiguous | 0.91 | Ambiguous | 1.57 | Destabilizing | -3.56 | Deleterious | 0.940 | Possibly Damaging | 0.641 | Possibly Damaging | 4.06 | Benign | 0.07 | Tolerated | -2 | -3 | -8.0 | 0.94 | ||||||||||||||||||||||||||
| c.614T>C | I205T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I205T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the remaining predictions (FoldX, premPS, AlphaMissense‑Default) are uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, classifies the variant as benign. Taken together, the consensus of both general and high‑accuracy predictors indicates that I205T is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.264545 | Structured | 0.409933 | Uncertain | 0.821 | 0.414 | 0.125 | -6.869 | Likely Benign | 0.450 | Ambiguous | Likely Benign | 0.118 | Likely Benign | 0.0933 | 0.0541 | 0.65 | Ambiguous | 0.0 | 0.28 | Likely Benign | 0.47 | Likely Benign | 0.81 | Ambiguous | -2.19 | Neutral | 0.421 | Benign | 0.156 | Benign | 4.16 | Benign | 0.15 | Tolerated | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||
| c.614T>G | I205S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I205S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and ESM1b. Tools with uncertain or inconclusive results (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of available predictions lean toward a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.264545 | Structured | 0.409933 | Uncertain | 0.821 | 0.414 | 0.125 | -8.694 | Likely Pathogenic | 0.518 | Ambiguous | Likely Benign | 0.178 | Likely Benign | 0.2346 | 0.0800 | 1.17 | Ambiguous | 0.2 | 0.95 | Ambiguous | 1.06 | Ambiguous | 0.88 | Ambiguous | -2.73 | Deleterious | 0.838 | Possibly Damaging | 0.368 | Benign | 4.12 | Benign | 0.24 | Tolerated | -1 | -2 | -5.3 | -26.08 | ||||||||||||||||||||||||||
| c.615T>G | I205M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I205M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Uncertain results come from Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta as benign. Based on the majority of predictions and the high‑accuracy tools, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.264545 | Structured | 0.409933 | Uncertain | 0.821 | 0.414 | 0.125 | -6.693 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.119 | Likely Benign | 0.0593 | 0.2000 | 0.20 | Likely Benign | 0.2 | 0.63 | Ambiguous | 0.42 | Likely Benign | 0.65 | Ambiguous | -1.16 | Neutral | 0.838 | Possibly Damaging | 0.467 | Possibly Damaging | 4.07 | Benign | 0.07 | Tolerated | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||
| c.616A>C | I206L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I206L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and Foldetta. Those that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. Uncertain or inconclusive results come from premPS, AlphaMissense‑Optimized, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta predicts a benign outcome. Overall, the majority of tools (seven benign vs two pathogenic) support a benign classification. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.298791 | Structured | 0.405123 | Uncertain | 0.863 | 0.391 | 0.125 | -9.488 | Likely Pathogenic | 0.790 | Likely Pathogenic | Ambiguous | 0.080 | Likely Benign | 0.0632 | 0.3608 | 0.05 | Likely Benign | 0.1 | 0.75 | Ambiguous | 0.40 | Likely Benign | 0.78 | Ambiguous | -1.72 | Neutral | 0.004 | Benign | 0.012 | Benign | 3.78 | Benign | 0.08 | Tolerated | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||
| c.616A>G | I206V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I206V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and Rosetta. No tool predicts a pathogenic outcome; the only inconclusive results are from FoldX (uncertain) and Foldetta (uncertain). High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, while Foldetta remains uncertain. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.298791 | Structured | 0.405123 | Uncertain | 0.863 | 0.391 | 0.125 | -5.709 | Likely Benign | 0.165 | Likely Benign | Likely Benign | 0.051 | Likely Benign | 0.0833 | 0.2920 | 1.22 | Ambiguous | 0.1 | 0.24 | Likely Benign | 0.73 | Ambiguous | 0.40 | Likely Benign | -0.51 | Neutral | 0.001 | Benign | 0.007 | Benign | 4.27 | Benign | 0.53 | Tolerated | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||
| c.616A>T | I206F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I206F 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, FATHMM, and polyPhen‑2 HumVar. Those that predict a pathogenic effect comprise SGM‑Consensus, Foldetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Rosetta. Predictions that are uncertain or inconclusive are FoldX and premPS. High‑accuracy methods all support a deleterious outcome: AlphaMissense‑Optimized reports 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. Based on the collective evidence, 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 | PH | 0.298791 | Structured | 0.405123 | Uncertain | 0.863 | 0.391 | 0.125 | -12.669 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.133 | Likely Benign | 0.0428 | 0.2721 | 1.82 | Ambiguous | 0.4 | 3.39 | Destabilizing | 2.61 | Destabilizing | 0.70 | Ambiguous | -3.40 | Deleterious | 0.838 | Possibly Damaging | 0.368 | Benign | 3.64 | Benign | 0.01 | Affected | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||
| c.617T>A | I206N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I206N is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL and FATHMM, while the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: 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 stability predictions, is pathogenic. No prediction or folding result is missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.298791 | Structured | 0.405123 | Uncertain | 0.863 | 0.391 | 0.125 | -15.211 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.334 | Likely Benign | 0.0689 | 0.0340 | 2.98 | Destabilizing | 0.2 | 2.57 | Destabilizing | 2.78 | Destabilizing | 2.04 | Destabilizing | -5.55 | Deleterious | 0.940 | Possibly Damaging | 0.641 | Possibly Damaging | 3.62 | Benign | 0.00 | Affected | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||
| c.617T>C | I206T 2D AIThe SynGAP1 I206T missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give consistent 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. No predictions or stability results are missing or inconclusive. Based on the overall evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not currently listed. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.298791 | Structured | 0.405123 | Uncertain | 0.863 | 0.391 | 0.125 | -10.812 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.252 | Likely Benign | 0.0830 | 0.0669 | 2.43 | Destabilizing | 0.5 | 2.68 | Destabilizing | 2.56 | Destabilizing | 1.94 | Destabilizing | -3.78 | Deleterious | 0.421 | Benign | 0.156 | Benign | 3.65 | Benign | 0.00 | Affected | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||
| c.617T>G | I206S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I206S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and polyPhen‑2 HumVar. All other evaluated algorithms (SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic or likely 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 predictions, is pathogenic. Based on the preponderance of evidence from these tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.298791 | Structured | 0.405123 | Uncertain | 0.863 | 0.391 | 0.125 | -13.711 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.251 | Likely Benign | 0.2189 | 0.0728 | 3.73 | Destabilizing | 0.3 | 3.89 | Destabilizing | 3.81 | Destabilizing | 1.74 | Destabilizing | -4.86 | Deleterious | 0.838 | Possibly Damaging | 0.368 | Benign | 3.63 | Benign | 0.00 | Affected | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||
| c.618C>G | I206M 2D AIThe SynGAP1 I206M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, and FATHMM, whereas tools that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. With six pathogenic predictions versus four benign and three uncertain, the overall evidence leans toward pathogenicity. 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. | PH | 0.298791 | Structured | 0.405123 | Uncertain | 0.863 | 0.391 | 0.125 | -10.008 | Likely Pathogenic | 0.878 | Likely Pathogenic | Ambiguous | 0.085 | Likely Benign | 0.0576 | 0.2716 | 0.42 | Likely Benign | 0.6 | 1.21 | Ambiguous | 0.82 | Ambiguous | 1.08 | Destabilizing | -2.42 | Neutral | 0.838 | Possibly Damaging | 0.467 | Possibly Damaging | 3.64 | Benign | 0.01 | Affected | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||
| c.619A>C | K207Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 K207Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, SIFT, and FATHMM; pathogenic predictions from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. High‑accuracy assessments give a mixed picture: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect; AlphaMissense‑Optimized is uncertain; Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign impact. Folding‑stability scores from FoldX and Rosetta are inconclusive, and premPS is unavailable. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.374039 | Structured | 0.406823 | Uncertain | 0.847 | 0.359 | 0.125 | -9.544 | Likely Pathogenic | 0.874 | Likely Pathogenic | Ambiguous | 0.250 | Likely Benign | 0.4010 | 0.1797 | 0.57 | Ambiguous | 0.1 | -0.57 | Ambiguous | 0.00 | Likely Benign | 0.61 | Ambiguous | -2.95 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 4.00 | Benign | 0.10 | Tolerated | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||
| c.619A>G | K207E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K207E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a larger group predicts pathogenicity: premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, the SGM Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. The remaining stability predictions (FoldX and Rosetta) are uncertain. Overall, the majority of evidence points to a pathogenic effect for K207E, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.374039 | Structured | 0.406823 | Uncertain | 0.847 | 0.359 | 0.125 | -14.387 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.265 | Likely Benign | 0.3504 | 0.1557 | 1.39 | Ambiguous | 0.1 | 1.21 | Ambiguous | 1.30 | Ambiguous | 1.09 | Destabilizing | -3.00 | Deleterious | 0.982 | Probably Damaging | 0.679 | Possibly Damaging | 4.02 | Benign | 0.07 | Tolerated | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||
| c.620A>C | K207T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K207T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from Rosetta, Foldetta, and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic; Foldetta’s stability analysis is inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for K207T, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.374039 | Structured | 0.406823 | Uncertain | 0.847 | 0.359 | 0.125 | -11.002 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 0.239 | Likely Benign | 0.1636 | 0.4031 | 2.15 | Destabilizing | 0.8 | 0.57 | Ambiguous | 1.36 | Ambiguous | 0.78 | Ambiguous | -4.57 | Deleterious | 0.982 | Probably Damaging | 0.747 | Possibly Damaging | 3.99 | Benign | 0.07 | Tolerated | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||
| c.620A>G | K207R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change K207R is not listed in ClinVar and has no reported allele in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a benign or likely benign outcome. In contrast, polyPhen‑2 HumDiv and HumVar classify the variant as pathogenic. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, providing no definitive support for either outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Taken together, the majority of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.374039 | Structured | 0.406823 | Uncertain | 0.847 | 0.359 | 0.125 | -5.157 | Likely Benign | 0.217 | Likely Benign | Likely Benign | 0.140 | Likely Benign | 0.4640 | 0.1704 | -0.58 | Ambiguous | 0.1 | -1.07 | Ambiguous | -0.83 | Ambiguous | 0.37 | Likely Benign | -1.77 | Neutral | 0.982 | Probably Damaging | 0.679 | Possibly Damaging | 4.09 | Benign | 0.20 | Tolerated | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||
| c.620A>T | K207M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K207M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized) predict a pathogenic impact; premPS is uncertain. High‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign. Overall, the balance of evidence favors 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 | PH | 0.374039 | Structured | 0.406823 | Uncertain | 0.847 | 0.359 | 0.125 | -12.596 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.336 | Likely Benign | 0.0982 | 0.4705 | -0.22 | Likely Benign | 0.0 | -0.47 | Likely Benign | -0.35 | Likely Benign | 0.59 | Ambiguous | -4.67 | Deleterious | 0.985 | Probably Damaging | 0.832 | Possibly Damaging | 3.94 | Benign | 0.03 | Affected | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||
| c.621G>C | K207N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K207N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicating likely pathogenic, while Foldetta’s stability prediction is unavailable. Overall, the preponderance of evidence points to a pathogenic effect for K207N, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.374039 | Structured | 0.406823 | Uncertain | 0.847 | 0.359 | 0.125 | -12.881 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.123 | Likely Benign | 0.3184 | 0.2335 | 0.72 | Ambiguous | 0.1 | 1.48 | Ambiguous | 1.10 | Ambiguous | 1.00 | Destabilizing | -3.54 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.98 | Benign | 0.07 | Tolerated | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.621G>T | K207N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K207N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions arise from premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, and the SGM Consensus (majority vote) also predicts Pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the preponderance of evidence indicates that K207N is most likely pathogenic, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.374039 | Structured | 0.406823 | Uncertain | 0.847 | 0.359 | 0.125 | -12.881 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.124 | Likely Benign | 0.3184 | 0.2335 | 0.72 | Ambiguous | 0.1 | 1.48 | Ambiguous | 1.10 | Ambiguous | 1.00 | Destabilizing | -3.54 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.98 | Benign | 0.07 | Tolerated | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.622C>A | P208T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P208T 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, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and Foldetta; premPS and Rosetta are uncertain. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts benign, but the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta also predicts pathogenic. With the majority of tools, including the high‑accuracy ones, indicating pathogenicity, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as the variant is currently unreported there. 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 | -9.016 | Likely Pathogenic | 0.727 | Likely Pathogenic | Likely Benign | 0.270 | Likely Benign | 0.1857 | 0.5197 | 3.20 | Destabilizing | 0.5 | 1.27 | Ambiguous | 2.24 | Destabilizing | 0.94 | Ambiguous | -6.80 | Deleterious | 1.000 | Probably Damaging | 0.994 | Probably Damaging | 3.76 | Benign | 0.01 | Affected | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||
| c.622C>G | P208A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P208A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. Predictions that are inconclusive are Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points toward a benign effect, and this is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.271506 | Structured | 0.399506 | Uncertain | 0.864 | 0.345 | 0.125 | -5.623 | Likely Benign | 0.172 | Likely Benign | Likely Benign | 0.245 | Likely Benign | 0.3727 | 0.4390 | 2.19 | Destabilizing | 0.3 | 1.31 | Ambiguous | 1.75 | Ambiguous | 1.03 | Destabilizing | -6.80 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 3.80 | Benign | 0.04 | Affected | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||
| c.622C>T | P208S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P208S 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, FATHMM, and AlphaMissense‑Optimized. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and Foldetta. Rosetta’s output is uncertain and therefore not counted as evidence. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts benign, but the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to pathogenic, and Foldetta also predicts pathogenic. With no ClinVar annotation to contradict, the overall evidence strongly favors a pathogenic classification for P208S. 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 | -8.363 | Likely Pathogenic | 0.587 | Likely Pathogenic | Likely Benign | 0.270 | Likely Benign | 0.3808 | 0.4537 | 2.68 | Destabilizing | 0.3 | 1.53 | Ambiguous | 2.11 | Destabilizing | 1.21 | Destabilizing | -6.78 | Deleterious | 1.000 | Probably Damaging | 0.994 | Probably Damaging | 3.79 | Benign | 0.02 | Affected | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||
| c.623C>A | P208Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 P208Q 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 tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and Foldetta. Two tools give uncertain results (AlphaMissense‑Optimized and Rosetta) and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as Pathogenic, reinforcing a deleterious prediction. Overall, the evidence strongly favors a pathogenic classification, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.271506 | Structured | 0.399506 | Uncertain | 0.864 | 0.345 | 0.125 | -9.746 | Likely Pathogenic | 0.906 | Likely Pathogenic | Ambiguous | 0.411 | Likely Benign | 0.1570 | 0.4663 | 3.30 | Destabilizing | 0.7 | 0.75 | Ambiguous | 2.03 | Destabilizing | 1.23 | Destabilizing | -6.78 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.78 | Benign | 0.00 | Affected | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||
| 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 | 0.472 | Likely Benign | 0.1676 | 0.3118 | 5.25 | Destabilizing | 1.6 | 1.39 | Ambiguous | 3.32 | Destabilizing | 1.16 | Destabilizing | -7.50 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.75 | Benign | 0.00 | Affected | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||
| c.623C>T | P208L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P208L has no ClinVar entry and is present in gnomAD (ID 6‑33435265‑C‑T). Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, while those that agree on a pathogenic effect include FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Predictions that are inconclusive are Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus as likely pathogenic, and Foldetta as uncertain. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.271506 | Structured | 0.399506 | Uncertain | 0.864 | 0.345 | 0.125 | 6-33435265-C-T | 1 | 6.20e-7 | -10.013 | Likely Pathogenic | 0.889 | Likely Pathogenic | Ambiguous | 0.466 | Likely Benign | 0.2219 | 0.6191 | 2.35 | Destabilizing | 0.5 | 0.04 | Likely Benign | 1.20 | Ambiguous | 0.67 | Ambiguous | -8.49 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.75 | Benign | 0.01 | Affected | 3.44 | 12 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||
| c.625G>A | V209M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 V209M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Five tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) give uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.247041 | Structured | 0.397624 | Uncertain | 0.874 | 0.331 | 0.125 | -8.112 | Likely Pathogenic | 0.932 | Likely Pathogenic | Ambiguous | 0.115 | Likely Benign | 0.0669 | 0.3982 | 0.70 | Ambiguous | 0.4 | 0.77 | Ambiguous | 0.74 | Ambiguous | 0.78 | Ambiguous | -1.48 | Neutral | 0.995 | Probably Damaging | 0.880 | Possibly Damaging | 3.68 | Benign | 0.02 | Affected | 2 | 1 | -2.3 | 32.06 | ||||||||||||||||||||||||||
| c.625G>C | V209L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 V209L missense change is not reported in ClinVar and is absent from gnomAD. Consensus‐based predictors that agree on a benign outcome include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Predictors that flag a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show that AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.247041 | Structured | 0.397624 | Uncertain | 0.874 | 0.331 | 0.125 | -5.516 | Likely Benign | 0.837 | Likely Pathogenic | Ambiguous | 0.084 | Likely Benign | 0.0814 | 0.4188 | 0.26 | Likely Benign | 0.4 | -0.12 | Likely Benign | 0.07 | Likely Benign | 0.08 | Likely Benign | -0.96 | Neutral | 0.787 | Possibly Damaging | 0.259 | Benign | 4.08 | Benign | 0.39 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.625G>T | V209L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V209L is not reported in ClinVar and is absent from gnomAD. Consensus predictions from most in silico tools classify the change as benign: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Only two tools predict a pathogenic effect: polyPhen‑2 HumDiv and AlphaMissense‑Default. The AlphaMissense‑Optimized score is uncertain. High‑accuracy assessments further support a benign outcome: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is benign; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.247041 | Structured | 0.397624 | Uncertain | 0.874 | 0.331 | 0.125 | -5.516 | Likely Benign | 0.837 | Likely Pathogenic | Ambiguous | 0.084 | Likely Benign | 0.0814 | 0.4188 | 0.26 | Likely Benign | 0.4 | -0.12 | Likely Benign | 0.07 | Likely Benign | 0.08 | Likely Benign | -0.96 | Neutral | 0.787 | Possibly Damaging | 0.259 | Benign | 4.08 | Benign | 0.39 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.626T>A | V209E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V209E is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the remaining 13 tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) all predict a pathogenic outcome. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, V209E 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 | PH | 0.247041 | Structured | 0.397624 | Uncertain | 0.874 | 0.331 | 0.125 | -14.366 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.403 | Likely Benign | 0.0826 | 0.1652 | 3.53 | Destabilizing | 1.3 | 2.35 | Destabilizing | 2.94 | Destabilizing | 1.52 | Destabilizing | -4.54 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.65 | Benign | 0.00 | Affected | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||
| c.626T>C | V209A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V209A is reported in gnomAD (ID 6‑33435268‑T‑C) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL and FATHMM. In contrast, a majority of tools predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Stability‑based methods FoldX, Rosetta, and the combined Foldetta score are uncertain and therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence from multiple independent predictors indicates that V209A is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.247041 | Structured | 0.397624 | Uncertain | 0.874 | 0.331 | 0.125 | 6-33435268-T-C | 1 | 6.20e-7 | -9.796 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.236 | Likely Benign | 0.2237 | 0.1919 | 1.56 | Ambiguous | 0.3 | 1.85 | Ambiguous | 1.71 | Ambiguous | 1.60 | Destabilizing | -2.79 | Deleterious | 0.958 | Probably Damaging | 0.581 | Possibly Damaging | 3.70 | Benign | 0.02 | Affected | 3.41 | 13 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||
| c.626T>G | V209G 2D  AIThe SynGAP1 missense variant V209G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a pathogenic classification; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. Taken together, the overwhelming majority of computational evidence indicates that V209G is 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. | PH | 0.247041 | Structured | 0.397624 | Uncertain | 0.874 | 0.331 | 0.125 | -13.763 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.390 | Likely Benign | 0.1600 | 0.2035 | 3.05 | Destabilizing | 0.5 | 3.99 | Destabilizing | 3.52 | Destabilizing | 1.27 | Destabilizing | -5.49 | Deleterious | 0.829 | Possibly Damaging | 0.995 | Probably Damaging | 3.65 | Benign | 0.04 | Affected | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||
| c.628C>A | H210N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H210N missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, and FATHMM, while pathogenic predictions are made by premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus score (Likely Pathogenic). Two tools give uncertain results: Foldetta (combining FoldX‑MD and Rosetta outputs) and Rosetta alone. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as Likely Pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points toward a pathogenic effect for H210N. 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 | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -13.699 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.375 | Likely Benign | 0.1166 | 0.1839 | 0.19 | Likely Benign | 0.3 | 1.24 | Ambiguous | 0.72 | Ambiguous | 1.12 | Destabilizing | -6.01 | Deleterious | 0.895 | Possibly Damaging | 0.533 | Possibly Damaging | 3.11 | Benign | 0.00 | Affected | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||
| c.628C>G | H210D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H210D is not 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, and FATHMM. In contrast, the majority of tools predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain, and Rosetta alone is also uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for H210D, 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 | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -16.440 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.489 | Likely Benign | 0.2025 | 0.1255 | 0.13 | Likely Benign | 0.4 | 1.23 | Ambiguous | 0.68 | Ambiguous | 1.23 | Destabilizing | -7.73 | Deleterious | 0.895 | Possibly Damaging | 0.533 | Possibly Damaging | 3.18 | Benign | 0.00 | Affected | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||
| c.628C>T | H210Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H210Y missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as Benign. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar classification because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -12.828 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.427 | Likely Benign | 0.0497 | 0.3662 | 0.27 | Likely Benign | 0.8 | 0.38 | Likely Benign | 0.33 | Likely Benign | 0.39 | Likely Benign | -5.12 | Deleterious | 0.963 | Probably Damaging | 0.628 | Possibly Damaging | 3.07 | Benign | 0.00 | Affected | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||
| c.629A>C | H210P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H210P is 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; all other evaluated algorithms—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 from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -14.634 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.512 | Likely Pathogenic | 0.1805 | 0.3175 | 2.26 | Destabilizing | 0.5 | 2.80 | Destabilizing | 2.53 | Destabilizing | 1.00 | Destabilizing | -8.55 | Deleterious | 0.989 | Probably Damaging | 0.795 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||
| c.629A>G | H210R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H210R missense variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and FoldX, whereas a majority of tools predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). The high‑accuracy AlphaMissense‑Optimized result is pathogenic; the SGM Consensus, based on the same set of predictors, is also pathogenic; Foldetta’s stability assessment is uncertain and therefore not considered evidence. Overall, the balance of evidence points to a pathogenic effect for H210R. This prediction does not contradict the ClinVar “Uncertain” classification, which remains unresolved. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | Uncertain | 1 | -14.254 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.431 | Likely Benign | 0.1427 | 0.1982 | 0.40 | Likely Benign | 0.4 | 3.05 | Destabilizing | 1.73 | Ambiguous | 1.12 | Destabilizing | -6.74 | Deleterious | 0.808 | Possibly Damaging | 0.452 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||
| c.629A>T | H210L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H210L missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools cluster into two groups: benign predictions come from REVEL, Foldetta, premPS, and FATHMM, while pathogenic predictions arise from SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Rosetta provide uncertain results. High‑accuracy assessments further highlight the discrepancy: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, whereas Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of evidence points to a pathogenic effect, 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 | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -14.516 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.421 | Likely Benign | 0.0617 | 0.4452 | -0.71 | Ambiguous | 0.1 | 1.35 | Ambiguous | 0.32 | Likely Benign | 0.49 | Likely Benign | -9.41 | Deleterious | 0.895 | Possibly Damaging | 0.614 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||
| c.630C>A | H210Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant H210Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign calls come from REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar) and FATHMM, whereas pathogenic calls are made by premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN, favors a pathogenic outcome (3/4). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote) also predicts pathogenic. Foldetta, a protein‑folding stability predictor that integrates FoldX‑MD and Rosetta, is inconclusive and therefore not used as evidence. Overall, the majority of reliable predictors indicate a pathogenic effect for H210Q, 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. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -12.639 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.258 | Likely Benign | 0.1016 | 0.2852 | 0.26 | Likely Benign | 0.3 | 1.96 | Ambiguous | 1.11 | Ambiguous | 1.20 | Destabilizing | -6.84 | Deleterious | 0.141 | Benign | 0.064 | Benign | 3.10 | Benign | 0.00 | Affected | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||
| c.630C>G | H210Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H210Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls from REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar) and FATHMM, whereas pathogenic calls come from premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized. When predictions are grouped, five tools favor a benign effect and six favor a pathogenic effect. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenic, and the Foldetta stability analysis is inconclusive. No evidence from ClinVar contradicts these findings. Therefore, the variant is most likely pathogenic based on the aggregate computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -12.639 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.258 | Likely Benign | 0.1016 | 0.2852 | 0.26 | Likely Benign | 0.3 | 1.96 | Ambiguous | 1.11 | Ambiguous | 1.20 | Destabilizing | -6.84 | Deleterious | 0.141 | Benign | 0.064 | Benign | 3.10 | Benign | 0.00 | Affected | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||
| 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 | 0.132 | Likely Benign | 0.1003 | 0.3592 | 0.49 | Likely Benign | 1.0 | 0.20 | Likely Benign | 0.35 | Likely Benign | 0.97 | Ambiguous | -4.00 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.95 | Benign | 0.02 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||
| c.631A>G | S211G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 HumDiv, and ESM1b; Rosetta is uncertain. High‑accuracy methods give a benign result for AlphaMissense‑Optimized and for Foldetta. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs two pathogenic). No evidence from ClinVar contradicts these predictions. Overall, the balance of evidence—including the unanimous benign calls from the high‑accuracy tools—suggests that the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -9.895 | Likely Pathogenic | 0.265 | Likely Benign | Likely Benign | 0.067 | Likely Benign | 0.2560 | 0.4337 | 0.30 | Likely Benign | 0.2 | 0.54 | Ambiguous | 0.42 | Likely Benign | 1.07 | Destabilizing | -3.17 | Deleterious | 0.787 | Possibly Damaging | 0.404 | Benign | 3.92 | Benign | 0.07 | Tolerated | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||
| c.631A>T | S211C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, AlphaMissense‑Optimized, and premPS, whereas a separate group predicts pathogenicity: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Two tools (Rosetta and AlphaMissense‑Default) return uncertain results. 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. Because the consensus of the most reliable predictors is split (two benign, one pathogenic) and the overall tool distribution is evenly divided, the variant’s impact remains ambiguous. Based on the available predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -10.567 | Likely Pathogenic | 0.547 | Ambiguous | Likely Benign | 0.263 | Likely Benign | 0.1292 | 0.5638 | 0.28 | Likely Benign | 0.1 | 0.63 | Ambiguous | 0.46 | Likely Benign | 0.11 | Likely Benign | -4.14 | Deleterious | 0.999 | Probably Damaging | 0.908 | Possibly Damaging | 3.89 | Benign | 0.01 | Affected | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||
| c.632G>A | S211N 2D AIThe SynGAP1 S211N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and premPS. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Consequently, the overall prediction leans toward pathogenicity, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -9.995 | Likely Pathogenic | 0.794 | Likely Pathogenic | Ambiguous | 0.174 | Likely Benign | 0.1534 | 0.4863 | 0.60 | Ambiguous | 1.2 | 1.39 | Ambiguous | 1.00 | Ambiguous | 1.21 | Destabilizing | -2.22 | Neutral | 0.982 | Probably Damaging | 0.747 | Possibly Damaging | 3.95 | Benign | 0.09 | Tolerated | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||
| c.632G>C | S211T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Two tools, FoldX and Rosetta, give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign and Foldetta as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -10.301 | Likely Pathogenic | 0.678 | Likely Pathogenic | Likely Benign | 0.157 | Likely Benign | 0.1678 | 0.5960 | 0.98 | Ambiguous | 0.5 | -0.78 | Ambiguous | 0.10 | Likely Benign | 0.50 | Likely Benign | -2.33 | Neutral | 0.948 | Possibly Damaging | 0.484 | Possibly Damaging | 3.95 | Benign | 0.07 | Tolerated | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||
| c.632G>T | S211I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S211I missense variant 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; pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. No evidence from FoldX or Rosetta is available. Overall, the preponderance of evidence indicates 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 | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -17.090 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.251 | Likely Benign | 0.0909 | 0.5220 | 1.06 | Ambiguous | 1.1 | 1.05 | Ambiguous | 1.06 | Ambiguous | 0.12 | Likely Benign | -4.94 | Deleterious | 0.995 | Probably Damaging | 0.767 | Possibly Damaging | 3.90 | Benign | 0.01 | Affected | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||
| 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 | 0.144 | Likely Benign | 0.1003 | 0.3592 | 0.49 | Likely Benign | 1.0 | 0.20 | Likely Benign | 0.35 | Likely Benign | 0.97 | Ambiguous | -4.00 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.95 | Benign | 0.02 | Affected | 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 | 0.144 | Likely Benign | 0.1003 | 0.3592 | 0.49 | Likely Benign | 1.0 | 0.20 | Likely Benign | 0.35 | Likely Benign | 0.97 | Ambiguous | -4.00 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.95 | Benign | 0.02 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||
| c.634T>A | S212T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S212T is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include FoldX and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. With most evidence pointing to deleterious effects and no conflicting ClinVar annotation, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.381517 | Uncertain | 0.846 | 0.278 | 0.125 | -11.473 | Likely Pathogenic | 0.939 | Likely Pathogenic | Ambiguous | 0.767 | Likely Pathogenic | 0.1077 | 0.6284 | 0.32 | Likely Benign | 0.2 | 2.03 | Destabilizing | 1.18 | Ambiguous | 0.58 | Ambiguous | -2.58 | Deleterious | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 5.79 | Benign | 0.01 | Affected | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| c.634T>C | S212P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S212P is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX and FATHMM, whereas the remaining tools—REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict it to be pathogenic. High‑accuracy methods give consistent pathogenic results: AlphaMissense‑Optimized scores it as pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. With the overwhelming majority of tools supporting pathogenicity and no ClinVar entry to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.381517 | Uncertain | 0.846 | 0.278 | 0.125 | -13.051 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.809 | Likely Pathogenic | 0.1859 | 0.5679 | 0.02 | Likely Benign | 0.9 | 6.30 | Destabilizing | 3.16 | Destabilizing | 0.90 | Ambiguous | -4.13 | Deleterious | 0.995 | Probably Damaging | 0.979 | Probably Damaging | 5.75 | Benign | 0.01 | Affected | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||
| c.634T>G | S212A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S212A has no ClinVar record and is not listed in gnomAD. Prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, Foldetta, PROVEAN, and FATHMM, while pathogenic predictions arise from REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools report uncertainty: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta predicts benign stability. Overall, the majority of conventional tools lean toward pathogenicity, whereas the most reliable high‑accuracy methods are either benign or inconclusive. 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. | PH | 0.158265 | Structured | 0.381517 | Uncertain | 0.846 | 0.278 | 0.125 | -8.890 | Likely Pathogenic | 0.869 | Likely Pathogenic | Ambiguous | 0.752 | Likely Pathogenic | 0.4639 | 0.4509 | -0.13 | Likely Benign | 0.1 | 0.13 | Likely Benign | 0.00 | Likely Benign | 0.75 | Ambiguous | -2.48 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 5.83 | Benign | 0.01 | Affected | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||
| 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 | 0.819 | Likely Pathogenic | 0.0555 | 0.6120 | 0.43 | Likely Benign | 0.5 | 2.32 | Destabilizing | 1.38 | Ambiguous | 0.22 | Likely Benign | -5.15 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 5.76 | Benign | 0.00 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||
| c.635C>G | S212C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S212C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include FoldX, premPS, and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are inconclusive are Rosetta and Foldetta. The high‑accuracy consensus methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence from multiple independent 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 | 0.158265 | Structured | 0.381517 | Uncertain | 0.846 | 0.278 | 0.125 | -11.656 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.840 | Likely Pathogenic | 0.0785 | 0.6270 | 0.16 | Likely Benign | 0.1 | 0.98 | Ambiguous | 0.57 | Ambiguous | 0.47 | Likely Benign | -4.29 | Deleterious | 0.999 | Probably Damaging | 0.990 | Probably Damaging | 5.73 | Benign | 0.00 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||
| 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 | 0.820 | Likely Pathogenic | 0.0503 | 0.6259 | 0.11 | Likely Benign | 1.6 | 0.88 | Ambiguous | 0.50 | Ambiguous | -0.02 | Likely Benign | -5.15 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 5.76 | Benign | 0.00 | Affected | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||
| c.637A>C | I213L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I213L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM all classify the variant as benign, while AlphaMissense‑Default predicts it as pathogenic and ESM1b remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also reports a benign effect. No prediction or stability result is missing or inconclusive. Overall, the variant is most likely benign based on the collective evidence, and this benign prediction does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -7.673 | In-Between | 0.577 | Likely Pathogenic | Likely Benign | 0.489 | Likely Benign | 0.0771 | 0.2857 | 0.29 | Likely Benign | 0.4 | 0.20 | Likely Benign | 0.25 | Likely Benign | 0.45 | Likely Benign | -1.45 | Neutral | 0.447 | Benign | 0.177 | Benign | 5.89 | Benign | 0.18 | Tolerated | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||
| c.637A>G | I213V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I213V missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). No tool predicts a pathogenic outcome. Predictions that are inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta’s stability analysis is uncertain. Overall, the evidence strongly favors a benign classification, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -6.133 | Likely Benign | 0.364 | Ambiguous | Likely Benign | 0.413 | Likely Benign | 0.1008 | 0.2959 | 0.67 | Ambiguous | 0.2 | 0.58 | Ambiguous | 0.63 | Ambiguous | 0.47 | Likely Benign | -0.69 | Neutral | 0.128 | Benign | 0.048 | Benign | 5.82 | Benign | 0.10 | Tolerated | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||
| c.637A>T | I213F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I213F missense variant 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 only FATHMM, while the remaining evaluated algorithms (SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact; FoldX and premPS are uncertain and are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain and thus not considered. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -12.212 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.815 | Likely Pathogenic | 0.0473 | 0.2560 | 0.96 | Ambiguous | 0.7 | 2.66 | Destabilizing | 1.81 | Ambiguous | 0.73 | Ambiguous | -3.30 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 5.79 | Benign | 0.01 | Affected | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||
| c.638T>A | I213N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I213N is 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 evaluated algorithms—SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; FoldX is uncertain and is treated as unavailable. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. 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 | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -15.069 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.862 | Likely Pathogenic | 0.0750 | 0.0412 | 1.71 | Ambiguous | 0.8 | 2.81 | Destabilizing | 2.26 | Destabilizing | 1.85 | Destabilizing | -5.81 | Deleterious | 0.995 | Probably Damaging | 0.880 | Possibly Damaging | 5.83 | Benign | 0.00 | Affected | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||
| c.638T>C | I213T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I213T missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining evidence—SGM‑Consensus (Likely Pathogenic), REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently indicates pathogenicity. FoldX, Rosetta, and Foldetta provide uncertain results. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence supports a pathogenic classification for I213T, 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 | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -11.080 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.882 | Likely Pathogenic | 0.0905 | 0.0708 | 1.46 | Ambiguous | 0.8 | 1.32 | Ambiguous | 1.39 | Ambiguous | 1.49 | Destabilizing | -3.99 | Deleterious | 0.948 | Possibly Damaging | 0.588 | Possibly Damaging | 5.82 | Benign | 0.00 | Affected | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||
| c.638T>G | I213S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I213S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the change as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -12.858 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.879 | Likely Pathogenic | 0.2290 | 0.0800 | 2.00 | Destabilizing | 1.1 | 2.95 | Destabilizing | 2.48 | Destabilizing | 1.53 | Destabilizing | -4.88 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 5.83 | Benign | 0.00 | Affected | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||
| c.639C>G | I213M 2D AIThe SynGAP1 missense variant I213M 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 PROVEAN and FATHMM, while a larger group—REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) return uncertain or inconclusive results and are therefore treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie, and Foldetta is uncertain. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -10.777 | Likely Pathogenic | 0.906 | Likely Pathogenic | Ambiguous | 0.680 | Likely Pathogenic | 0.0611 | 0.2524 | 0.66 | Ambiguous | 0.5 | 1.58 | Ambiguous | 1.12 | Ambiguous | 0.85 | Ambiguous | -2.31 | Neutral | 0.995 | Probably Damaging | 0.880 | Possibly Damaging | 5.85 | Benign | 0.01 | Affected | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||
| c.640C>A | L214M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L214M 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 PROVEAN and FATHMM, whereas the majority of tools (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; the remaining tools (FoldX, Rosetta, Foldetta, premPS) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs two benign) and Foldetta is uncertain. Thus, the available evidence points to a pathogenic effect. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.155435 | Structured | 0.372604 | Uncertain | 0.818 | 0.302 | 0.125 | -9.347 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.646 | Likely Pathogenic | 0.0805 | 0.4054 | 0.74 | Ambiguous | 0.3 | 1.43 | Ambiguous | 1.09 | Ambiguous | 0.80 | Ambiguous | -1.72 | Neutral | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 5.73 | Benign | 0.01 | Affected | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||
| c.640C>G | L214V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L214V 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The remaining methods—FoldX, Rosetta, premPS, and AlphaMissense‑Optimized—yield uncertain results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.155435 | Structured | 0.372604 | Uncertain | 0.818 | 0.302 | 0.125 | -9.913 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.495 | Likely Benign | 0.1469 | 0.3887 | 1.80 | Ambiguous | 0.4 | 0.54 | Ambiguous | 1.17 | Ambiguous | 0.89 | Ambiguous | -2.54 | Deleterious | 0.384 | Benign | 0.070 | Benign | 5.78 | Benign | 0.01 | Affected | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.641T>A | L214Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change at residue 214 (Leu→Gln) is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, the majority (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic effect, while only FATHMM predicts a benign outcome. Three tools (FoldX, Rosetta, Foldetta) return uncertain results. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta is uncertain. Taken together, the overwhelming consensus of pathogenic predictions indicates that the variant is most likely pathogenic, with no ClinVar evidence contradicting this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.155435 | Structured | 0.372604 | Uncertain | 0.818 | 0.302 | 0.125 | -10.119 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.912 | Likely Pathogenic | 0.1140 | 0.0930 | 1.60 | Ambiguous | 0.6 | 1.71 | Ambiguous | 1.66 | Ambiguous | 1.73 | Destabilizing | -5.12 | Deleterious | 0.997 | Probably Damaging | 0.936 | Probably Damaging | 5.74 | Benign | 0.00 | Affected | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||
| c.641T>C | L214P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L214P is 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, while the remaining 15 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, and the consensus of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) uniformly predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Based on the overwhelming agreement among predictive algorithms, 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 | 0.155435 | Structured | 0.372604 | Uncertain | 0.818 | 0.302 | 0.125 | -11.348 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.930 | Likely Pathogenic | 0.3448 | 0.1553 | 3.38 | Destabilizing | 1.3 | 7.51 | Destabilizing | 5.45 | Destabilizing | 1.30 | Destabilizing | -5.98 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 5.76 | Benign | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.641T>G | L214R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L214R 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 only FATHMM, whereas the majority of tools (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX, 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 evidence strongly favors a pathogenic effect for this variant, 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 | 0.155435 | Structured | 0.372604 | Uncertain | 0.818 | 0.302 | 0.125 | -11.458 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.927 | Likely Pathogenic | 0.1335 | 0.0772 | 1.35 | Ambiguous | 0.6 | 0.92 | Ambiguous | 1.14 | Ambiguous | 1.68 | Destabilizing | -4.98 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 5.75 | Benign | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||
| c.643G>A | G215S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G215S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining pathogenic predictors (SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all indicate pathogenicity. Uncertain results come from Rosetta, Foldetta, and premPS. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the variant is most likely pathogenic based on the consensus of predictive tools, 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 | PH | 0.155435 | Structured | 0.382818 | Uncertain | 0.791 | 0.291 | 0.000 | -9.067 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.864 | Likely Pathogenic | 0.2701 | 0.5761 | 2.30 | Destabilizing | 0.3 | 1.20 | Ambiguous | 1.75 | Ambiguous | 0.55 | Ambiguous | -5.05 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 5.66 | Benign | 0.02 | Affected | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||
| 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 | 0.823 | Likely Pathogenic | 0.1048 | 0.4890 | 1.75 | Ambiguous | 0.1 | 1.25 | Ambiguous | 1.50 | Ambiguous | 0.56 | Ambiguous | -6.84 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 5.71 | Benign | 0.01 | Affected | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||
| c.643G>T | G215C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G215C 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 premPS and FATHMM; those that agree on a pathogenic effect include SGM‑Consensus, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Rosetta gives an uncertain result and is listed separately. High‑accuracy methods all predict pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Based on the overwhelming agreement among both general and high‑accuracy predictors, 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 | PH | 0.155435 | Structured | 0.382818 | Uncertain | 0.791 | 0.291 | 0.000 | -12.295 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.869 | Likely Pathogenic | 0.1274 | 0.4640 | 2.39 | Destabilizing | 0.2 | 1.76 | Ambiguous | 2.08 | Destabilizing | 0.33 | Likely Benign | -7.69 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 5.56 | Benign | 0.00 | Affected | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||
| 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 | 0.807 | Likely Pathogenic | 0.1888 | 0.2947 | 2.23 | Destabilizing | 0.3 | 0.91 | Ambiguous | 1.57 | Ambiguous | 0.57 | Ambiguous | -5.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 5.71 | Benign | 0.02 | Affected | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||
| c.644G>C | G215A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G215A is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tool predicting a benign outcome is FATHMM. Predictions that are uncertain or inconclusive are Foldetta, Rosetta, and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta is uncertain. Overall, the majority of evidence indicates that G215A is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.155435 | Structured | 0.382818 | Uncertain | 0.791 | 0.291 | 0.000 | -8.930 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.874 | Likely Pathogenic | 0.3897 | 0.5525 | 2.36 | Destabilizing | 0.2 | 1.35 | Ambiguous | 1.86 | Ambiguous | 0.59 | Ambiguous | -5.08 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.61 | Benign | 0.02 | Affected | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||
| c.644G>T | G215V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G215V is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining twelve tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the variant as pathogenic. premPS is uncertain and does not influence the consensus. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.155435 | Structured | 0.382818 | Uncertain | 0.791 | 0.291 | 0.000 | -12.960 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.884 | Likely Pathogenic | 0.1087 | 0.4777 | 3.69 | Destabilizing | 0.2 | 5.41 | Destabilizing | 4.55 | Destabilizing | 0.53 | Ambiguous | -7.66 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 5.56 | Benign | 0.00 | Affected | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||
| c.646C>A | Q216K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216K is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or folding stability result is missing or inconclusive. Overall, the majority of tools lean toward a benign classification, but the presence of several pathogenic predictions and a high‑accuracy consensus that is pathogenic introduces uncertainty. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -10.908 | Likely Pathogenic | 0.826 | Likely Pathogenic | Ambiguous | 0.617 | Likely Pathogenic | 0.2431 | 0.4591 | -0.35 | Likely Benign | 0.1 | 0.38 | Likely Benign | 0.02 | Likely Benign | 0.17 | Likely Benign | -2.71 | Deleterious | 0.779 | Possibly Damaging | 0.351 | Benign | 5.92 | Benign | 0.12 | Tolerated | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||
| c.646C>G | Q216E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as benign. No predictions or stability results are missing or inconclusive. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -9.215 | Likely Pathogenic | 0.550 | Ambiguous | Likely Benign | 0.474 | Likely Benign | 0.1872 | 0.3117 | 0.49 | Likely Benign | 0.3 | 0.30 | Likely Benign | 0.40 | Likely Benign | 0.35 | Likely Benign | -1.89 | Neutral | 0.779 | Possibly Damaging | 0.351 | Benign | 5.85 | Benign | 0.13 | Tolerated | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||
| c.647A>C | Q216P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216P 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 FATHMM, which scores the variant as benign. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic or likely pathogenic impact. The high‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; SGM‑Consensus indicates likely pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. premPS is inconclusive and is treated as unavailable. Based on the collective predictions, the variant is most likely pathogenic, and this assessment is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -13.128 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.830 | Likely Pathogenic | 0.2603 | 0.5736 | 4.35 | Destabilizing | 0.8 | 4.05 | Destabilizing | 4.20 | Destabilizing | 0.53 | Ambiguous | -4.69 | Deleterious | 0.989 | Probably Damaging | 0.737 | Possibly Damaging | 5.84 | Benign | 0.01 | Affected | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||
| c.647A>G | Q216R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q216R is not reported in ClinVar and has no gnomAD entry. Prediction tools that call the variant benign include FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM, while pathogenic calls come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as Benign. Overall, the predictions are split, with a slight edge toward pathogenicity. The variant is therefore most likely pathogenic based on the current computational evidence, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -10.149 | Likely Pathogenic | 0.821 | Likely Pathogenic | Ambiguous | 0.513 | Likely Pathogenic | 0.1972 | 0.2748 | -0.42 | Likely Benign | 0.0 | 0.09 | Likely Benign | -0.17 | Likely Benign | -0.01 | Likely Benign | -2.70 | Deleterious | 0.963 | Probably Damaging | 0.549 | Possibly Damaging | 6.00 | Benign | 0.19 | Tolerated | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||
| c.647A>T | Q216L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216L is not reported in ClinVar (ClinVar ID: None) and has no entry in gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, and FATHMM, while those that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain (treated as unavailable), SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts benign. Overall, the majority of tools (8 pathogenic vs. 5 benign) and the consensus high‑accuracy prediction lean toward pathogenicity. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -11.303 | Likely Pathogenic | 0.886 | Likely Pathogenic | Ambiguous | 0.797 | Likely Pathogenic | 0.1036 | 0.6410 | -0.17 | Likely Benign | 0.3 | 0.28 | Likely Benign | 0.06 | Likely Benign | 0.30 | Likely Benign | -5.58 | Deleterious | 0.963 | Probably Damaging | 0.452 | Possibly Damaging | 5.87 | Benign | 0.01 | Affected | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||
| c.648G>C | Q216H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas those that predict a pathogenic impact are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the balance of evidence favors a pathogenic classification; this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -10.532 | Likely Pathogenic | 0.951 | Likely Pathogenic | Ambiguous | 0.638 | Likely Pathogenic | 0.1909 | 0.4660 | 0.29 | Likely Benign | 0.0 | 0.30 | Likely Benign | 0.30 | Likely Benign | 0.50 | Likely Benign | -3.84 | Deleterious | 0.989 | Probably Damaging | 0.809 | Possibly Damaging | 5.85 | Benign | 0.01 | Affected | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||
| c.648G>T | Q216H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas a larger group predicts pathogenicity: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -10.532 | Likely Pathogenic | 0.951 | Likely Pathogenic | Ambiguous | 0.638 | Likely Pathogenic | 0.1909 | 0.4660 | 0.29 | Likely Benign | 0.0 | 0.30 | Likely Benign | 0.30 | Likely Benign | 0.50 | Likely Benign | -3.84 | Deleterious | 0.989 | Probably Damaging | 0.809 | Possibly Damaging | 5.85 | Benign | 0.01 | Affected | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||
| c.649G>A | E217K 2D 3DClick to see structure in 3D Viewer AISynGAP1 E217K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Computational predictions cluster into two groups: benign calls from premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM; pathogenic calls from REVEL, Rosetta, polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized. Three tools give uncertain results: FoldX, Foldetta, and ESM1b. High‑accuracy methods give conflicting outcomes: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields benign; Foldetta remains uncertain. Because the majority of standard tools are split evenly and the high‑accuracy predictions are discordant, the evidence does not decisively support either outcome. The variant is therefore most likely pathogenic based on the preponderance of pathogenic predictions, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.278302 | Structured | 0.404912 | Uncertain | 0.823 | 0.284 | 0.000 | -7.169 | In-Between | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.563 | Likely Pathogenic | 0.2742 | 0.8216 | 0.52 | Ambiguous | 0.5 | 2.14 | Destabilizing | 1.33 | Ambiguous | 0.45 | Likely Benign | -2.38 | Neutral | 0.900 | Possibly Damaging | 0.307 | Benign | 5.95 | Benign | 0.13 | Tolerated | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||
| c.649G>C | E217Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E217Q is reported in gnomAD (ID 6‑33435291‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. With six benign versus three pathogenic calls and a benign consensus from the high‑accuracy panel, the variant is most likely benign. This conclusion does not contradict ClinVar, which contains no classification for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.278302 | Structured | 0.404912 | Uncertain | 0.823 | 0.284 | 0.000 | 6-33435291-G-C | 1 | 6.20e-7 | -6.810 | Likely Benign | 0.949 | Likely Pathogenic | Ambiguous | 0.459 | Likely Benign | 0.1474 | 0.8473 | 0.25 | Likely Benign | 0.2 | 1.61 | Ambiguous | 0.93 | Ambiguous | 0.67 | Ambiguous | -1.89 | Neutral | 0.900 | Possibly Damaging | 0.461 | Possibly Damaging | 5.83 | Benign | 0.14 | Tolerated | 3.41 | 13 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||
| c.650A>C | E217A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E217A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, polyPhen‑2 HumVar, SIFT, and FATHMM, whereas those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized. Four tools (FoldX, Rosetta, Foldetta, and ESM1b) returned uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; Foldetta’s stability prediction is uncertain. Overall, the majority of available predictions support a pathogenic impact for E217A. This conclusion is not contradicted by ClinVar status, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.278302 | Structured | 0.404912 | Uncertain | 0.823 | 0.284 | 0.000 | -7.294 | In-Between | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.619 | Likely Pathogenic | 0.4442 | 0.8090 | 0.67 | Ambiguous | 0.5 | 0.61 | Ambiguous | 0.64 | Ambiguous | 0.50 | Likely Benign | -3.88 | Deleterious | 0.900 | Possibly Damaging | 0.307 | Benign | 5.81 | Benign | 0.12 | Tolerated | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||
| c.650A>G | E217G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E217G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumVar, SIFT, and FATHMM, while those that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized predicts a pathogenic impact, the SGM‑Consensus also indicates a likely pathogenic outcome, and Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence points to a pathogenic effect for E217G, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.278302 | Structured | 0.404912 | Uncertain | 0.823 | 0.284 | 0.000 | -8.076 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.684 | Likely Pathogenic | 0.3278 | 0.6941 | 1.13 | Ambiguous | 0.4 | 1.87 | Ambiguous | 1.50 | Ambiguous | 0.59 | Ambiguous | -3.93 | Deleterious | 0.816 | Possibly Damaging | 0.307 | Benign | 5.82 | Benign | 0.06 | Tolerated | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.650A>T | E217V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E217V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include Rosetta, FATHMM, and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). FoldX and Foldetta give uncertain results. 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 preponderance of evidence points to a pathogenic effect for E217V. This conclusion is not contradicted by ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.278302 | Structured | 0.404912 | Uncertain | 0.823 | 0.284 | 0.000 | -10.194 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.723 | Likely Pathogenic | 0.0919 | 0.8340 | 0.76 | Ambiguous | 0.6 | 0.39 | Likely Benign | 0.58 | Ambiguous | 0.23 | Likely Benign | -4.84 | Deleterious | 0.900 | Possibly Damaging | 0.461 | Possibly Damaging | 5.79 | Benign | 0.03 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.651G>C | E217D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E217D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all classify the change as benign. The only inconclusive result comes from AlphaMissense‑Default, which is listed as uncertain. High‑accuracy assessments corroborate this benign profile: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a benign outcome. No pathogenic predictions are present. Therefore, based on the available computational evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.278302 | Structured | 0.404912 | Uncertain | 0.823 | 0.284 | 0.000 | -2.268 | Likely Benign | 0.453 | Ambiguous | Likely Benign | 0.276 | Likely Benign | 0.2066 | 0.5976 | 0.24 | Likely Benign | 0.3 | -0.07 | Likely Benign | 0.09 | Likely Benign | -0.34 | Likely Benign | 0.66 | Neutral | 0.014 | Benign | 0.007 | Benign | 5.85 | Benign | 0.85 | Tolerated | 3.41 | 13 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||
| c.651G>T | E217D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E217D is present in gnomAD (6‑33435293‑G‑T) but has no ClinVar entry. Functional prediction tools uniformly classify it as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and Foldetta all report benign or benign‑like outcomes. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized indicates benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports benign. AlphaMissense‑Default remains uncertain and is treated as unavailable. Overall, the evidence strongly supports a benign effect for E217D, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.278302 | Structured | 0.404912 | Uncertain | 0.823 | 0.284 | 0.000 | 6-33435293-G-T | 1 | 6.20e-7 | -2.268 | Likely Benign | 0.453 | Ambiguous | Likely Benign | 0.276 | Likely Benign | 0.2066 | 0.5976 | 0.24 | Likely Benign | 0.3 | -0.07 | Likely Benign | 0.09 | Likely Benign | -0.34 | Likely Benign | 0.66 | Neutral | 0.014 | Benign | 0.007 | Benign | 5.85 | Benign | 0.85 | Tolerated | 3.41 | 13 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||
| c.652T>A | F218I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218I is reported in gnomAD (variant ID 6‑33435294‑T‑A) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while benign predictions are limited to polyPhen‑2 (HumVar), SIFT, and FATHMM. High‑accuracy assessments reinforce the pathogenic view: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.281712 | Structured | 0.408725 | Uncertain | 0.848 | 0.272 | 0.000 | 6-33435294-T-A | 1 | 6.20e-7 | -12.211 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.612 | Likely Pathogenic | 0.2106 | 0.2459 | 4.69 | Destabilizing | 0.2 | 5.93 | Destabilizing | 5.31 | Destabilizing | 1.18 | Destabilizing | -3.81 | Deleterious | 0.510 | Possibly Damaging | 0.066 | Benign | 5.85 | Benign | 0.08 | Tolerated | 3.41 | 13 | 0 | 1 | 1.7 | -34.02 | ||||||||||||||||||||
| c.652T>C | F218L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect comprise REVEL, Rosetta, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). FoldX and Foldetta provide uncertain results and are therefore considered unavailable for interpretation. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact for F218L, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.281712 | Structured | 0.408725 | Uncertain | 0.848 | 0.272 | 0.000 | -8.861 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.546 | Likely Pathogenic | 0.2331 | 0.3241 | 0.96 | Ambiguous | 0.4 | 2.36 | Destabilizing | 1.66 | Ambiguous | 1.08 | Destabilizing | -3.80 | Deleterious | 0.158 | Benign | 0.025 | Benign | 5.90 | Benign | 0.15 | Tolerated | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.652T>G | F218V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; pathogenic predictions arise from REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled “Likely Pathogenic.” High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus agrees on a likely pathogenic outcome, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenicity. No predictions or stability results are missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion aligns with the absence of a ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.281712 | Structured | 0.408725 | Uncertain | 0.848 | 0.272 | 0.000 | -10.081 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.691 | Likely Pathogenic | 0.2173 | 0.2258 | 4.18 | Destabilizing | 0.2 | 6.35 | Destabilizing | 5.27 | Destabilizing | 1.15 | Destabilizing | -4.14 | Deleterious | 0.300 | Benign | 0.066 | Benign | 5.81 | Benign | 0.08 | Tolerated | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||
| c.653T>A | F218Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). All available in silico predictors classify the substitution as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a benign effect. The high‑accuracy folding‑stability tool Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a benign impact. No tool predicts pathogenicity, and no contradictory evidence exists in ClinVar. **Based on the consensus of all predictions, the variant is most likely benign, and this assessment does not conflict with ClinVar status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.281712 | Structured | 0.408725 | Uncertain | 0.848 | 0.272 | 0.000 | -3.596 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.229 | Likely Benign | 0.1532 | 0.2725 | 0.26 | Likely Benign | 0.1 | -0.40 | Likely Benign | -0.07 | Likely Benign | -0.44 | Likely Benign | 0.63 | Neutral | 0.001 | Benign | 0.002 | Benign | 5.95 | Benign | 0.52 | Tolerated | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||
| c.653T>C | F218S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218S has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumVar, SIFT, and FATHMM, whereas the remaining tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.281712 | Structured | 0.408725 | Uncertain | 0.848 | 0.272 | 0.000 | -8.882 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.731 | Likely Pathogenic | 0.3802 | 0.0454 | 2.35 | Destabilizing | 0.1 | 3.00 | Destabilizing | 2.68 | Destabilizing | 1.22 | Destabilizing | -4.62 | Deleterious | 0.808 | Possibly Damaging | 0.225 | Benign | 5.80 | Benign | 0.07 | Tolerated | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||
| c.653T>G | F218C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218C is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33435295‑T‑G). Prediction tools that agree on a benign effect include only FATHMM, whereas the majority of tools (REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact. Results that are uncertain or unavailable are FoldX, ESM1b, AlphaMissense‑Optimized, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic prediction (2 pathogenic vs. 1 benign votes); and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for F218C, 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. | PH | 0.281712 | Structured | 0.408725 | Uncertain | 0.848 | 0.272 | 0.000 | 6-33435295-T-G | 1 | 6.20e-7 | -7.234 | In-Between | 0.948 | Likely Pathogenic | Ambiguous | 0.744 | Likely Pathogenic | 0.2330 | 0.1321 | 1.49 | Ambiguous | 0.1 | 2.20 | Destabilizing | 1.85 | Ambiguous | 1.02 | Destabilizing | -4.92 | Deleterious | 0.994 | Probably Damaging | 0.667 | Possibly Damaging | 5.78 | Benign | 0.03 | Affected | 3.41 | 13 | -2 | -4 | -0.3 | -44.04 | |||||||||||||||||||||
| c.654C>A | F218L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218L is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that agree on a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), Rosetta, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Foldetta are inconclusive and are treated as unavailable. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts Likely Pathogenic; Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact. There is no ClinVar annotation to contradict this assessment, so the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.281712 | Structured | 0.408725 | Uncertain | 0.848 | 0.272 | 0.000 | -8.861 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.477 | Likely Benign | 0.2331 | 0.3241 | 0.96 | Ambiguous | 0.4 | 2.36 | Destabilizing | 1.66 | Ambiguous | 1.08 | Destabilizing | -3.80 | Deleterious | 0.158 | Benign | 0.025 | Benign | 5.90 | Benign | 0.15 | Tolerated | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.654C>G | F218L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218L is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that agree on a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), Rosetta, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Foldetta are inconclusive and are treated as unavailable. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts Likely Pathogenic; Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact. There is no ClinVar annotation to contradict this assessment, so the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.281712 | Structured | 0.408725 | Uncertain | 0.848 | 0.272 | 0.000 | -8.861 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.477 | Likely Benign | 0.2331 | 0.3241 | 0.96 | Ambiguous | 0.4 | 2.36 | Destabilizing | 1.66 | Ambiguous | 1.08 | Destabilizing | -3.80 | Deleterious | 0.158 | Benign | 0.025 | Benign | 5.90 | Benign | 0.15 | Tolerated | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.655T>A | C219S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign calls come from FoldX, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions are made by SGM‑Consensus (Likely Pathogenic), REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. With the majority of evidence pointing to a damaging effect and no ClinVar annotation to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | -12.962 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.892 | Likely Pathogenic | 0.3568 | 0.1454 | 0.09 | Likely Benign | 0.4 | 1.53 | Ambiguous | 0.81 | Ambiguous | 1.56 | Destabilizing | -8.35 | Deleterious | 0.900 | Possibly Damaging | 0.380 | Benign | 5.95 | Benign | 0.04 | Affected | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||
| c.655T>C | C219R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219R is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, while the remaining 13 tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts Pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | -15.727 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.904 | Likely Pathogenic | 0.1381 | 0.1837 | 3.00 | Destabilizing | 1.5 | 2.20 | Destabilizing | 2.60 | Destabilizing | 1.33 | Destabilizing | -9.90 | Deleterious | 0.969 | Probably Damaging | 0.680 | Possibly Damaging | 5.80 | Benign | 0.00 | Affected | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||
| c.655T>G | C219G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining 11 tools—including REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized returns a pathogenic score, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is inconclusive. Taken together, the overwhelming majority of evidence points to a pathogenic effect for C219G. This conclusion aligns with the absence of a ClinVar entry and does not contradict any existing clinical annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | -15.072 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.900 | Likely Pathogenic | 0.2159 | 0.2169 | 0.72 | Ambiguous | 0.3 | 1.98 | Ambiguous | 1.35 | Ambiguous | 1.18 | Destabilizing | -10.09 | Deleterious | 0.900 | Possibly Damaging | 0.461 | Possibly Damaging | 5.83 | Benign | 0.02 | Affected | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||
| c.656G>A | C219Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports pathogenicity; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. 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, as none is available. 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 | -14.797 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.812 | Likely Pathogenic | 0.0772 | 0.3285 | 8.98 | Destabilizing | 2.0 | 2.84 | Destabilizing | 5.91 | Destabilizing | 0.55 | Ambiguous | -9.09 | Deleterious | 0.990 | Probably Damaging | 0.758 | Possibly Damaging | 5.81 | Benign | 0.00 | Affected | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||
| c.656G>C | C219S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219S is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, polyPhen‑2 HumVar, and FATHMM, whereas the majority of tools predict it to be pathogenic: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenicity, and Foldetta’s stability analysis is inconclusive (treated as unavailable). Taken together, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic impact for C219S. 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. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | -12.962 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.817 | Likely Pathogenic | 0.3568 | 0.1454 | 0.09 | Likely Benign | 0.4 | 1.53 | Ambiguous | 0.81 | Ambiguous | 1.56 | Destabilizing | -8.35 | Deleterious | 0.900 | Possibly Damaging | 0.380 | Benign | 5.95 | Benign | 0.04 | Affected | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||
| c.656G>T | C219F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219F 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 premPS and FATHMM, while the remaining 13 tools—including SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized reports 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 outputs, also predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among the majority of tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | -14.322 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.814 | Likely Pathogenic | 0.0959 | 0.3804 | 7.31 | Destabilizing | 1.9 | 2.45 | Destabilizing | 4.88 | Destabilizing | 0.47 | Likely Benign | -9.18 | Deleterious | 0.940 | Possibly Damaging | 0.505 | Possibly Damaging | 5.82 | Benign | 0.00 | Affected | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||
| 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 | 0.706 | Likely Pathogenic | 0.1131 | 0.3285 | 10.10 | Destabilizing | 3.6 | 1.20 | Ambiguous | 5.65 | Destabilizing | 0.52 | Ambiguous | -9.23 | Deleterious | 0.997 | Probably Damaging | 0.808 | Possibly Damaging | 5.77 | Benign | 0.00 | Affected | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||
| c.658T>A | F220I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220I 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 polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic effect. The SGM‑Consensus result is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yielding 3 pathogenic versus 1 benign calls, thus supporting a pathogenic classification. High‑accuracy tools specifically report pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -12.041 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.921 | Likely Pathogenic | 0.2292 | 0.3127 | 3.11 | Destabilizing | 0.1 | 2.35 | Destabilizing | 2.73 | Destabilizing | 1.03 | Destabilizing | -4.98 | Deleterious | 0.300 | Benign | 0.098 | Benign | 4.06 | Benign | 0.01 | Affected | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||
| c.658T>C | F220L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220L 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 polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—indicate a pathogenic effect. The SGM‑Consensus result is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN (3 pathogenic, 1 benign), thus supporting a pathogenic classification. High‑accuracy assessments further corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -9.601 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.850 | Likely Pathogenic | 0.2589 | 0.4108 | 2.08 | Destabilizing | 0.1 | 2.24 | Destabilizing | 2.16 | Destabilizing | 1.33 | Destabilizing | -4.95 | Deleterious | 0.003 | Benign | 0.005 | Benign | 4.24 | Benign | 0.02 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.658T>G | F220V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220V is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic effect. 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, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -11.599 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.911 | Likely Pathogenic | 0.2351 | 0.3315 | 3.83 | Destabilizing | 0.1 | 4.11 | Destabilizing | 3.97 | Destabilizing | 1.56 | Destabilizing | -5.81 | Deleterious | 0.075 | Benign | 0.015 | Benign | 4.04 | Benign | 0.01 | Affected | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||
| c.659T>A | F220Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, FATHMM, and polyPhen‑2 HumVar. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is classified as pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain and therefore not considered evidence. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that F220Y 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 | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -12.541 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.879 | Likely Pathogenic | 0.1479 | 0.2661 | 2.25 | Destabilizing | 0.1 | 0.35 | Likely Benign | 1.30 | Ambiguous | 1.14 | Destabilizing | -2.54 | Deleterious | 0.928 | Possibly Damaging | 0.395 | Benign | 4.07 | Benign | 0.00 | Affected | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||
| c.659T>C | F220S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: all available scores (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, AlphaMissense‑Default) indicate pathogenicity, while only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also labels it 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 any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -15.258 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.954 | Likely Pathogenic | 0.3813 | 0.1143 | 4.06 | Destabilizing | 0.1 | 4.67 | Destabilizing | 4.37 | Destabilizing | 1.44 | Destabilizing | -6.67 | Deleterious | 0.928 | Possibly Damaging | 0.477 | Possibly Damaging | 4.03 | Benign | 0.01 | Affected | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||
| c.659T>G | F220C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220C is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -12.948 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.941 | Likely Pathogenic | 0.2264 | 0.2012 | 3.67 | Destabilizing | 0.0 | 5.03 | Destabilizing | 4.35 | Destabilizing | 2.22 | Destabilizing | -6.72 | Deleterious | 0.994 | Probably Damaging | 0.753 | Possibly Damaging | 4.03 | Benign | 0.00 | Affected | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||
| c.660T>A | F220L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220L 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 polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—indicate a pathogenic effect. The SGM‑Consensus result is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN (3 pathogenic, 1 benign), thus supporting a pathogenic classification. High‑accuracy assessments further corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -9.601 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.752 | Likely Pathogenic | 0.2589 | 0.4108 | 2.08 | Destabilizing | 0.1 | 2.24 | Destabilizing | 2.16 | Destabilizing | 1.33 | Destabilizing | -4.95 | Deleterious | 0.003 | Benign | 0.005 | Benign | 4.24 | Benign | 0.02 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.660T>G | F220L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220L 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 polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—indicate a pathogenic effect. The SGM‑Consensus result is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN (3 pathogenic, 1 benign), thus supporting a pathogenic classification. High‑accuracy assessments further corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -9.601 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.752 | Likely Pathogenic | 0.2589 | 0.4108 | 2.08 | Destabilizing | 0.1 | 2.24 | Destabilizing | 2.16 | Destabilizing | 1.33 | Destabilizing | -4.95 | Deleterious | 0.003 | Benign | 0.005 | Benign | 4.24 | Benign | 0.02 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.661G>A | E221K 2D AIThe SynGAP1 E221K 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 Rosetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. FoldX and Foldetta give uncertain results. High‑accuracy methods show AlphaMissense‑Optimized as pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts pathogenic (3 pathogenic vs 1 benign). Foldetta remains uncertain. Overall, the majority of reliable predictors indicate a pathogenic 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 Pathogenic | PH | 0.127496 | Structured | 0.413334 | Uncertain | 0.891 | 0.283 | 0.000 | -12.331 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.815 | Likely Pathogenic | 0.2491 | 0.8002 | -1.01 | Ambiguous | 0.4 | -0.18 | Likely Benign | -0.60 | Ambiguous | 0.19 | Likely Benign | -2.92 | Deleterious | 0.131 | Benign | 0.058 | Benign | 5.92 | Benign | 0.02 | Affected | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||
| c.661G>C | E221Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E221Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Two tools predict a pathogenic outcome: ESM1b and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs two benign), and Foldetta predicts a benign effect. Overall, the majority of evidence (10 benign vs 2 pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.127496 | Structured | 0.413334 | Uncertain | 0.891 | 0.283 | 0.000 | -8.243 | Likely Pathogenic | 0.825 | Likely Pathogenic | Ambiguous | 0.455 | Likely Benign | 0.1207 | 0.7690 | -0.26 | Likely Benign | 0.1 | -0.33 | Likely Benign | -0.30 | Likely Benign | 0.12 | Likely Benign | -1.64 | Neutral | 0.028 | Benign | 0.015 | Benign | 6.13 | Benign | 0.23 | Tolerated | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||
| c.662A>C | E221A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E221A missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as benign. Overall, the predictions are split, but the two high‑confidence pathogenic calls outweigh the single high‑confidence benign call, suggesting the variant is most likely pathogenic. This assessment 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 | PH | 0.127496 | Structured | 0.413334 | Uncertain | 0.891 | 0.283 | 0.000 | -12.906 | Likely Pathogenic | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.796 | Likely Pathogenic | 0.3486 | 0.7335 | 0.31 | Likely Benign | 0.0 | -0.11 | Likely Benign | 0.10 | Likely Benign | 0.52 | Ambiguous | -4.70 | Deleterious | 0.231 | Benign | 0.081 | Benign | 5.82 | Benign | 0.01 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.662A>G | E221G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E221G missense variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumVar and FATHMM, while the majority of other in silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) indicate a pathogenic impact; FoldX, Rosetta, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Based on the collective evidence, the variant is most likely pathogenic, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.413334 | Uncertain | 0.891 | 0.283 | 0.000 | Uncertain | 1 | -12.221 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.863 | Likely Pathogenic | 0.2611 | 0.6370 | 1.40 | Ambiguous | 0.1 | 1.74 | Ambiguous | 1.57 | Ambiguous | 0.71 | Ambiguous | -5.56 | Deleterious | 0.596 | Possibly Damaging | 0.201 | Benign | 5.79 | Benign | 0.00 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||
| c.662A>T | E221V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E221V missense variant is reported in ClinVar as Pathogenic (ClinVar ID 2413181.0) and is not found in gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Benign predictions are limited to premPS, polyPhen‑2 HumVar, and FATHMM. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments reinforce the pathogenic interpretation: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus also indicates Likely Pathogenic, while Foldetta remains Uncertain. Taken together, the preponderance of evidence supports a pathogenic effect for E221V, and this conclusion aligns with the ClinVar classification, showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.413334 | Uncertain | 0.891 | 0.283 | 0.000 | Likely Pathogenic | 1 | -14.954 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.875 | Likely Pathogenic | 0.0806 | 0.8138 | -0.66 | Ambiguous | 0.2 | -0.89 | Ambiguous | -0.78 | Ambiguous | 0.49 | Likely Benign | -5.54 | Deleterious | 0.596 | Possibly Damaging | 0.203 | Benign | 5.86 | Benign | 0.00 | Affected | 3.41 | 13 | -2 | -2 | 7.7 | -29.98 | 234.5 | 50.6 | 0.0 | 0.0 | -0.4 | 0.2 | X | Uncertain | The introduced residue Val221 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Unlike the carboxylate group of Glu221, Val221 cannot form hydrogen bonds with Thr223 or a salt bridge with the amino group of the Lys207 side chain. Despite this, the WT simulations containing Glu221 do not show significant differences compared to the variant simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||||||
| c.663G>C | E221D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E221D 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 PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that agree on a pathogenic effect are REVEL, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs 2 benign), and Foldetta remains uncertain. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.127496 | Structured | 0.413334 | Uncertain | 0.891 | 0.283 | 0.000 | -12.237 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.750 | Likely Pathogenic | 0.1755 | 0.5228 | 1.59 | Ambiguous | 0.1 | 1.07 | Ambiguous | 1.33 | Ambiguous | 0.84 | Ambiguous | -2.43 | Neutral | 0.421 | Benign | 0.107 | Benign | 5.80 | Benign | 0.02 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||
| c.663G>T | E221D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E221D 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 PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that agree on a pathogenic effect are REVEL, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain results. 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 is uncertain. Overall, the majority of available predictions lean toward pathogenicity, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.127496 | Structured | 0.413334 | Uncertain | 0.891 | 0.283 | 0.000 | -12.237 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.750 | Likely Pathogenic | 0.1755 | 0.5228 | 1.59 | Ambiguous | 0.1 | 1.07 | Ambiguous | 1.33 | Ambiguous | 0.84 | Ambiguous | -2.43 | Neutral | 0.421 | Benign | 0.107 | Benign | 5.80 | Benign | 0.02 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||
| c.664G>A | V222I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 V222I missense change is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The high‑accuracy consensus methods give a benign signal: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, while Foldetta’s stability assessment is uncertain. Overall, the majority of evidence points to a benign effect. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.116183 | Structured | 0.402706 | Uncertain | 0.885 | 0.310 | 0.125 | -6.347 | Likely Benign | 0.604 | Likely Pathogenic | Likely Benign | 0.612 | Likely Pathogenic | 0.0637 | 0.3574 | 0.21 | Likely Benign | 0.2 | 1.45 | Ambiguous | 0.83 | Ambiguous | 0.09 | Likely Benign | -0.87 | Neutral | 0.984 | Probably Damaging | 0.956 | Probably Damaging | 5.77 | Benign | 0.08 | Tolerated | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||
| c.664G>C | V222L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V222L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, FATHMM, and Foldetta, whereas those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (premPS and ESM1b) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic)—also predicts pathogenic; Foldetta, a protein‑folding stability method, predicts benign. Overall, the majority of evidence (seven pathogenic vs. four benign) points to a pathogenic effect. The variant’s predicted pathogenicity is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.116183 | Structured | 0.402706 | Uncertain | 0.885 | 0.310 | 0.125 | -7.626 | In-Between | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.617 | Likely Pathogenic | 0.0863 | 0.4349 | 0.00 | Likely Benign | 0.3 | 0.06 | Likely Benign | 0.03 | Likely Benign | 0.60 | Ambiguous | -2.59 | Deleterious | 0.984 | Probably Damaging | 0.956 | Probably Damaging | 5.49 | Benign | 0.05 | Affected | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||
| c.664G>T | V222L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V222L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, FATHMM, and Foldetta, whereas those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (premPS and ESM1b) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic)—also predicts pathogenic; Foldetta, a protein‑folding stability method, predicts benign. Overall, the majority of evidence (seven pathogenic vs. four benign) points to a pathogenic effect. The variant’s predicted pathogenicity is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.116183 | Structured | 0.402706 | Uncertain | 0.885 | 0.310 | 0.125 | -7.626 | In-Between | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.617 | Likely Pathogenic | 0.0863 | 0.4349 | 0.00 | Likely Benign | 0.3 | 0.06 | Likely Benign | 0.03 | Likely Benign | 0.60 | Ambiguous | -2.59 | Deleterious | 0.984 | Probably Damaging | 0.956 | Probably Damaging | 5.49 | Benign | 0.05 | Affected | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||
| c.665T>A | V222E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V222E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus 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 conclusion is consistent with the lack of ClinVar reporting (i.e., no contradictory evidence). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.116183 | Structured | 0.402706 | Uncertain | 0.885 | 0.310 | 0.125 | -18.017 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.960 | Likely Pathogenic | 0.0833 | 0.1495 | 4.04 | Destabilizing | 0.2 | 3.46 | Destabilizing | 3.75 | Destabilizing | 1.64 | Destabilizing | -5.20 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 5.20 | Benign | 0.00 | Affected | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||
| c.665T>C | V222A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V222A missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity largely agree: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. Only FATHMM predicts a benign outcome. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.116183 | Structured | 0.402706 | Uncertain | 0.885 | 0.310 | 0.125 | -10.248 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.894 | Likely Pathogenic | 0.2386 | 0.2081 | 2.89 | Destabilizing | 0.3 | 2.98 | Destabilizing | 2.94 | Destabilizing | 2.06 | Destabilizing | -3.50 | Deleterious | 0.984 | Probably Damaging | 0.956 | Probably Damaging | 5.26 | Benign | 0.04 | Affected | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||
| c.665T>G | V222G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V222G resides in the PH domain. ClinVar has no entry for this variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining eleven tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) all predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Thus, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict the ClinVar status, which currently contains no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.116183 | Structured | 0.402706 | Uncertain | 0.885 | 0.310 | 0.125 | -14.857 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.962 | Likely Pathogenic | 0.1678 | 0.1996 | 4.54 | Destabilizing | 0.4 | 5.25 | Destabilizing | 4.90 | Destabilizing | 2.05 | Destabilizing | -6.05 | Deleterious | 0.987 | Probably Damaging | 0.998 | Probably Damaging | 5.21 | Benign | 0.00 | Affected | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||
| c.667A>C | T223P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T223P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as Uncertain. No other high‑accuracy tools provide a definitive prediction. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.070400 | Structured | 0.382605 | Uncertain | 0.867 | 0.316 | 0.125 | -13.707 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 0.898 | Likely Pathogenic | 0.1464 | 0.3728 | 0.42 | Likely Benign | 0.3 | 3.45 | Destabilizing | 1.94 | Ambiguous | 0.67 | Ambiguous | -4.54 | Deleterious | 0.838 | Possibly Damaging | 0.367 | Benign | 5.72 | Benign | 0.01 | Affected | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||
| c.667A>G | T223A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T223A is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33435518‑A‑G). Functional prediction tools that agree on a benign effect include FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL and PROVEAN. Predictions that are inconclusive are Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also resolves to benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.070400 | Structured | 0.382605 | Uncertain | 0.867 | 0.316 | 0.125 | Uncertain | 1 | 6-33435518-A-G | 3 | 1.86e-6 | -7.076 | In-Between | 0.316 | Likely Benign | Likely Benign | 0.574 | Likely Pathogenic | 0.2982 | 0.3031 | 0.30 | Likely Benign | 0.1 | 0.77 | Ambiguous | 0.54 | Ambiguous | 0.74 | Ambiguous | -3.36 | Deleterious | 0.231 | Benign | 0.058 | Benign | 5.74 | Benign | 0.09 | Tolerated | 3.41 | 13 | 1 | 0 | 2.5 | -30.03 | 186.4 | 44.0 | 0.0 | 0.0 | 0.0 | 0.0 | X | X | Uncertain | The introduced residue Ala223 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Unlike the hydroxyl group of the Thr223 side chain in the WT protein, the methyl side chain of Ala223 cannot form hydrogen bonds with nearby residues Thr228 and Lys207. Without these hydrogen-bonding interactions at the β sheet surface, the secondary structure element becomes unstable and partially unfolds in the variant simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||
| c.667A>T | T223S 2D 3DClick to see structure in 3D Viewer AISynGAP1 T223S is listed in ClinVar as a variant of uncertain significance and is present in the gnomAD database (ID 6‑33435518‑A‑T). Functional prediction tools that reach consensus classify the variant as benign: FoldX, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict pathogenicity include REVEL, PROVEAN, and SIFT. Predictions that are inconclusive or uncertain are Rosetta, premPS, AlphaMissense‑Default, and ESM1b. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, Foldetta is benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 1‑to‑1 split between benign and pathogenic calls. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.070400 | Structured | 0.382605 | Uncertain | 0.867 | 0.316 | 0.125 | Conflicting | 2 | 6-33435518-A-T | 3 | 1.86e-6 | -7.714 | In-Between | 0.410 | Ambiguous | Likely Benign | 0.535 | Likely Pathogenic | 0.2388 | 0.2972 | 0.26 | Likely Benign | 0.1 | 0.50 | Ambiguous | 0.38 | Likely Benign | 0.62 | Ambiguous | -2.86 | Deleterious | 0.421 | Benign | 0.058 | Benign | 5.80 | Benign | 0.02 | Affected | 3.41 | 13 | 1 | 1 | -0.1 | -14.03 | 200.7 | 17.3 | -0.2 | 0.2 | 0.0 | 0.0 | X | Uncertain | The introduced residue Ser223 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Its hydroxyl group forms hydrogen bonds with nearby residues Thr228 and Lys207 in the variant simulations, similar to the hydroxyl group of Thr223 in the WT simulations. These hydrogen-bonding interactions at the β sheet surface contribute to the stability of the secondary structure element and may prevent it from unfolding. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||||
| c.668C>A | T223K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T223K missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The remaining tools, premPS and AlphaMissense‑Optimized, are uncertain and therefore treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the balance of evidence leans toward a benign impact, with no contradiction to the ClinVar status (which is currently unreported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.070400 | Structured | 0.382605 | Uncertain | 0.867 | 0.316 | 0.125 | -12.084 | Likely Pathogenic | 0.853 | Likely Pathogenic | Ambiguous | 0.810 | Likely Pathogenic | 0.0793 | 0.2462 | -0.30 | Likely Benign | 0.1 | 0.42 | Likely Benign | 0.06 | Likely Benign | 0.93 | Ambiguous | -4.60 | Deleterious | 0.267 | Benign | 0.086 | Benign | 5.78 | Benign | 0.01 | Affected | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||
| c.668C>G | T223R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T223R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a mixed profile: benign calls come from FoldX, Rosetta, Foldetta, polyPhen‑2 HumVar, SIFT, and FATHMM, while pathogenic calls arise from REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Two tools report uncertainty: premPS and AlphaMissense‑Optimized. High‑accuracy consensus (SGM Consensus) favors pathogenicity (3/4 votes pathogenic), whereas Foldetta predicts benign stability. Because the majority of individual predictors lean benign and the high‑accuracy consensus is split, the overall assessment remains inconclusive. The variant is most likely benign, but the presence of several pathogenic predictions and the SGM Consensus result indicates that pathogenicity cannot be ruled out. This conclusion does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.070400 | Structured | 0.382605 | Uncertain | 0.867 | 0.316 | 0.125 | -12.079 | Likely Pathogenic | 0.794 | Likely Pathogenic | Ambiguous | 0.827 | Likely Pathogenic | 0.0708 | 0.2407 | -0.36 | Likely Benign | 0.1 | -0.27 | Likely Benign | -0.32 | Likely Benign | 0.75 | Ambiguous | -4.62 | Deleterious | 0.561 | Possibly Damaging | 0.178 | Benign | 5.73 | Benign | 0.06 | Tolerated | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||
| c.668C>T | T223I 2D AIThe SynGAP1 T223I variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that clearly indicate benign impact include FoldX, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict pathogenicity are REVEL and PROVEAN. Predictions that are inconclusive (Rosetta, Foldetta, AlphaMissense‑Default) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta remains uncertain. Overall, the majority of definitive predictions support a benign effect. Thus, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.070400 | Structured | 0.382605 | Uncertain | 0.867 | 0.316 | 0.125 | -6.543 | Likely Benign | 0.356 | Ambiguous | Likely Benign | 0.640 | Likely Pathogenic | 0.0569 | 0.5393 | -0.24 | Likely Benign | 0.8 | -0.99 | Ambiguous | -0.62 | Ambiguous | 0.30 | Likely Benign | -4.09 | Deleterious | 0.010 | Benign | 0.005 | Benign | 5.93 | Benign | 0.07 | Tolerated | 0 | -1 | 5.2 | 12.05 | ||||||||||||||||||||||||||
| c.670A>C | T224P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T224P is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are SIFT and FATHMM, while the remaining tools (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b) all predict a pathogenic impact; premPS is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | -11.812 | Likely Pathogenic | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.765 | Likely Pathogenic | 0.2355 | 0.6063 | 3.63 | Destabilizing | 0.4 | 2.68 | Destabilizing | 3.16 | Destabilizing | 0.57 | Ambiguous | -3.65 | Deleterious | 0.971 | Probably Damaging | 0.543 | Possibly Damaging | 5.56 | Benign | 0.23 | Tolerated | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||
| c.670A>G | T224A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T224A is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33435521‑A‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN and AlphaMissense‑Default. The remaining tools (Rosetta, Foldetta, premPS, ESM1b) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | Uncertain | 3 | 6-33435521-A-G | 2 | 1.24e-6 | -7.379 | In-Between | 0.651 | Likely Pathogenic | Likely Benign | 0.464 | Likely Benign | 0.4253 | 0.5053 | 0.33 | Likely Benign | 0.1 | 1.05 | Ambiguous | 0.69 | Ambiguous | 0.91 | Ambiguous | -2.96 | Deleterious | 0.243 | Benign | 0.079 | Benign | 5.57 | Benign | 0.57 | Tolerated | 3.41 | 13 | 1 | 0 | 2.5 | -30.03 | 169.0 | 41.4 | -0.5 | 1.1 | -0.4 | 0.0 | X | X | Uncertain | The introduced residue Ala224 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Unlike the hydroxyl group of the Thr224 side chain in the WT model, the methyl side chain of Ala224 cannot form hydrogen bonds with nearby residues Ser204, Ser226, and Gly227. Without these hydrogen-bonding interactions at the β sheet surface, the secondary structure element becomes unstable and unfolds during the variant simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||
| c.670A>T | T224S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T224S missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 (HumDiv) predicts a pathogenic outcome; the remaining tools (Foldetta, premPS, AlphaMissense‑Default, Rosetta) give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Overall, the preponderance of evidence points to a benign effect. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | -5.928 | Likely Benign | 0.558 | Ambiguous | Likely Benign | 0.412 | Likely Benign | 0.3498 | 0.4994 | 0.29 | Likely Benign | 0.1 | 0.70 | Ambiguous | 0.50 | Ambiguous | 0.71 | Ambiguous | -2.09 | Neutral | 0.608 | Possibly Damaging | 0.079 | Benign | 5.56 | Benign | 0.66 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||
| c.671C>A | T224N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T224N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, and AlphaMissense‑Default. Uncertain or inconclusive results come from FoldX, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, indicating no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | -7.342 | In-Between | 0.814 | Likely Pathogenic | Ambiguous | 0.370 | Likely Benign | 0.1460 | 0.5079 | 0.66 | Ambiguous | 0.2 | -0.06 | Likely Benign | 0.30 | Likely Benign | 1.15 | Destabilizing | -2.40 | Neutral | 0.845 | Possibly Damaging | 0.368 | Benign | 5.54 | Benign | 0.34 | Tolerated | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||||||
| c.671C>G | T224S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T224S missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 (HumDiv) predicts a pathogenic outcome; the remaining tools (Foldetta, premPS, AlphaMissense‑Default, Rosetta) give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Overall, the preponderance of evidence points to a benign effect. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | -5.928 | Likely Benign | 0.558 | Ambiguous | Likely Benign | 0.374 | Likely Benign | 0.3498 | 0.4994 | 0.29 | Likely Benign | 0.1 | 0.70 | Ambiguous | 0.50 | Ambiguous | 0.71 | Ambiguous | -2.09 | Neutral | 0.608 | Possibly Damaging | 0.079 | Benign | 5.56 | Benign | 0.66 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||
| c.671C>T | T224I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T224I missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as benign. With an equal split of benign and pathogenic calls overall, the two high‑accuracy pathogenic predictions outweigh the single high‑accuracy benign prediction, indicating that the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar assertion is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | -8.831 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.657 | Likely Pathogenic | 0.1015 | 0.7225 | 0.49 | Likely Benign | 0.2 | 0.35 | Likely Benign | 0.42 | Likely Benign | 0.02 | Likely Benign | -3.47 | Deleterious | 0.608 | Possibly Damaging | 0.154 | Benign | 5.58 | Benign | 0.38 | Tolerated | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||
| c.673T>A | S225T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S225T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also benign; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. No pathogenic predictions are present. Therefore, based on the available computational evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.150080 | Structured | 0.344191 | Uncertain | 0.817 | 0.319 | 0.250 | -6.351 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.244 | Likely Benign | 0.1419 | 0.7395 | 0.64 | Ambiguous | 0.4 | 0.59 | Ambiguous | 0.62 | Ambiguous | 0.03 | Likely Benign | -1.98 | Neutral | 0.118 | Benign | 0.049 | Benign | 5.73 | Benign | 0.55 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| c.673T>C | S225P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S225P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign calls come from premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic calls arise from REVEL, FoldX, PROVEAN, and ESM1b. Two tools—Rosetta and Foldetta—return uncertain results and are treated as unavailable. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts benign, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta remains unavailable. Overall, the majority of evidence leans toward a benign effect, and this conclusion does not conflict with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.150080 | Structured | 0.344191 | Uncertain | 0.817 | 0.319 | 0.250 | -8.084 | Likely Pathogenic | 0.156 | Likely Benign | Likely Benign | 0.503 | Likely Pathogenic | 0.2128 | 0.6946 | 2.22 | Destabilizing | 1.8 | 1.14 | Ambiguous | 1.68 | Ambiguous | 0.15 | Likely Benign | -3.31 | Deleterious | 0.396 | Benign | 0.133 | Benign | 5.91 | Benign | 0.17 | Tolerated | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||
| c.673T>G | S225A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S225A is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. The high‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also benign. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive (uncertain) and therefore does not alter the overall benign assessment. Consequently, the variant is most likely benign based on the available predictions, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.150080 | Structured | 0.344191 | Uncertain | 0.817 | 0.319 | 0.250 | -3.752 | Likely Benign | 0.052 | Likely Benign | Likely Benign | 0.201 | Likely Benign | 0.4840 | 0.5897 | 0.31 | Likely Benign | 0.3 | 0.79 | Ambiguous | 0.55 | Ambiguous | 0.11 | Likely Benign | -1.52 | Neutral | 0.001 | Benign | 0.001 | Benign | 5.79 | Benign | 0.58 | Tolerated | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||
| c.674C>T | S225L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S225L is reported in gnomAD (6‑33435525‑C‑T) but has no ClinVar entry. In silico predictors that agree on a benign effect include REVEL, FoldX, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only PROVEAN predicts a pathogenic outcome. Predictions that are inconclusive are Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as Uncertain. Overall, the majority of evidence points to a benign effect for S225L, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.150080 | Structured | 0.344191 | Uncertain | 0.817 | 0.319 | 0.250 | 6-33435525-C-T | 1 | 6.20e-7 | -6.644 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.320 | Likely Benign | 0.1039 | 0.6554 | 0.29 | Likely Benign | 0.4 | 1.18 | Ambiguous | 0.74 | Ambiguous | 0.18 | Likely Benign | -3.76 | Deleterious | 0.000 | Benign | 0.001 | Benign | 5.70 | Benign | 0.28 | Tolerated | 3.41 | 13 | -2 | -3 | 4.6 | 26.08 | ||||||||||||||||||||
| c.676T>A | S226T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S226T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while FoldX is uncertain and therefore treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.129801 | Structured | 0.334959 | Uncertain | 0.800 | 0.324 | 0.250 | -5.066 | Likely Benign | 0.102 | Likely Benign | Likely Benign | 0.326 | Likely Benign | 0.1991 | 0.6681 | 0.53 | Ambiguous | 0.2 | 0.12 | Likely Benign | 0.33 | Likely Benign | -0.10 | Likely Benign | -1.47 | Neutral | 0.390 | Benign | 0.079 | Benign | 5.75 | Benign | 0.05 | Affected | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| c.676T>C | S226P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S226P is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) all predict a pathogenic or likely pathogenic outcome. Uncertain results are reported by FoldX, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Overall, the preponderance of evidence indicates that S226P is most likely pathogenic, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.129801 | Structured | 0.334959 | Uncertain | 0.800 | 0.324 | 0.250 | -11.030 | Likely Pathogenic | 0.933 | Likely Pathogenic | Ambiguous | 0.776 | Likely Pathogenic | 0.2837 | 0.7038 | 1.51 | Ambiguous | 1.1 | 5.29 | Destabilizing | 3.40 | Destabilizing | 0.57 | Ambiguous | -3.22 | Deleterious | 0.971 | Probably Damaging | 0.543 | Possibly Damaging | 5.74 | Benign | 0.04 | Affected | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||
| c.676T>G | S226A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S226A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the variant as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus predicts likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.129801 | Structured | 0.334959 | Uncertain | 0.800 | 0.324 | 0.250 | -4.665 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.339 | Likely Benign | 0.4812 | 0.5599 | 0.06 | Likely Benign | 0.0 | 0.25 | Likely Benign | 0.16 | Likely Benign | -0.02 | Likely Benign | -1.64 | Neutral | 0.123 | Benign | 0.050 | Benign | 5.76 | Benign | 0.06 | Tolerated | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||
| c.677C>T | S226L 2D AIThe SynGAP1 missense variant S226L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, PROVEAN, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote) also indicates benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts benign. No prediction or folding result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.129801 | Structured | 0.334959 | Uncertain | 0.800 | 0.324 | 0.250 | -6.098 | Likely Benign | 0.239 | Likely Benign | Likely Benign | 0.578 | Likely Pathogenic | 0.1525 | 0.5907 | -0.12 | Likely Benign | 0.5 | -0.14 | Likely Benign | -0.13 | Likely Benign | 0.36 | Likely Benign | -3.87 | Deleterious | 0.437 | Benign | 0.048 | Benign | 5.73 | Benign | 0.03 | Affected | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||
| 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 | 0.765 | Likely Pathogenic | 0.0997 | 0.4195 | 2.31 | Destabilizing | 0.3 | 5.29 | Destabilizing | 3.80 | Destabilizing | 0.90 | Ambiguous | -6.49 | Deleterious | 0.020 | Benign | 0.018 | Benign | 6.02 | Benign | 0.01 | Affected | 3.43 | 12 | -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 | 0.765 | Likely Pathogenic | 0.0997 | 0.4195 | 2.31 | Destabilizing | 0.3 | 5.29 | Destabilizing | 3.80 | Destabilizing | 0.90 | Ambiguous | -6.49 | Deleterious | 0.020 | Benign | 0.018 | Benign | 6.02 | Benign | 0.01 | Affected | 3.43 | 12 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||
| 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 | 0.792 | Likely Pathogenic | 0.1414 | 0.4049 | 2.56 | Destabilizing | 0.4 | 5.36 | Destabilizing | 3.96 | Destabilizing | 0.94 | Ambiguous | -6.49 | Deleterious | 0.906 | Possibly Damaging | 0.360 | Benign | 5.72 | Benign | 0.01 | Affected | 3.43 | 12 | 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.680G>C | G227A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G227A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that agree on a pathogenic effect are REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, and AlphaMissense‑Default. Predictions that remain uncertain are premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic majority, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the overall consensus of the majority of tools and the high‑accuracy predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.106997 | Structured | 0.329995 | Uncertain | 0.800 | 0.329 | 0.250 | -7.344 | In-Between | 0.920 | Likely Pathogenic | Ambiguous | 0.682 | Likely Pathogenic | 0.3987 | 0.5221 | 2.45 | Destabilizing | 0.4 | 5.14 | Destabilizing | 3.80 | Destabilizing | 0.78 | Ambiguous | -5.08 | Deleterious | 0.097 | Benign | 0.023 | Benign | 5.71 | Benign | 0.04 | Affected | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||
| c.680G>T | G227V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G227V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining twelve tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. The high‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “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 collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any 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 | -9.329 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.839 | Likely Pathogenic | 0.1130 | 0.4703 | 3.57 | Destabilizing | 0.4 | 6.24 | Destabilizing | 4.91 | Destabilizing | 0.78 | Ambiguous | -7.58 | Deleterious | 0.952 | Possibly Damaging | 0.521 | Possibly Damaging | 5.67 | Benign | 0.01 | Affected | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||
| c.682A>C | T228P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T228P 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 FATHMM, Rosetta, and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is inconclusive, but the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates a pathogenic effect. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.104810 | Structured | 0.321733 | Uncertain | 0.829 | 0.316 | 0.125 | -8.559 | Likely Pathogenic | 0.939 | Likely Pathogenic | Ambiguous | 0.690 | Likely Pathogenic | 0.2207 | 0.6360 | 1.65 | Ambiguous | 0.6 | 0.47 | Likely Benign | 1.06 | Ambiguous | 0.21 | Likely Benign | -3.54 | Deleterious | 0.984 | Probably Damaging | 0.690 | Possibly Damaging | 5.64 | Benign | 0.02 | Affected | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||
| c.682A>G | T228A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T228A variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), 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 effect are REVEL, SIFT, and AlphaMissense‑Default. Predictions that are inconclusive or uncertain are Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as benign (majority of its constituent predictors are benign), and Foldetta as uncertain. Overall, the balance of evidence favors a benign interpretation; 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 | PH | 0.104810 | Structured | 0.321733 | Uncertain | 0.829 | 0.316 | 0.125 | -5.190 | Likely Benign | 0.793 | Likely Pathogenic | Ambiguous | 0.520 | Likely Pathogenic | 0.4072 | 0.5014 | 0.44 | Likely Benign | 0.0 | 0.82 | Ambiguous | 0.63 | Ambiguous | 0.58 | Ambiguous | -2.30 | Neutral | 0.363 | Benign | 0.138 | Benign | 5.63 | Benign | 0.04 | Affected | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||
| c.682A>T | T228S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T228S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while Rosetta and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a benign stability change. Taken together, the overwhelming majority of evidence indicates a benign impact for T228S. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.104810 | Structured | 0.321733 | Uncertain | 0.829 | 0.316 | 0.125 | -2.028 | Likely Benign | 0.493 | Ambiguous | Likely Benign | 0.458 | Likely Benign | 0.3395 | 0.5107 | 0.32 | Likely Benign | 0.1 | 0.63 | Ambiguous | 0.48 | Likely Benign | 0.05 | Likely Benign | -0.50 | Neutral | 0.734 | Possibly Damaging | 0.138 | Benign | 5.65 | Benign | 1.00 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||
| c.683C>A | T228K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T228K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, and FATHMM, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools give uncertain results (Rosetta and premPS). High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Overall, the balance of evidence favors a pathogenic classification, and this conclusion does not contradict any existing ClinVar annotation because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.104810 | Structured | 0.321733 | Uncertain | 0.829 | 0.316 | 0.125 | -9.143 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.676 | Likely Pathogenic | 0.1322 | 0.3590 | 0.03 | Likely Benign | 0.1 | 0.87 | Ambiguous | 0.45 | Likely Benign | 0.70 | Ambiguous | -3.00 | Deleterious | 0.906 | Possibly Damaging | 0.521 | Possibly Damaging | 5.60 | Benign | 0.02 | Affected | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||
| c.683C>G | T228R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T228R missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from Rosetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a pathogenic 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. | PH | 0.104810 | Structured | 0.321733 | Uncertain | 0.829 | 0.316 | 0.125 | -7.218 | In-Between | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.693 | Likely Pathogenic | 0.1108 | 0.3405 | -0.23 | Likely Benign | 0.1 | 0.69 | Ambiguous | 0.23 | Likely Benign | 0.67 | Ambiguous | -3.40 | Deleterious | 0.952 | Possibly Damaging | 0.694 | Possibly Damaging | 5.60 | Benign | 0.01 | Affected | -1 | -1 | -3.8 | 55.08 | ||||||||||||||||||||||||||
| c.683C>T | T228I 2D AIThe SynGAP1 missense variant T228I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM, while those that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. With eight tools favoring pathogenicity versus six favoring benign, and two of the three high‑accuracy methods supporting pathogenicity, the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, which currently contains no entry for T228I. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.104810 | Structured | 0.321733 | Uncertain | 0.829 | 0.316 | 0.125 | -8.605 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.692 | Likely Pathogenic | 0.0951 | 0.7051 | 0.02 | Likely Benign | 0.6 | 0.21 | Likely Benign | 0.12 | Likely Benign | 0.23 | Likely Benign | -3.99 | Deleterious | 0.984 | Probably Damaging | 0.690 | Possibly Damaging | 5.65 | Benign | 0.06 | Tolerated | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||
| c.685A>C | K229Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K229Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, FATHMM, and Foldetta; pathogenic predictions arise from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, and this assessment does not conflict with ClinVar status, which currently has no entry for K229Q. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -9.606 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.813 | Likely Pathogenic | 0.4456 | 0.1057 | 0.41 | Likely Benign | 0.0 | -0.05 | Likely Benign | 0.18 | Likely Benign | 0.55 | Ambiguous | -3.03 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 5.84 | Benign | 0.02 | Affected | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||
| c.685A>G | K229E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K229E is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that classify the variant as benign include FoldX, Rosetta, premPS, SIFT, and FATHMM. Tools that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall distribution of predictions, the variant is most likely pathogenic; this conclusion does not contradict the ClinVar status, which currently has no entry for K229E. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -12.828 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.816 | Likely Pathogenic | 0.3915 | 0.0793 | 0.47 | Likely Benign | 0.0 | 0.24 | Likely Benign | 0.36 | Likely Benign | 0.18 | Likely Benign | -3.10 | Deleterious | 0.993 | Probably Damaging | 0.971 | Probably Damaging | 5.84 | Benign | 0.09 | Tolerated | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||
| c.686A>C | K229T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K229T is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include Rosetta, Foldetta, premPS, and FATHMM. Those that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. High‑accuracy methods give a pathogenic result from AlphaMissense‑Optimized, a likely pathogenic verdict from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and a benign outcome from Foldetta. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -12.639 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.813 | Likely Pathogenic | 0.1890 | 0.3029 | 0.83 | Ambiguous | 0.0 | -0.08 | Likely Benign | 0.38 | Likely Benign | 0.00 | Likely Benign | -4.77 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 5.86 | Benign | 0.01 | Affected | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||
| c.686A>G | K229R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K229R missense variant is catalogued in gnomAD (ID 6‑33435537‑A‑G) but has no entry in ClinVar. Functional prediction tools largely agree on a benign effect: FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign. In contrast, REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar predict pathogenic. AlphaMissense‑Default is uncertain and is treated as unavailable. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | 6-33435537-A-G | 1 | 6.20e-7 | -5.651 | Likely Benign | 0.437 | Ambiguous | Likely Benign | 0.628 | Likely Pathogenic | 0.4921 | 0.0972 | 0.09 | Likely Benign | 0.0 | 0.02 | Likely Benign | 0.06 | Likely Benign | 0.40 | Likely Benign | -2.00 | Neutral | 0.993 | Probably Damaging | 0.971 | Probably Damaging | 5.84 | Benign | 0.19 | Tolerated | 3.43 | 12 | 2 | 3 | -0.6 | 28.01 | ||||||||||||||||||||
| c.686A>T | K229I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K229I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from FoldX, Foldetta, premPS, and FATHMM, whereas pathogenic predictions are returned by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a mixed picture: 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 stability outputs, reports benign. No prediction is inconclusive. Overall, the majority of tools, including the high‑accuracy ones, lean toward pathogenicity, and this does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -15.276 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.833 | Likely Pathogenic | 0.1202 | 0.3711 | -0.03 | Likely Benign | 0.1 | -0.63 | Ambiguous | -0.33 | Likely Benign | -0.19 | Likely Benign | -6.52 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 5.92 | Benign | 0.00 | Affected | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||
| c.687A>C | K229N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K229N 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 limited to FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. Four tools (FoldX, Rosetta, Foldetta, premPS) return uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. The variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -13.620 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.590 | Likely Pathogenic | 0.3682 | 0.1013 | 0.82 | Ambiguous | 0.1 | 0.64 | Ambiguous | 0.73 | Ambiguous | 0.61 | Ambiguous | -3.79 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 5.83 | Benign | 0.01 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.687A>T | K229N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K229N missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining nine tools—REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is uncertain and therefore not considered evidence for or against pathogenicity. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -13.620 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.588 | Likely Pathogenic | 0.3682 | 0.1013 | 0.82 | Ambiguous | 0.1 | 0.64 | Ambiguous | 0.73 | Ambiguous | 0.61 | Ambiguous | -3.79 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 5.83 | Benign | 0.01 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.688T>A | C230S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are REVEL, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as benign. With an equal split of 7 benign versus 7 pathogenic predictions overall, the higher‑confidence tools lean toward pathogenicity. Therefore, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.268042 | Structured | 0.308076 | Uncertain | 0.870 | 0.308 | 0.000 | -9.994 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.859 | Likely Pathogenic | 0.4926 | 0.1822 | 0.42 | Likely Benign | 0.1 | 0.05 | Likely Benign | 0.24 | Likely Benign | 1.08 | Destabilizing | -8.24 | Deleterious | 0.421 | Benign | 0.115 | Benign | 5.91 | Benign | 0.07 | Tolerated | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||
| c.688T>C | C230R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from FoldX and FATHMM, while pathogenic predictions are made by REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Rosetta and Foldetta. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a pathogenic effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; Foldetta remains inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for C230R, 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 | 0.268042 | Structured | 0.308076 | Uncertain | 0.870 | 0.308 | 0.000 | -12.478 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.905 | Likely Pathogenic | 0.1744 | 0.1637 | -0.48 | Likely Benign | 0.0 | -1.61 | Ambiguous | -1.05 | Ambiguous | 1.12 | Destabilizing | -9.88 | Deleterious | 0.838 | Possibly Damaging | 0.548 | Possibly Damaging | 5.91 | Benign | 0.01 | Affected | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||
| c.688T>G | C230G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reached a consensus fall into two groups: benign predictions come from polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain or inconclusive results from FoldX, Rosetta, Foldetta, and premPS are treated as unavailable and do not influence the overall assessment. High‑accuracy methods specifically indicate pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also Likely Pathogenic; Foldetta remains uncertain. Based on the aggregate predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.268042 | Structured | 0.308076 | Uncertain | 0.870 | 0.308 | 0.000 | -10.888 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.775 | Likely Pathogenic | 0.3313 | 0.2574 | 0.72 | Ambiguous | 0.1 | 0.86 | Ambiguous | 0.79 | Ambiguous | 0.81 | Ambiguous | -9.95 | Deleterious | 0.001 | Benign | 0.004 | Benign | 5.85 | Benign | 0.03 | Affected | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||
| 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 | 0.816 | Likely Pathogenic | 0.1159 | 0.3655 | -0.03 | Likely Benign | 0.1 | -2.24 | Stabilizing | -1.14 | Ambiguous | 0.00 | Likely Benign | -8.46 | Deleterious | 0.940 | Possibly Damaging | 0.641 | Possibly Damaging | 6.17 | Benign | 0.14 | Tolerated | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||
| c.689G>C | C230S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant C230S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools cluster into two groups: benign calls come from FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM; pathogenic calls come from REVEL, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as benign. No prediction or stability result is missing. Overall, the predictions are evenly split between benign and pathogenic, leaving the variant’s functional impact uncertain. This uncertainty does not contradict ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.268042 | Structured | 0.308076 | Uncertain | 0.870 | 0.308 | 0.000 | -9.994 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.844 | Likely Pathogenic | 0.4926 | 0.1822 | 0.42 | Likely Benign | 0.1 | 0.05 | Likely Benign | 0.24 | Likely Benign | 1.08 | Destabilizing | -8.24 | Deleterious | 0.421 | Benign | 0.115 | Benign | 5.91 | Benign | 0.07 | Tolerated | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||
| c.689G>T | C230F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Foldetta and premPS 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) is “Likely Pathogenic”; Foldetta remains uncertain. Overall, the preponderance of evidence indicates that C230F 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 | PH | 0.268042 | Structured | 0.308076 | Uncertain | 0.870 | 0.308 | 0.000 | -11.134 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.840 | Likely Pathogenic | 0.1329 | 0.4173 | -0.09 | Likely Benign | 0.1 | -2.03 | Stabilizing | -1.06 | Ambiguous | 0.51 | Ambiguous | -8.73 | Deleterious | 0.940 | Possibly Damaging | 0.641 | Possibly Damaging | 5.96 | Benign | 0.03 | Affected | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||
| 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 | 0.739 | Likely Pathogenic | 0.1589 | 0.3663 | -0.21 | Likely Benign | 0.0 | -1.87 | Ambiguous | -1.04 | Ambiguous | 0.74 | Ambiguous | -8.79 | Deleterious | 0.983 | Probably Damaging | 0.841 | Possibly Damaging | 5.84 | Benign | 0.01 | Affected | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||
| c.691T>A | F231I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 HumVar and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta’s stability prediction is uncertain and thus not considered evidence. No other tools provide definitive pathogenic or benign conclusions. Based on the preponderance of pathogenic predictions and the lack of contrary evidence, the variant is most likely pathogenic; this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -13.827 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.894 | Likely Pathogenic | 0.2122 | 0.2813 | 1.16 | Ambiguous | 0.4 | 1.65 | Ambiguous | 1.41 | Ambiguous | 0.94 | Ambiguous | -5.01 | Deleterious | 0.759 | Possibly Damaging | 0.328 | Benign | 5.76 | Benign | 0.00 | Affected | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||
| c.691T>C | F231L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231L 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. Tools that agree on a pathogenic effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus score is “Likely Pathogenic.” Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a pathogenic impact for F231L, 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 | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -9.482 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.801 | Likely Pathogenic | 0.2338 | 0.3794 | 1.07 | Ambiguous | 0.3 | 1.26 | Ambiguous | 1.17 | Ambiguous | 0.85 | Ambiguous | -5.08 | Deleterious | 0.390 | Benign | 0.142 | Benign | 6.04 | Benign | 0.01 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.691T>G | F231V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are polyPhen‑2 HumVar and FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic status; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also indicates pathogenicity. Taken together, the evidence overwhelmingly points to a pathogenic effect for F231V, 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 | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -13.201 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.910 | Likely Pathogenic | 0.2212 | 0.3030 | 2.16 | Destabilizing | 0.3 | 2.30 | Destabilizing | 2.23 | Destabilizing | 1.13 | Destabilizing | -5.90 | Deleterious | 0.759 | Possibly Damaging | 0.328 | Benign | 5.72 | Benign | 0.00 | Affected | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||
| c.692T>A | F231Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign effects include Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict pathogenicity are REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX and premPS are inconclusive. High‑accuracy methods give AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of standard tools lean benign, but the two most accurate predictors and the consensus vote favor pathogenicity. Thus, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which currently has no classification for F231Y. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -9.831 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.687 | Likely Pathogenic | 0.1355 | 0.2732 | 0.69 | Ambiguous | 0.1 | 0.00 | Likely Benign | 0.35 | Likely Benign | 0.85 | Ambiguous | -2.60 | Deleterious | 0.437 | Benign | 0.079 | Benign | 5.50 | Benign | 0.12 | Tolerated | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||
| c.692T>C | F231S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231S 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 polyPhen‑2 HumVar and FATHMM; all other evaluated algorithms—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -14.655 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.909 | Likely Pathogenic | 0.4297 | 0.0544 | 2.89 | Destabilizing | 0.4 | 4.22 | Destabilizing | 3.56 | Destabilizing | 2.22 | Destabilizing | -6.92 | Deleterious | 0.608 | Possibly Damaging | 0.205 | Benign | 5.48 | Benign | 0.00 | Affected | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||
| c.692T>G | F231C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231C is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity largely agree: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a deleterious effect, while only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among the majority of tools and the high‑accuracy methods, 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 | PH | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -13.315 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.937 | Likely Pathogenic | 0.2527 | 0.1612 | 2.26 | Destabilizing | 0.3 | 2.82 | Destabilizing | 2.54 | Destabilizing | 2.04 | Destabilizing | -6.89 | Deleterious | 0.992 | Probably Damaging | 0.707 | Possibly Damaging | 5.49 | Benign | 0.00 | Affected | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||
| c.693T>A | F231L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231L 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. Tools that agree on a pathogenic effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus score is “Likely Pathogenic.” Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a pathogenic impact for F231L, 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 | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -9.482 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.662 | Likely Pathogenic | 0.2338 | 0.3794 | 1.07 | Ambiguous | 0.3 | 1.26 | Ambiguous | 1.17 | Ambiguous | 0.85 | Ambiguous | -5.08 | Deleterious | 0.390 | Benign | 0.142 | Benign | 6.04 | Benign | 0.01 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.693T>G | F231L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231L is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar and FATHMM, whereas REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized all predict a pathogenic effect. The SGM‑Consensus score is labeled Likely Pathogenic, and the remaining tools (FoldX, Rosetta, Foldetta, premPS) are inconclusive. High‑accuracy methods give a pathogenic verdict from AlphaMissense‑Optimized, a Likely Pathogenic result from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and an uncertain outcome from Foldetta. Overall, the majority of evidence points to a pathogenic impact for F231L, 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 | PH | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -9.482 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.661 | Likely Pathogenic | 0.2338 | 0.3794 | 1.07 | Ambiguous | 0.3 | 1.26 | Ambiguous | 1.17 | Ambiguous | 0.85 | Ambiguous | -5.08 | Deleterious | 0.390 | Benign | 0.142 | Benign | 6.04 | Benign | 0.01 | Affected | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.694G>A | A232T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232T is listed in ClinVar as Benign (ClinVar ID 1165963.0) and is present in gnomAD (ID 6‑33435545‑G‑A). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. Predictions that are inconclusive are premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports Benign. Overall, the majority of evidence supports a benign impact, which is consistent with the ClinVar classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | Benign | 1 | 6-33435545-G-A | 1 | 6.20e-7 | -7.655 | In-Between | 0.874 | Likely Pathogenic | Ambiguous | 0.469 | Likely Benign | 0.1621 | 0.6488 | 0.47 | Likely Benign | 0.1 | -0.04 | Likely Benign | 0.22 | Likely Benign | 0.61 | Ambiguous | -1.42 | Neutral | 0.608 | Possibly Damaging | 0.240 | Benign | 5.80 | Benign | 0.09 | Tolerated | 3.40 | 14 | 1 | 0 | -2.5 | 30.03 | 210.8 | -42.0 | 0.5 | 0.1 | 0.4 | 0.5 | X | Uncertain | The hydroxyl group of Thr232, located at the end of an anti-parallel β sheet strand (res. Thr228-Ala232), forms hydrogen bonds with nearby residues Glu217, Cys233, and Cys219 in the variant simulations. These hydrogen-bonding interactions at the β sheet surface contribute to the stability of the secondary structure element and prevent it from unfolding. The new hydrogen bond interactions may be more favorable for structural stability than the steric interactions of the methyl side chain of Ala with the side chains of Gln216 and Cys219 in the WT. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||||
| c.694G>C | A232P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, SIFT, and FATHMM. Tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results come from Rosetta, premPS, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome, and Foldetta remains uncertain. Overall, the majority of evaluated tools predict a pathogenic impact, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | -12.697 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.748 | Likely Pathogenic | 0.2163 | 0.5259 | 0.05 | Likely Benign | 0.8 | 1.25 | Ambiguous | 0.65 | Ambiguous | 0.71 | Ambiguous | -2.75 | Deleterious | 0.917 | Possibly Damaging | 0.502 | Possibly Damaging | 5.78 | Benign | 0.06 | Tolerated | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.694G>T | A232S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Across the evaluated in‑silico predictors, all tools except AlphaMissense‑Default converge on a benign interpretation: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all predict benign. AlphaMissense‑Default is uncertain, while AlphaMissense‑Optimized predicts benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | -3.264 | Likely Benign | 0.344 | Ambiguous | Likely Benign | 0.378 | Likely Benign | 0.2777 | 0.5300 | 0.23 | Likely Benign | 0.1 | -0.23 | Likely Benign | 0.00 | Likely Benign | -0.20 | Likely Benign | 0.54 | Neutral | 0.057 | Benign | 0.025 | Benign | 5.95 | Benign | 1.00 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| c.695C>A | A232D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232D is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus. Uncertain or inconclusive results are reported for Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as pathogenic, while Foldetta remains uncertain. Overall, the majority of available predictions support a pathogenic impact. Thus, the variant is most likely pathogenic, and this assessment 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 | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | -13.956 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.725 | Likely Pathogenic | 0.2066 | 0.2896 | 0.14 | Likely Benign | 0.2 | 1.55 | Ambiguous | 0.85 | Ambiguous | 0.77 | Ambiguous | -2.50 | Deleterious | 0.845 | Possibly Damaging | 0.348 | Benign | 5.78 | Benign | 0.02 | Affected | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||
| c.695C>G | A232G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A232G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the change as benign include REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Those that predict pathogenicity are polyPhen‑2 HumDiv and AlphaMissense‑Default. Uncertain or inconclusive results come from Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the preponderance of evidence points to a benign effect; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | -4.924 | Likely Benign | 0.835 | Likely Pathogenic | Ambiguous | 0.453 | Likely Benign | 0.2012 | 0.4724 | 0.43 | Likely Benign | 0.1 | 1.43 | Ambiguous | 0.93 | Ambiguous | 0.53 | Ambiguous | -1.39 | Neutral | 0.608 | Possibly Damaging | 0.172 | Benign | 5.81 | Benign | 0.11 | Tolerated | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.695C>T | A232V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A232V is catalogued in gnomAD (ID 6‑33435546‑C‑T) but has no ClinVar entry. Functional prediction tools show mixed results: benign calls come from FoldX, Rosetta, Foldetta, polyPhen‑2 HumVar, SIFT, and FATHMM, whereas pathogenic calls are reported by REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, and the Foldetta stability assessment predicts benign. premPS is inconclusive and therefore not considered. Overall, the majority of independent predictors lean toward pathogenicity, but the stability‑based Foldetta suggests a benign effect. With no ClinVar classification to contradict, the variant is most likely pathogenic according to the prevailing computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | 6-33435546-C-T | 2 | 1.24e-6 | -9.418 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.539 | Likely Pathogenic | 0.1202 | 0.6027 | 0.40 | Likely Benign | 0.1 | 0.23 | Likely Benign | 0.32 | Likely Benign | 0.55 | Ambiguous | -2.99 | Deleterious | 0.608 | Possibly Damaging | 0.240 | Benign | 5.85 | Benign | 0.06 | Tolerated | 3.40 | 14 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||
| c.697T>A | C233S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors pathogenicity (3 pathogenic vs 1 benign). Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact. This conclusion 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 Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -10.862 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.764 | Likely Pathogenic | 0.4528 | 0.2833 | 0.61 | Ambiguous | 0.1 | 1.25 | Ambiguous | 0.93 | Ambiguous | 1.50 | Destabilizing | -8.89 | Deleterious | 0.421 | Benign | 0.080 | Benign | 5.79 | Benign | 0.03 | Affected | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||
| c.697T>C | C233R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overall consensus of the majority of tools and the high‑accuracy methods, the variant is most likely pathogenic, which is consistent with the lack of ClinVar annotation and gnomAD presence. 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 | -16.789 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.830 | Likely Pathogenic | 0.1733 | 0.2212 | 3.79 | Destabilizing | 3.4 | 2.17 | Destabilizing | 2.98 | Destabilizing | 1.75 | Destabilizing | -10.68 | Deleterious | 0.002 | Benign | 0.002 | Benign | 5.71 | Benign | 0.01 | Affected | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||
| c.697T>G | C233G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233G is not reported in ClinVar (ClinVar ID = None) and has no entry in gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta are inconclusive and are treated as unavailable. High‑accuracy predictions: AlphaMissense‑Optimized reports Pathogenic; SGM‑Consensus reports Likely Pathogenic; Foldetta is Uncertain. Overall, the majority of available predictions indicate a pathogenic impact. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -14.155 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.849 | Likely Pathogenic | 0.3317 | 0.3570 | 1.29 | Ambiguous | 0.1 | 1.01 | Ambiguous | 1.15 | Ambiguous | 1.31 | Destabilizing | -10.68 | Deleterious | 0.596 | Possibly Damaging | 0.107 | Benign | 5.79 | Benign | 0.09 | Tolerated | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||
| 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 | 0.904 | Likely Pathogenic | 0.1324 | 0.5284 | 13.15 | Destabilizing | 4.6 | 0.04 | Likely Benign | 6.60 | Destabilizing | 0.71 | Ambiguous | -9.79 | Deleterious | 0.940 | Possibly Damaging | 0.459 | Possibly Damaging | 5.71 | Benign | 0.00 | Affected | 4.29 | 391 | 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.698G>C | C233S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable evidence. Overall, the preponderance of evidence points to a pathogenic impact for C233S, 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 | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -10.862 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.830 | Likely Pathogenic | 0.4528 | 0.2833 | 0.61 | Ambiguous | 0.1 | 1.25 | Ambiguous | 0.93 | Ambiguous | 1.50 | Destabilizing | -8.89 | Deleterious | 0.421 | Benign | 0.080 | Benign | 5.79 | Benign | 0.03 | Affected | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||
| c.698G>T | C233F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include Rosetta, premPS, and FATHMM, whereas the remaining tools—REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, and Foldetta—predict a pathogenic or likely pathogenic impact. High‑accuracy methods give consistent results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Overall, the majority of evidence supports a pathogenic effect, and this conclusion does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -14.564 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.901 | Likely Pathogenic | 0.1524 | 0.5231 | 9.36 | Destabilizing | 3.0 | -0.19 | Likely Benign | 4.59 | Destabilizing | 0.37 | Likely Benign | -9.79 | Deleterious | 0.940 | Possibly Damaging | 0.459 | Possibly Damaging | 5.73 | Benign | 0.00 | Affected | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||
| 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 | 0.772 | Likely Pathogenic | 0.1727 | 0.5292 | 14.72 | Destabilizing | 6.6 | 1.07 | Ambiguous | 7.90 | Destabilizing | 0.54 | Ambiguous | -9.79 | Deleterious | 0.983 | Probably Damaging | 0.715 | Possibly Damaging | 5.71 | Benign | 0.00 | Affected | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||
| c.700C>G | R234G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R234G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that agree on a pathogenic effect are REVEL, PROVEAN, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, Foldetta, premPS, ESM1b, and AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy methods show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of individual predictors lean toward pathogenicity, and the high‑accuracy consensus also supports a pathogenic classification. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.239899 | Structured | 0.311558 | Uncertain | 0.804 | 0.322 | 0.000 | -7.163 | In-Between | 0.923 | Likely Pathogenic | Ambiguous | 0.724 | Likely Pathogenic | 0.3194 | 0.3426 | 1.50 | Ambiguous | 0.2 | 0.88 | Ambiguous | 1.19 | Ambiguous | 0.61 | Ambiguous | -4.31 | Deleterious | 0.276 | Benign | 0.103 | Benign | 5.82 | Benign | 0.12 | Tolerated | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||
| c.700C>T | R234W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R234W missense variant is listed in ClinVar (ID 856396.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33435551‑C‑T). Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of other in‑silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) indicate a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain”; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is “Uncertain.” Overall, the preponderance of evidence points to a pathogenic effect, which is consistent with the ClinVar designation of uncertainty rather than a benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.311558 | Uncertain | 0.804 | 0.322 | 0.000 | Uncertain | 1 | 6-33435551-C-T | 3 | 1.86e-6 | -12.625 | Likely Pathogenic | 0.947 | Likely Pathogenic | Ambiguous | 0.805 | Likely Pathogenic | 0.1302 | 0.4035 | 0.96 | Ambiguous | 0.3 | 0.69 | Ambiguous | 0.83 | Ambiguous | 0.13 | Likely Benign | -5.52 | Deleterious | 0.997 | Probably Damaging | 0.803 | Possibly Damaging | 5.76 | Benign | 0.01 | Affected | 3.40 | 14 | 2 | -3 | 3.6 | 30.03 | 262.8 | 39.6 | -0.1 | 0.0 | -0.2 | 0.2 | X | Potentially Pathogenic | The guanidinium group of Arg234, located in a β-α loop between an anti-parallel β sheet strand (residues Gly227-Phe231) and an α helix (res. Ala236-Val250), forms a salt bridge with the carboxylate group of Glu238 in the α helix. Occasionally, it also bonds with the GAP domain residues Ser678 and Glu680. Thus, the positively charged Arg234 could contribute to the tertiary structure assembly between the PH and GAP domains. In contrast, the indole side chain of Trp234 in the variant is located on the protein surface in the variant simulations and is unable to form any interactions. | |||||||||
| c.701G>A | R234Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R234Q missense variant is not reported in ClinVar (ClinVar ID = None) but is present in gnomAD (ID = 6‑33435552‑G‑A). Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default; premPS is uncertain and treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of evidence points to a benign effect. The variant’s predicted benign status does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.239899 | Structured | 0.311558 | Uncertain | 0.804 | 0.322 | 0.000 | 6-33435552-G-A | 8 | 4.96e-6 | -9.675 | Likely Pathogenic | 0.666 | Likely Pathogenic | Likely Benign | 0.627 | Likely Pathogenic | 0.3256 | 0.2520 | 0.21 | Likely Benign | 0.1 | 0.27 | Likely Benign | 0.24 | Likely Benign | 0.57 | Ambiguous | -2.32 | Neutral | 0.892 | Possibly Damaging | 0.213 | Benign | 5.81 | Benign | 0.11 | Tolerated | 3.40 | 14 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||
| c.701G>C | R234P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R234P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of evaluated algorithms (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as inconclusive. Based on the collective evidence, 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 | PH | 0.239899 | Structured | 0.311558 | Uncertain | 0.804 | 0.322 | 0.000 | -10.126 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.826 | Likely Pathogenic | 0.1972 | 0.4336 | 1.33 | Ambiguous | 0.6 | 1.36 | Ambiguous | 1.35 | Ambiguous | 0.13 | Likely Benign | -4.43 | Deleterious | 0.929 | Possibly Damaging | 0.519 | Possibly Damaging | 5.93 | Benign | 0.04 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||
| c.701G>T | R234L 2D AIThe SynGAP1 missense variant R234L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, polyPhen‑2 HumVar, SIFT, and FATHMM, while those that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy methods show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions (7 pathogenic vs. 4 benign) and the pathogenic consensus from the high‑accuracy SGM‑Consensus suggest that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.311558 | Uncertain | 0.804 | 0.322 | 0.000 | -11.153 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 0.734 | Likely Pathogenic | 0.1846 | 0.4783 | 1.38 | Ambiguous | 0.9 | 0.50 | Ambiguous | 0.94 | Ambiguous | 0.20 | Likely Benign | -4.64 | Deleterious | 0.649 | Possibly Damaging | 0.199 | Benign | 5.78 | Benign | 0.11 | Tolerated | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||
| c.703T>A | S235T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only ESM1b predicts a pathogenic outcome, while FoldX, Rosetta, and AlphaMissense‑Default are uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No prediction or folding result is missing or inconclusive. Based on the overall consensus of the available tools, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | -9.422 | Likely Pathogenic | 0.451 | Ambiguous | Likely Benign | 0.453 | Likely Benign | 0.1674 | 0.6337 | 0.80 | Ambiguous | 0.0 | -0.54 | Ambiguous | 0.13 | Likely Benign | 0.21 | Likely Benign | -2.02 | Neutral | 0.057 | Benign | 0.020 | Benign | 5.75 | Benign | 0.13 | Tolerated | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||
| c.703T>C | S235P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235P is listed in ClinVar as Pathogenic (ClinVar ID 1067856.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect are polyPhen‑2 HumVar and FATHMM; all other evaluated algorithms—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports pathogenic. No predictions or stability results are missing or inconclusive. **Based on the collective predictions, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | Likely Pathogenic | 1 | -14.857 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.870 | Likely Pathogenic | 0.2432 | 0.5307 | 4.02 | Destabilizing | 0.1 | 6.91 | Destabilizing | 5.47 | Destabilizing | 1.23 | Destabilizing | -4.24 | Deleterious | 0.917 | Possibly Damaging | 0.446 | Benign | 5.47 | Benign | 0.01 | Affected | 3.40 | 14 | 1 | -1 | -0.8 | 10.04 | 201.5 | 17.0 | 0.1 | 0.0 | -0.6 | 0.0 | X | Potentially Pathogenic | In the WT, the hydroxyl group of Ser235, located in a β-α loop between an anti-parallel β sheet strand (res. Gly227-Phe231) and an α helix (residues Ala236-Val250), forms hydrogen bonds with the GAP domain loop residue Glu680 and with the backbone amide groups of Ala237 and Glu238 from the α helix. In the variant simulations, the pyrrolidine ring of Pro235 cannot stabilize the α helix end or maintain tertiary bonding interactions between the PH and GAP domains via hydrogen bonding as effectively as serine. | ||||||||||||
| c.703T>G | S235A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235A has no ClinVar entry and is not present in gnomAD. Prediction tools that indicate benign effects include Rosetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. FoldX and Foldetta return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as pathogenic; Foldetta remains uncertain. Overall, the balance of evidence leans toward a benign interpretation, but the SGM Consensus introduces a pathogenic signal, resulting in a conflicting prediction profile. This assessment does not contradict ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | -10.861 | Likely Pathogenic | 0.707 | Likely Pathogenic | Likely Benign | 0.646 | Likely Pathogenic | 0.5168 | 0.4563 | Weaken | 1.92 | Ambiguous | 0.1 | 0.19 | Likely Benign | 1.06 | Ambiguous | 0.48 | Likely Benign | -2.52 | Deleterious | 0.002 | Benign | 0.004 | Benign | 5.49 | Benign | 0.01 | Affected | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||
| 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 | 0.887 | Likely Pathogenic | 0.0733 | 0.5269 | 3.53 | Destabilizing | 1.8 | 0.43 | Likely Benign | 1.98 | Ambiguous | 0.66 | Ambiguous | -5.14 | Deleterious | 0.971 | Probably Damaging | 0.641 | Possibly Damaging | 5.45 | Benign | 0.00 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||
| c.704C>G | S235C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FATHMM and Rosetta, whereas a majority of tools (REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. Results from high‑accuracy methods are mixed: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta is uncertain. Because the uncertain predictions are treated as unavailable, the overall evidence still favors pathogenicity. Thus, the variant is most likely pathogenic, and this assessment does not contradict the current ClinVar status, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | -11.350 | Likely Pathogenic | 0.800 | Likely Pathogenic | Ambiguous | 0.878 | Likely Pathogenic | 0.1284 | 0.6015 | 1.74 | Ambiguous | 0.1 | 0.42 | Likely Benign | 1.08 | Ambiguous | 0.76 | Ambiguous | -4.24 | Deleterious | 0.977 | Probably Damaging | 0.620 | Possibly Damaging | 5.45 | Benign | 0.00 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||
| 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 | 0.919 | Likely Pathogenic | 0.0617 | 0.5393 | 3.03 | Destabilizing | 1.7 | 0.46 | Likely Benign | 1.75 | Ambiguous | 0.56 | Ambiguous | -5.14 | Deleterious | 0.917 | Possibly Damaging | 0.548 | Possibly Damaging | 5.45 | Benign | 0.00 | Affected | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||
| c.706G>A | A236T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A236T 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 FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie and thus unavailable. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. Overall, six tools favor pathogenicity versus three favor benign, and no high‑confidence consensus tool contradicts this trend. Therefore, the variant is most likely pathogenic, and this assessment does not conflict with any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | -8.319 | Likely Pathogenic | 0.240 | Likely Benign | Likely Benign | 0.811 | Likely Pathogenic | 0.1342 | 0.6926 | 0.73 | Ambiguous | 0.2 | 1.58 | Ambiguous | 1.16 | Ambiguous | 0.83 | Ambiguous | -3.35 | Deleterious | 0.982 | Probably Damaging | 0.747 | Possibly Damaging | 5.79 | Benign | 0.03 | Affected | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||
| c.706G>C | A236P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A236P missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include Foldetta, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas those that predict a pathogenic outcome are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and AlphaMissense‑Default; the remaining tools (FoldX, Rosetta, premPS, ESM1b) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. No prediction or stability result is missing or inconclusive. Overall, the majority of individual tools lean toward pathogenicity, but the two most reliable high‑accuracy methods (AlphaMissense‑Optimized and Foldetta) suggest a benign effect, while the SGM Consensus indicates pathogenicity. Given the mixed evidence, the variant is most likely benign based on the strongest high‑accuracy predictions, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | -7.932 | In-Between | 0.621 | Likely Pathogenic | Likely Benign | 0.862 | Likely Pathogenic | 0.1980 | 0.4897 | -0.99 | Ambiguous | 0.1 | 1.44 | Ambiguous | 0.23 | Likely Benign | 0.67 | Ambiguous | -4.31 | Deleterious | 0.995 | Probably Damaging | 0.880 | Possibly Damaging | 5.78 | Benign | 0.12 | Tolerated | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||
| c.706G>T | A236S 2D AIThe SynGAP1 A236S variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include FoldX, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Predictions that are inconclusive or uncertain are Rosetta, Foldetta, premPS, and ESM1b. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for A236S, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | -7.845 | In-Between | 0.106 | Likely Benign | Likely Benign | 0.648 | Likely Pathogenic | 0.2641 | 0.5547 | 0.40 | Likely Benign | 0.5 | 1.24 | Ambiguous | 0.82 | Ambiguous | 0.65 | Ambiguous | -2.30 | Neutral | 0.948 | Possibly Damaging | 0.588 | Possibly Damaging | 5.83 | Benign | 0.13 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| 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 | 0.844 | Likely Pathogenic | 0.1075 | 0.1970 | -0.75 | Ambiguous | 0.2 | 0.28 | Likely Benign | -0.24 | Likely Benign | 1.08 | Destabilizing | -4.24 | Deleterious | 0.998 | Probably Damaging | 0.900 | Possibly Damaging | 6.06 | Benign | 0.02 | Affected | 3.40 | 14 | -1 | 0 | -5.3 | 58.04 | ||||||||||||||||||||
| c.707C>G | A236G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A236G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, premPS, and PROVEAN. Four tools (FoldX, Rosetta, Foldetta, and ESM1b) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also favors benign, while Foldetta remains uncertain. Overall, the majority of available predictions support a benign impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | -7.412 | In-Between | 0.162 | Likely Benign | Likely Benign | 0.615 | Likely Pathogenic | 0.2200 | 0.3899 | 0.92 | Ambiguous | 0.1 | 1.15 | Ambiguous | 1.04 | Ambiguous | 1.09 | Destabilizing | -3.35 | Deleterious | 0.067 | Benign | 0.028 | Benign | 5.74 | Benign | 0.07 | Tolerated | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||
| c.707C>T | A236V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A236V is listed in ClinVar as Benign (ID 469162.0) and is present in gnomAD (6‑33435558‑C‑T). Prediction tools that report benign include polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, and ESM1b. Four tools give uncertain or inconclusive results: FoldX, Rosetta, Foldetta, and premPS. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because the votes are evenly split. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as uncertain, and the SGM Consensus as unavailable. Consequently, the overall prediction profile is mixed, but the most reliable high‑accuracy evidence points toward a benign effect. Therefore, the variant is most likely benign, which aligns with its ClinVar classification and does not contradict the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | Benign/Likely benign | 2 | 6-33435558-C-T | 6 | 3.72e-6 | -8.752 | Likely Pathogenic | 0.267 | Likely Benign | Likely Benign | 0.777 | Likely Pathogenic | 0.0913 | 0.5859 | 0.61 | Ambiguous | 0.2 | 1.08 | Ambiguous | 0.85 | Ambiguous | 0.64 | Ambiguous | -3.55 | Deleterious | 0.981 | Probably Damaging | 0.446 | Benign | 5.79 | Benign | 0.03 | Affected | 3.40 | 14 | 0 | 0 | 2.4 | 28.05 | 213.8 | -44.7 | 0.0 | 0.0 | -0.2 | 0.2 | X | Potentially Benign | The methyl side chain of Ala236, located on an α helix (residues Ala236-Val250) facing an anti-parallel β sheet strand (residues Ile205-Val209), interacts hydrophobically with nearby residues such as Arg239 and Phe218. In the variant simulations, the isopropyl branched hydrocarbon side chain of Val236 maintains similar hydrophobic interactions as alanine in the WT, with an overall arrangement remarkably similar to Ala236. The residue swap does not affect the protein structure based on the simulations. | ||||||||||
| c.709G>A | A237T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A237T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 (HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv), and ESM1b. Four tools (FoldX, Rosetta, Foldetta, premPS) return uncertain results. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split; Foldetta also yields an inconclusive stability assessment. Overall, the majority of evidence leans toward a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.200174 | Structured | 0.334699 | Uncertain | 0.719 | 0.352 | 0.000 | -8.664 | Likely Pathogenic | 0.213 | Likely Benign | Likely Benign | 0.539 | Likely Pathogenic | 0.0975 | 0.5737 | 0.74 | Ambiguous | 0.3 | 0.55 | Ambiguous | 0.65 | Ambiguous | 0.71 | Ambiguous | -2.66 | Deleterious | 0.900 | Possibly Damaging | 0.348 | Benign | 5.80 | Benign | 0.06 | Tolerated | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||
| c.709G>C | A237P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A237P is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include FoldX and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, Rosetta, and Foldetta. High‑accuracy assessments further support pathogenicity: the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, Foldetta is pathogenic, and AlphaMissense‑Optimized is uncertain (treated as unavailable). Overall, the preponderance of evidence indicates that A237P is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar status is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.200174 | Structured | 0.334699 | Uncertain | 0.719 | 0.352 | 0.000 | -9.119 | Likely Pathogenic | 0.827 | Likely Pathogenic | Ambiguous | 0.752 | Likely Pathogenic | 0.1593 | 0.3724 | 0.10 | Likely Benign | 0.5 | 4.20 | Destabilizing | 2.15 | Destabilizing | 1.04 | Destabilizing | -3.68 | Deleterious | 0.995 | Probably Damaging | 0.832 | Possibly Damaging | 5.77 | Benign | 0.03 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.709G>T | A237S 2D AIThe SynGAP1 missense variant A237S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and FATHMM. No tool predicts a pathogenic outcome; the only inconclusive results come from premPS and ESM1b, which are treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.200174 | Structured | 0.334699 | Uncertain | 0.719 | 0.352 | 0.000 | -7.696 | In-Between | 0.112 | Likely Benign | Likely Benign | 0.421 | Likely Benign | 0.2209 | 0.4357 | 0.48 | Likely Benign | 0.6 | 0.34 | Likely Benign | 0.41 | Likely Benign | 0.61 | Ambiguous | -1.41 | Neutral | 0.259 | Benign | 0.048 | Benign | 5.82 | Benign | 0.31 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| c.710C>A | A237D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A237D is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, while the remaining tools—SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict pathogenicity. Two tools, FoldX and AlphaMissense‑Optimized, return uncertain results. High‑accuracy assessments further support a deleterious impact: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) favors pathogenicity, AlphaMissense‑Optimized is uncertain, and Foldetta predicts a destabilizing, pathogenic effect. Overall, the evidence overwhelmingly indicates that the variant is pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.200174 | Structured | 0.334699 | Uncertain | 0.719 | 0.352 | 0.000 | -8.880 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | 0.769 | Likely Pathogenic | 0.1419 | 0.2302 | 1.23 | Ambiguous | 0.4 | 3.49 | Destabilizing | 2.36 | Destabilizing | 1.20 | Destabilizing | -3.97 | Deleterious | 0.969 | Probably Damaging | 0.704 | Possibly Damaging | 5.88 | Benign | 0.05 | Affected | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||
| c.710C>G | A237G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A237G is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Given the balance of evidence, the majority of high‑confidence predictions lean toward a benign impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.200174 | Structured | 0.334699 | Uncertain | 0.719 | 0.352 | 0.000 | -6.647 | Likely Benign | 0.316 | Likely Benign | Likely Benign | 0.538 | Likely Pathogenic | 0.1809 | 0.2910 | 1.00 | Ambiguous | 0.0 | 2.01 | Destabilizing | 1.51 | Ambiguous | 1.14 | Destabilizing | -2.91 | Deleterious | 0.900 | Possibly Damaging | 0.430 | Benign | 5.81 | Benign | 0.05 | Affected | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.710C>T | A237V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A237V is not reported in ClinVar and is absent from gnomAD. Standard in‑silico predictors are divided: benign calls come from premPS, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic calls come from REVEL, PROVEAN, polyPhen‑2 HumDiv, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) are uncertain. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, a pathogenic outcome from the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and an uncertain result from Foldetta. Because the majority of conventional predictors and the optimized AlphaMissense model favor benign, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.200174 | Structured | 0.334699 | Uncertain | 0.719 | 0.352 | 0.000 | -8.927 | Likely Pathogenic | 0.397 | Ambiguous | Likely Benign | 0.565 | Likely Pathogenic | 0.0771 | 0.4853 | 0.87 | Ambiguous | 0.4 | 0.97 | Ambiguous | 0.92 | Ambiguous | 0.18 | Likely Benign | -3.26 | Deleterious | 0.900 | Possibly Damaging | 0.430 | Benign | 5.87 | Benign | 0.10 | Tolerated | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||
| c.712G>A | E238K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E238K missense change is not reported in ClinVar and is absent from gnomAD. In silico predictors cluster into two groups: a single benign call from FATHMM, and a consensus of pathogenic predictions from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain results and are not considered evidence. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, while Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E238K. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | -13.475 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.858 | Likely Pathogenic | 0.2812 | 0.5524 | 0.56 | Ambiguous | 0.4 | 1.83 | Ambiguous | 1.20 | Ambiguous | 0.83 | Ambiguous | -3.63 | Deleterious | 0.995 | Probably Damaging | 0.695 | Possibly Damaging | 5.46 | Benign | 0.01 | Affected | 4.29 | 391 | 0 | 1 | -0.4 | -0.94 | 209.0 | 55.9 | 0.0 | 0.0 | -0.1 | 0.0 | X | Potentially Pathogenic | The negatively charged residue Glu238, located in an α helix (res. Ala236-Val250), is replaced by the positively charged residue Lys238. This charge reversal removes the periodically formed salt bridge between the carboxylate group of Glu238 and the guanidinium group of Arg234 observed in the WT simulations. In the variant simulations, both Lys238 and Arg234 form alternative salt bridges with the carboxylate group of Glu680 in the GAP domain loop. Although not visible in the simulations, the absence of the Glu238-Arg234 salt bridge could weaken the integrity of the α helix (residues Ala236-Val250) and potentially affect the tertiary assembly between the PH and GAP domains. | ||||||||||||||
| c.712G>C | E238Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E238Q missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two consensus groups: benign predictions come from SIFT and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Stability‑based methods (FoldX, Rosetta, premPS) and Foldetta give uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | -11.476 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.723 | Likely Pathogenic | 0.1372 | 0.5412 | 0.63 | Ambiguous | 0.5 | 0.59 | Ambiguous | 0.61 | Ambiguous | 0.52 | Ambiguous | -2.72 | Deleterious | 0.996 | Probably Damaging | 0.891 | Possibly Damaging | 5.44 | Benign | 0.06 | Tolerated | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.713A>C | E238A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E238A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: FATHMM predicts benign, whereas the remaining evaluated algorithms (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. Four methods (FoldX, Rosetta, Foldetta, premPS) return uncertain results and are treated as unavailable. High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta is uncertain. Overall, the preponderance of evidence indicates that E238A is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | -13.252 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.879 | Likely Pathogenic | 0.4164 | 0.5610 | 0.91 | Ambiguous | 0.3 | 1.89 | Ambiguous | 1.40 | Ambiguous | 0.57 | Ambiguous | -5.44 | Deleterious | 0.970 | Probably Damaging | 0.681 | Possibly Damaging | 5.44 | Benign | 0.04 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.713A>G | E238G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E238G is reported in gnomAD (variant ID 6‑33435564‑A‑G) but has no entry in ClinVar. Functional prediction tools largely agree on a deleterious effect: the benign‑predicting tool FATHMM is the only one that classifies it as benign, whereas the pathogenic‑predicting tools (REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Pathogenic” call) all predict a harmful impact. Predictions of uncertain status (FoldX, premPS) are treated as unavailable. High‑accuracy assessments reinforce the pathogenic view: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the overwhelming agreement among high‑confidence tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | 6-33435564-A-G | 1 | 6.19e-7 | -12.582 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.889 | Likely Pathogenic | 0.3137 | 0.4833 | 1.09 | Ambiguous | 0.2 | 3.42 | Destabilizing | 2.26 | Destabilizing | 0.87 | Ambiguous | -6.35 | Deleterious | 0.970 | Probably Damaging | 0.607 | Possibly Damaging | 5.39 | Benign | 0.00 | Affected | 3.40 | 14 | -2 | 0 | 3.1 | -72.06 | ||||||||||||||||||||
| c.713A>T | E238V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E238V is 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 and FATHMM, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E238V. This conclusion is not contradicted by 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 | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | -14.329 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.890 | Likely Pathogenic | 0.0848 | 0.6093 | 0.88 | Ambiguous | 0.4 | 0.75 | Ambiguous | 0.82 | Ambiguous | 0.45 | Likely Benign | -6.35 | Deleterious | 0.997 | Probably Damaging | 0.879 | Possibly Damaging | 5.42 | Benign | 0.00 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.714A>C | E238D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E238D missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact; the remaining methods (FoldX, Rosetta, Foldetta, premPS, ESM1b) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. The variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status because no ClinVar record exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | -7.861 | In-Between | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.691 | Likely Pathogenic | 0.1975 | 0.3619 | 1.25 | Ambiguous | 0.4 | 1.72 | Ambiguous | 1.49 | Ambiguous | 0.78 | Ambiguous | -2.72 | Deleterious | 0.868 | Possibly Damaging | 0.504 | Possibly Damaging | 5.57 | Benign | 0.05 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||
| c.714A>T | E238D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E238D missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact; the remaining methods (FoldX, Rosetta, Foldetta, premPS, ESM1b) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. The variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status because no ClinVar record exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | -7.861 | In-Between | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.691 | Likely Pathogenic | 0.1975 | 0.3619 | 1.25 | Ambiguous | 0.4 | 1.72 | Ambiguous | 1.49 | Ambiguous | 0.78 | Ambiguous | -2.72 | Deleterious | 0.868 | Possibly Damaging | 0.504 | Possibly Damaging | 5.57 | Benign | 0.05 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||
| c.715A>G | R239G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R239G missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining twelve tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts a pathogenic effect. Based on the collective predictions, 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 | 0.170161 | Structured | 0.336504 | Uncertain | 0.854 | 0.319 | 0.000 | -12.133 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.912 | Likely Pathogenic | 0.3415 | 0.3154 | 4.05 | Destabilizing | 0.1 | 3.41 | Destabilizing | 3.73 | Destabilizing | 1.33 | Destabilizing | -6.26 | Deleterious | 0.982 | Probably Damaging | 0.533 | Possibly Damaging | 5.62 | Benign | 0.02 | Affected | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||
| c.716G>A | R239K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 R239K missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are polyPhen‑2 HumVar and FATHMM, while the majority of other in silico predictors (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default) indicate a pathogenic impact. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Because uncertain or unavailable results are not taken as evidence for or against pathogenicity, the overall evidence still leans toward a deleterious effect. Consequently, 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 | 0.170161 | Structured | 0.336504 | Uncertain | 0.854 | 0.319 | 0.000 | -12.492 | Likely Pathogenic | 0.897 | Likely Pathogenic | Ambiguous | 0.719 | Likely Pathogenic | 0.5222 | 0.4000 | Weaken | 1.93 | Ambiguous | 0.2 | 1.62 | Ambiguous | 1.78 | Ambiguous | 1.41 | Destabilizing | -2.52 | Deleterious | 0.882 | Possibly Damaging | 0.428 | Benign | 5.78 | Benign | 0.03 | Affected | 3 | 2 | 0.6 | -28.01 | ||||||||||||||||||||||||
| c.716G>C | R239T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R239T is recorded in gnomAD (ID 6‑33435567‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; pathogenic predictions arise from REVEL, Rosetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). FoldX reports an uncertain effect and is therefore not considered. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. Consequently, the variant is most likely pathogenic according to the available computational evidence, and this assessment does not contradict any ClinVar classification because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.170161 | Structured | 0.336504 | Uncertain | 0.854 | 0.319 | 0.000 | 6-33435567-G-C | 1 | 6.19e-7 | -14.792 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.869 | Likely Pathogenic | 0.1805 | 0.4414 | 1.96 | Ambiguous | 0.3 | 2.44 | Destabilizing | 2.20 | Destabilizing | 1.21 | Destabilizing | -5.35 | Deleterious | 0.259 | Benign | 0.064 | Benign | 5.66 | Benign | 0.01 | Affected | 3.40 | 14 | -1 | -1 | 3.8 | -55.08 | ||||||||||||||||||||
| c.716G>T | R239I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R239I is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, while the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. No predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.170161 | Structured | 0.336504 | Uncertain | 0.854 | 0.319 | 0.000 | -19.414 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.890 | Likely Pathogenic | 0.1480 | 0.3985 | 4.32 | Destabilizing | 0.5 | 2.53 | Destabilizing | 3.43 | Destabilizing | 0.83 | Ambiguous | -7.16 | Deleterious | 0.985 | Probably Damaging | 0.724 | Possibly Damaging | 5.69 | Benign | 0.00 | Affected | -2 | -3 | 9.0 | -43.03 | |||||||||||||||||||||||||
| c.717A>C | R239S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R239S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumVar and FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic or 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) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.170161 | Structured | 0.336504 | Uncertain | 0.854 | 0.319 | 0.000 | -13.418 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.813 | Likely Pathogenic | 0.3160 | 0.3788 | 3.67 | Destabilizing | 0.1 | 2.94 | Destabilizing | 3.31 | Destabilizing | 1.26 | Destabilizing | -5.31 | Deleterious | 0.900 | Possibly Damaging | 0.376 | Benign | 5.64 | Benign | 0.02 | Affected | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||
| c.717A>T | R239S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R239S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumVar and FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic or 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) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.170161 | Structured | 0.336504 | Uncertain | 0.854 | 0.319 | 0.000 | -13.418 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.813 | Likely Pathogenic | 0.3160 | 0.3788 | 3.67 | Destabilizing | 0.1 | 2.94 | Destabilizing | 3.31 | Destabilizing | 1.26 | Destabilizing | -5.31 | Deleterious | 0.900 | Possibly Damaging | 0.376 | Benign | 5.64 | Benign | 0.02 | Affected | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||
| c.718G>A | D240N 2D AIThe SynGAP1 missense variant D240N is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Benign predictions are provided by FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions come from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus. High‑accuracy methods give a split: AlphaMissense‑Optimized predicts benign, SGM‑Consensus predicts pathogenic, and Foldetta predicts benign. Overall, the majority of tools favor a benign effect, and this consensus does not contradict the ClinVar uncertain status. 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 Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | Uncertain | 1 | -12.942 | Likely Pathogenic | 0.755 | Likely Pathogenic | Likely Benign | 0.701 | Likely Pathogenic | 0.0993 | 0.4973 | 0.22 | Likely Benign | 0.9 | 0.47 | Likely Benign | 0.35 | Likely Benign | 0.37 | Likely Benign | -4.37 | Deleterious | 0.993 | Probably Damaging | 0.984 | Probably Damaging | 5.88 | Benign | 0.01 | Affected | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||
| c.718G>C | D240H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240H missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX, Rosetta, and Foldetta are uncertain. High‑accuracy methods give a pathogenic verdict: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the consensus of the available predictions indicates that the variant is most likely pathogenic, 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 Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -14.551 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.865 | Likely Pathogenic | 0.1223 | 0.5398 | 1.14 | Ambiguous | 0.0 | 0.61 | Ambiguous | 0.88 | Ambiguous | 0.19 | Likely Benign | -6.12 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.78 | Benign | 0.00 | Affected | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||
| c.718G>T | D240Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240Y missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, premPS, and FATHMM; pathogenic predictions come from REVEL, 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, is also pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive and therefore not considered evidence. Taken together, the overwhelming majority of reliable predictors indicate a pathogenic effect for D240Y. This conclusion is consistent with the lack 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. | Likely Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -16.890 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.899 | Likely Pathogenic | 0.0439 | 0.4932 | 0.29 | Likely Benign | 0.3 | 1.07 | Ambiguous | 0.68 | Ambiguous | -0.01 | Likely Benign | -7.90 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.77 | Benign | 0.00 | Affected | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||
| c.719A>C | D240A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are premPS and FATHMM, while the remaining pathogenic‑predicting tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently flag the variant as deleterious. Tools with uncertain outcomes (FoldX, Rosetta, Foldetta) provide no definitive guidance. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenicity, and Foldetta remains inconclusive. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -12.935 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.872 | Likely Pathogenic | 0.3317 | 0.4992 | 0.75 | Ambiguous | 0.1 | 0.99 | Ambiguous | 0.87 | Ambiguous | 0.22 | Likely Benign | -7.03 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 5.80 | Benign | 0.05 | Affected | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||
| c.719A>G | D240G 2D AIThe SynGAP1 missense variant D240G is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Benign predictions are provided by premPS and FATHMM, whereas pathogenic predictions are made by REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta. FoldX‑MD is inconclusive, and AlphaMissense‑Optimized is uncertain. High‑accuracy methods show that AlphaMissense‑Optimized is inconclusive, SGM Consensus predicts pathogenic, and Foldetta predicts pathogenic. Overall, the majority of evidence points to a pathogenic effect, which is consistent with the ClinVar uncertain status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | Uncertain | 1 | -12.825 | Likely Pathogenic | 0.951 | Likely Pathogenic | Ambiguous | 0.912 | Likely Pathogenic | 0.3474 | 0.4989 | 1.85 | Ambiguous | 0.1 | 2.72 | Destabilizing | 2.29 | Destabilizing | 0.24 | Likely Benign | -6.19 | Deleterious | 0.993 | Probably Damaging | 0.984 | Probably Damaging | 5.79 | Benign | 0.01 | Affected | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||
| c.719A>T | D240V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240V missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, FATHMM, and premPS, whereas the majority of algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score—classify the change as pathogenic or likely pathogenic. FoldX and Foldetta return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for D240V. 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 | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -15.095 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.894 | Likely Pathogenic | 0.0610 | 0.4949 | 1.32 | Ambiguous | 0.1 | 0.28 | Likely Benign | 0.80 | Ambiguous | 0.11 | Likely Benign | -7.94 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 5.82 | Benign | 0.00 | Affected | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||
| c.720C>A | D240E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240E missense variant is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include FoldX, premPS, SIFT, and FATHMM, while those that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated predictors (seven pathogenic vs. four benign) lean toward a pathogenic interpretation. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -8.619 | Likely Pathogenic | 0.796 | Likely Pathogenic | Ambiguous | 0.713 | Likely Pathogenic | 0.1155 | 0.5066 | 0.49 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.50 | Ambiguous | 0.28 | Likely Benign | -3.43 | Deleterious | 0.984 | Probably Damaging | 0.967 | Probably Damaging | 5.84 | Benign | 0.10 | Tolerated | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||
| c.720C>G | D240E 2D 3DClick to see structure in 3D Viewer AISynGAP1 D240E is a missense change in the PH domain. No ClinVar entry exists for this variant, and it is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from SIFT, FoldX, premPS, and FATHMM, while pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Tools with inconclusive results—AlphaMissense‑Optimized, Rosetta, and Foldetta—are treated as unavailable. High‑accuracy assessments show the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifying the variant as Likely Pathogenic, whereas AlphaMissense‑Optimized and Foldetta provide no definitive verdict. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -8.619 | Likely Pathogenic | 0.796 | Likely Pathogenic | Ambiguous | 0.713 | Likely Pathogenic | 0.1155 | 0.5066 | 0.49 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.50 | Ambiguous | 0.28 | Likely Benign | -3.43 | Deleterious | 0.984 | Probably Damaging | 0.967 | Probably Damaging | 5.84 | Benign | 0.10 | Tolerated | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||
| c.721A>C | K241Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K241Q missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, FATHMM, and Foldetta, whereas the majority of tools predict it to be pathogenic: SGM‑Consensus, REVEL, 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 (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, nine tools predict pathogenicity versus four predicting benign, with no ClinVar evidence to contradict these findings. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -10.593 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.767 | Likely Pathogenic | 0.4225 | 0.1527 | 0.33 | Likely Benign | 0.0 | 0.46 | Likely Benign | 0.40 | Likely Benign | 0.63 | Ambiguous | -3.33 | Deleterious | 0.995 | Probably Damaging | 0.914 | Probably Damaging | 5.83 | Benign | 0.04 | Affected | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||
| c.721A>G | K241E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K241E missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include SIFT and FATHMM, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains uncertain. Overall, the preponderance of evidence from multiple independent predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -12.582 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.878 | Likely Pathogenic | 0.3610 | 0.1179 | 0.75 | Ambiguous | 0.1 | 1.36 | Ambiguous | 1.06 | Ambiguous | 0.68 | Ambiguous | -3.43 | Deleterious | 0.982 | Probably Damaging | 0.679 | Possibly Damaging | 6.00 | Benign | 0.10 | Tolerated | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||
| c.722A>C | K241T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K241T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Benign predictions are reported by Rosetta and FATHMM. Two tools (Foldetta and premPS) give uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenic; Foldetta remains uncertain. Overall, the consensus of the majority of evidence points to a pathogenic effect for K241T, 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 | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -10.911 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.853 | Likely Pathogenic | 0.2021 | 0.3951 | 2.00 | Destabilizing | 0.4 | 0.06 | Likely Benign | 1.03 | Ambiguous | 0.60 | Ambiguous | -5.14 | Deleterious | 0.995 | Probably Damaging | 0.747 | Possibly Damaging | 5.74 | Benign | 0.03 | Affected | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||
| c.722A>G | K241R 2D AIThe SynGAP1 missense variant K241R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -4.615 | Likely Benign | 0.444 | Ambiguous | Likely Benign | 0.602 | Likely Pathogenic | 0.4571 | 0.1242 | -0.23 | Likely Benign | 0.5 | -0.03 | Likely Benign | -0.13 | Likely Benign | 0.43 | Likely Benign | -2.12 | Neutral | 0.982 | Probably Damaging | 0.679 | Possibly Damaging | 5.89 | Benign | 0.14 | Tolerated | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||
| c.722A>T | K241I 2D 3DClick to see structure in 3D Viewer AISynGAP1 K241I is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Rosetta, premPS, and FATHMM. Those that predict a damaging effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). FoldX and Foldetta return uncertain results. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized reports pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, while Foldetta remains inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -14.370 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.852 | Likely Pathogenic | 0.1176 | 0.3868 | 1.31 | Ambiguous | 0.5 | 0.28 | Likely Benign | 0.80 | Ambiguous | 0.41 | Likely Benign | -6.96 | Deleterious | 0.985 | Probably Damaging | 0.704 | Possibly Damaging | 5.71 | Benign | 0.01 | Affected | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||
| c.723A>C | K241N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K241N is 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 the remaining tools—REVEL, 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 or likely pathogenic impact. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -10.198 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.663 | Likely Pathogenic | 0.3426 | 0.1872 | 0.92 | Ambiguous | 0.1 | 1.13 | Ambiguous | 1.03 | Ambiguous | 0.89 | Ambiguous | -4.23 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 5.81 | Benign | 0.03 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.723A>T | K241N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K241N is 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 predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported for FoldX, Rosetta, Foldetta, and premPS and are not used as evidence. 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. Based on the overall consensus of the available predictions, 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 | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -10.198 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.663 | Likely Pathogenic | 0.3426 | 0.1872 | 0.92 | Ambiguous | 0.1 | 1.13 | Ambiguous | 1.03 | Ambiguous | 0.89 | Ambiguous | -4.23 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 5.81 | Benign | 0.03 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.724T>A | W242R 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant W242R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that assess evolutionary conservation and protein function uniformly indicate a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool predicts a benign outcome; the only inconclusive results come from FoldX, Rosetta, and Foldetta, which are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. 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 | PH | 0.328603 | Structured | 0.352582 | Uncertain | 0.847 | 0.341 | 0.000 | -11.948 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.859 | Likely Pathogenic | 0.4206 | 0.0771 | 0.85 | Ambiguous | 0.5 | 1.15 | Ambiguous | 1.00 | Ambiguous | 1.34 | Destabilizing | -12.71 | Deleterious | 0.995 | Probably Damaging | 0.854 | Possibly Damaging | 1.52 | Pathogenic | 0.00 | Affected | 3.40 | 14 | -3 | 2 | -3.6 | -30.03 | |||||||||||||||||||||||
| c.724T>C | W242R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W242R is reported in gnomAD (ID 6‑33435575‑T‑C) but has no ClinVar entry. Across the evaluated predictors, every tool that provides a definitive call classifies the substitution as pathogenic: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No predictor reports a benign effect. FoldX, Rosetta, and Foldetta return uncertain results and are treated as unavailable evidence. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, while Foldetta remains inconclusive. Consequently, the variant is most likely pathogenic based on the consensus of pathogenic 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. | Likely Pathogenic | PH | 0.328603 | Structured | 0.352582 | Uncertain | 0.847 | 0.341 | 0.000 | 6-33435575-T-C | 2 | 1.24e-6 | -11.948 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.858 | Likely Pathogenic | 0.4206 | 0.0771 | 0.85 | Ambiguous | 0.5 | 1.15 | Ambiguous | 1.00 | Ambiguous | 1.34 | Destabilizing | -12.71 | Deleterious | 0.995 | Probably Damaging | 0.854 | Possibly Damaging | 1.52 | Pathogenic | 0.00 | Affected | 3.40 | 14 | -3 | 2 | -3.6 | -30.03 | ||||||||||||||||||||
| c.724T>G | W242G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W242G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD, so no population frequency data are available. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the single uncertain call from premPS is treated as unavailable. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the unanimous pathogenic predictions and the lack of benign 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 | PH | 0.328603 | Structured | 0.352582 | Uncertain | 0.847 | 0.341 | 0.000 | -14.319 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.883 | Likely Pathogenic | 0.4378 | 0.1851 | 2.70 | Destabilizing | 0.3 | 2.48 | Destabilizing | 2.59 | Destabilizing | 0.83 | Ambiguous | -11.80 | Deleterious | 0.900 | Possibly Damaging | 0.452 | Possibly Damaging | 1.52 | Pathogenic | 0.00 | Affected | -7 | -2 | 0.5 | -129.16 | |||||||||||||||||||||||||
| c.725G>C | W242S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W242S, located in the PH domain, is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool predicts a benign outcome. High‑accuracy assessments further support a harmful impact: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic,” while Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the consensus of available predictions indicates that W242S 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 | PH | 0.328603 | Structured | 0.352582 | Uncertain | 0.847 | 0.341 | 0.000 | -14.674 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.797 | Likely Pathogenic | 0.4424 | 0.1418 | 1.96 | Ambiguous | 0.2 | 1.97 | Ambiguous | 1.97 | Ambiguous | 0.83 | Ambiguous | -12.71 | Deleterious | 0.900 | Possibly Damaging | 0.535 | Possibly Damaging | 1.52 | Pathogenic | 0.00 | Affected | -2 | -3 | 0.1 | -99.14 | |||||||||||||||||||||||||
| c.725G>T | W242L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W242L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (FoldX, Rosetta, Foldetta, premPS) and pathogenic predictions (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score of Likely Pathogenic). High‑accuracy assessments further support this dichotomy: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a benign effect. Overall, the majority of evidence points toward a pathogenic impact for W242L. 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 | PH | 0.328603 | Structured | 0.352582 | Uncertain | 0.847 | 0.341 | 0.000 | -12.297 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.799 | Likely Pathogenic | 0.2370 | 0.2986 | -0.29 | Likely Benign | 0.3 | 0.12 | Likely Benign | -0.09 | Likely Benign | 0.44 | Likely Benign | -11.80 | Deleterious | 0.948 | Possibly Damaging | 0.533 | Possibly Damaging | 1.52 | Pathogenic | 0.01 | Affected | -2 | -2 | 4.7 | -73.05 | |||||||||||||||||||||||||
| c.726G>C | W242C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 W242C missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS, and no tools predict a benign outcome. 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. Based on the collective predictions, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as ClinVar has not yet classified the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.328603 | Structured | 0.352582 | Uncertain | 0.847 | 0.341 | 0.000 | -13.117 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.889 | Likely Pathogenic | 0.3626 | 0.1617 | 1.77 | Ambiguous | 0.4 | 1.62 | Ambiguous | 1.70 | Ambiguous | 0.63 | Ambiguous | -11.80 | Deleterious | 0.999 | Probably Damaging | 0.887 | Possibly Damaging | 1.52 | Pathogenic | 0.00 | Affected | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||
| c.726G>T | W242C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W242C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS, and no tools predict a benign outcome. 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. Based on the collective predictions, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as ClinVar has not yet classified the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.328603 | Structured | 0.352582 | Uncertain | 0.847 | 0.341 | 0.000 | -13.117 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.889 | Likely Pathogenic | 0.3626 | 0.1617 | 1.77 | Ambiguous | 0.4 | 1.62 | Ambiguous | 1.70 | Ambiguous | 0.63 | Ambiguous | -11.80 | Deleterious | 0.999 | Probably Damaging | 0.887 | Possibly Damaging | 1.52 | Pathogenic | 0.00 | Affected | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||
| c.727A>C | I243L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I243L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from AlphaMissense‑Default and ESM1b, which are treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields benign; and Foldetta also predicts benign. Overall, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -7.890 | In-Between | 0.524 | Ambiguous | Likely Benign | 0.380 | Likely Benign | 0.0626 | 0.2891 | -0.03 | Likely Benign | 0.2 | -0.35 | Likely Benign | -0.19 | Likely Benign | 0.32 | Likely Benign | -0.33 | Neutral | 0.048 | Benign | 0.039 | Benign | 5.74 | Benign | 0.19 | Tolerated | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||
| c.727A>G | I243V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I243V is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b. FoldX and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -8.237 | Likely Pathogenic | 0.314 | Likely Benign | Likely Benign | 0.445 | Likely Benign | 0.1019 | 0.2591 | 1.09 | Ambiguous | 0.1 | 0.19 | Likely Benign | 0.64 | Ambiguous | 0.39 | Likely Benign | -0.39 | Neutral | 0.617 | Possibly Damaging | 0.140 | Benign | 5.71 | Benign | 0.15 | Tolerated | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||
| c.727A>T | I243F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I243F 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, and FATHMM. Tools that agree on a pathogenic effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give inconclusive results: 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 is uncertain. Overall, the majority of available predictions (7 pathogenic vs. 3 benign) indicate a likely pathogenic impact. This assessment 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. | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -12.559 | Likely Pathogenic | 0.934 | Likely Pathogenic | Ambiguous | 0.793 | Likely Pathogenic | 0.0409 | 0.2205 | 2.92 | Destabilizing | 2.5 | 0.53 | Ambiguous | 1.73 | Ambiguous | 0.42 | Likely Benign | -2.21 | Neutral | 0.985 | Probably Damaging | 0.724 | Possibly Damaging | 5.53 | Benign | 0.02 | Affected | 1 | 0 | -1.7 | 34.02 | ||||||||||||||||||||||||||
| c.728T>A | I243N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant I243N is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into three groups: benign (FATHMM), pathogenic (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized), and uncertain (FoldX, Rosetta, Foldetta). High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -14.784 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.811 | Likely Pathogenic | 0.0899 | 0.0212 | 1.90 | Ambiguous | 0.2 | 1.43 | Ambiguous | 1.67 | Ambiguous | 1.76 | Destabilizing | -4.46 | Deleterious | 0.995 | Probably Damaging | 0.854 | Possibly Damaging | 5.49 | Benign | 0.00 | Affected | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||
| c.728T>C | I243T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I243T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all classify the variant as pathogenic. Only FATHMM predicts a benign outcome, while Foldetta, AlphaMissense‑Optimized, and Rosetta return uncertain results, which are treated as unavailable evidence. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that I243T is most likely pathogenic, and this conclusion does not contradict 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 | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -9.102 | Likely Pathogenic | 0.922 | Likely Pathogenic | Ambiguous | 0.816 | Likely Pathogenic | 0.1027 | 0.0541 | 2.15 | Destabilizing | 0.2 | 1.52 | Ambiguous | 1.84 | Ambiguous | 1.72 | Destabilizing | -3.06 | Deleterious | 0.982 | Probably Damaging | 0.702 | Possibly Damaging | 5.55 | Benign | 0.01 | Affected | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||
| c.728T>G | I243S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I243S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity largely agree: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. Only FATHMM predicts a benign outcome. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -14.097 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.802 | Likely Pathogenic | 0.2658 | 0.0600 | 2.52 | Destabilizing | 0.2 | 2.22 | Destabilizing | 2.37 | Destabilizing | 1.71 | Destabilizing | -3.55 | Deleterious | 0.995 | Probably Damaging | 0.795 | Possibly Damaging | 5.52 | Benign | 0.00 | Affected | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||
| c.729T>G | I243M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I243M has no ClinVar entry (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign”; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts a benign effect. Overall, the consensus of the majority of tools, including the high‑accuracy methods, indicates that the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -4.305 | Likely Benign | 0.175 | Likely Benign | Likely Benign | 0.474 | Likely Benign | 0.0553 | 0.2200 | 0.09 | Likely Benign | 0.1 | 0.16 | Likely Benign | 0.13 | Likely Benign | -0.01 | Likely Benign | 0.58 | Neutral | 0.985 | Probably Damaging | 0.798 | Possibly Damaging | 5.61 | Benign | 0.94 | Tolerated | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||
| c.730G>A | E244K 2D AISynGAP1 missense variant E244K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from FoldX, Rosetta, Foldetta, SIFT, and FATHMM, whereas pathogenic predictions are reported by REVEL, PROVEAN, both polyPhen‑2 HumDiv and HumVar, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (Likely Pathogenic). The high‑accuracy methods give a clearer picture: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus also indicates likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. With the majority of consensus tools leaning toward pathogenic and the two high‑accuracy pathogenic predictions outweighing the benign Foldetta result, the variant is most likely pathogenic. This assessment does not contradict any ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.450668 | Structured | 0.329406 | Uncertain | 0.778 | 0.360 | 0.000 | -13.975 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.841 | Likely Pathogenic | 0.1887 | 0.6177 | 0.40 | Likely Benign | 1.0 | 0.45 | Likely Benign | 0.43 | Likely Benign | 0.80 | Ambiguous | -3.37 | Deleterious | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 5.82 | Benign | 0.07 | Tolerated | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||
| c.730G>C | E244Q 2D AIThe SynGAP1 E244Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, premPS, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, six tools predict pathogenicity versus five predicting benignity, with no ClinVar evidence to contradict these findings. Thus, the variant is most likely pathogenic based on the current predictive landscape. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.450668 | Structured | 0.329406 | Uncertain | 0.778 | 0.360 | 0.000 | -10.245 | Likely Pathogenic | 0.928 | Likely Pathogenic | Ambiguous | 0.695 | Likely Pathogenic | 0.1016 | 0.5610 | 0.23 | Likely Benign | 0.9 | -0.77 | Ambiguous | -0.27 | Likely Benign | 0.40 | Likely Benign | -2.49 | Neutral | 0.990 | Probably Damaging | 0.815 | Possibly Damaging | 5.78 | Benign | 0.05 | Affected | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||
| c.731A>C | E244A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244A missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, and FATHMM, while pathogenic predictions are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign stability. Overall, the majority of evidence points toward a pathogenic effect, 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 | 0.450668 | Structured | 0.329406 | Uncertain | 0.778 | 0.360 | 0.000 | -11.227 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 0.865 | Likely Pathogenic | 0.2672 | 0.4926 | 0.39 | Likely Benign | 0.1 | -0.45 | Likely Benign | -0.03 | Likely Benign | 0.82 | Ambiguous | -4.99 | Deleterious | 0.970 | Probably Damaging | 0.584 | Possibly Damaging | 5.74 | Benign | 0.01 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.731A>G | E244G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome. Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, yields an uncertain result and is treated as unavailable evidence. Overall, the preponderance of computational evidence points to the variant being 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 | 0.450668 | Structured | 0.329406 | Uncertain | 0.778 | 0.360 | 0.000 | -10.452 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.900 | Likely Pathogenic | 0.2266 | 0.5252 | 1.28 | Ambiguous | 0.0 | 0.74 | Ambiguous | 1.01 | Ambiguous | 1.01 | Destabilizing | -5.67 | Deleterious | 0.990 | Probably Damaging | 0.815 | Possibly Damaging | 5.73 | Benign | 0.01 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.731A>T | E244V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244V 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 only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts pathogenicity; Foldetta remains 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 contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.450668 | Structured | 0.329406 | Uncertain | 0.778 | 0.360 | 0.000 | -12.118 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.925 | Likely Pathogenic | 0.0636 | 0.6073 | 1.04 | Ambiguous | 0.1 | 1.02 | Ambiguous | 1.03 | Ambiguous | 0.56 | Ambiguous | -5.90 | Deleterious | 0.997 | Probably Damaging | 0.879 | Possibly Damaging | 5.68 | Benign | 0.00 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.732G>C | E244D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX and FATHMM, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence favors a pathogenic classification for E244D, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.450668 | Structured | 0.329406 | Uncertain | 0.778 | 0.360 | 0.000 | -7.839 | In-Between | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.730 | Likely Pathogenic | 0.1740 | 0.3783 | 0.46 | Likely Benign | 0.1 | 1.61 | Ambiguous | 1.04 | Ambiguous | 0.93 | Ambiguous | -2.53 | Deleterious | 0.976 | Probably Damaging | 0.675 | Possibly Damaging | 5.78 | Benign | 0.03 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||
| c.732G>T | E244D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX and FATHMM, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results come from Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence points to a likely pathogenic effect for E244D, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.450668 | Structured | 0.329406 | Uncertain | 0.778 | 0.360 | 0.000 | -7.839 | In-Between | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.730 | Likely Pathogenic | 0.1740 | 0.3783 | 0.46 | Likely Benign | 0.1 | 1.61 | Ambiguous | 1.04 | Ambiguous | 0.93 | Ambiguous | -2.53 | Deleterious | 0.976 | Probably Damaging | 0.675 | Possibly Damaging | 5.78 | Benign | 0.03 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||
| c.733A>C | N245H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245H is not reported in ClinVar and is absent from gnomAD. Among in‑silico predictors, benign calls come from FoldX, Rosetta, and FATHMM, whereas pathogenic calls are made by SGM‑Consensus, REVEL, 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 (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. The overall pattern of predictions leans toward pathogenicity, with a majority of tools indicating a deleterious effect. Thus, 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 | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -11.536 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.825 | Likely Pathogenic | 0.1437 | 0.7271 | 0.23 | Likely Benign | 0.1 | -0.20 | Likely Benign | 0.02 | Likely Benign | 0.55 | Ambiguous | -4.15 | Deleterious | 0.995 | Probably Damaging | 0.880 | Possibly Damaging | 5.84 | Benign | 0.01 | Affected | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||
| c.733A>G | N245D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, SIFT, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools, premPS and ESM1b, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions (six pathogenic vs five benign) and the consensus of high‑accuracy methods lean toward a pathogenic interpretation. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -7.847 | In-Between | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.712 | Likely Pathogenic | 0.1953 | 0.4599 | 0.27 | Likely Benign | 0.0 | 0.09 | Likely Benign | 0.18 | Likely Benign | 0.79 | Ambiguous | -3.62 | Deleterious | 0.982 | Probably Damaging | 0.679 | Possibly Damaging | 5.84 | Benign | 0.13 | Tolerated | 2 | 1 | 0.0 | 0.98 | ||||||||||||||||||||||||||
| c.733A>T | N245Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N245Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Rosetta, Foldetta, and FATHMM, whereas pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a pathogenic majority (3/4). AlphaMissense‑Optimized independently predicts pathogenicity, while Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. premPS remains uncertain. Overall, the majority of evidence points toward a pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Thus, the variant is most likely pathogenic, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -12.476 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.855 | Likely Pathogenic | 0.0706 | 0.6771 | -0.36 | Likely Benign | 0.1 | 0.11 | Likely Benign | -0.13 | Likely Benign | 0.59 | Ambiguous | -6.68 | Deleterious | 0.995 | Probably Damaging | 0.880 | Possibly Damaging | 5.86 | Benign | 0.00 | Affected | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||
| c.734A>C | N245T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245T is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include FATHMM, Rosetta, and Foldetta, whereas the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support this dichotomy: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic, while Foldetta predicts a benign effect. No predictions are missing or inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for the variant, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -11.955 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.794 | Likely Pathogenic | 0.1397 | 0.7734 | 0.52 | Ambiguous | 0.1 | 0.04 | Likely Benign | 0.28 | Likely Benign | 0.76 | Ambiguous | -4.79 | Deleterious | 0.948 | Possibly Damaging | 0.588 | Possibly Damaging | 5.87 | Benign | 0.01 | Affected | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||
| c.734A>G | N245S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence (8 benign vs. 5 pathogenic) supports a benign classification. This conclusion does not contradict ClinVar, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -6.792 | Likely Benign | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.524 | Likely Pathogenic | 0.3557 | 0.7229 | 0.46 | Likely Benign | 0.1 | -0.16 | Likely Benign | 0.15 | Likely Benign | 0.42 | Likely Benign | -3.75 | Deleterious | 0.787 | Possibly Damaging | 0.404 | Benign | 5.90 | Benign | 0.07 | Tolerated | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||
| c.734A>T | N245I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245I is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include Rosetta, Foldetta, and FATHMM, while those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, as the variant is currently unreported in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -14.527 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.831 | Likely Pathogenic | 0.0672 | 0.6999 | -0.56 | Ambiguous | 0.1 | 0.04 | Likely Benign | -0.26 | Likely Benign | 0.60 | Ambiguous | -7.46 | Deleterious | 0.995 | Probably Damaging | 0.832 | Possibly Damaging | 5.88 | Benign | 0.00 | Affected | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||
| c.735T>A | N245K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245K is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, FoldX, Rosetta, and FATHMM, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM, aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and yields a majority pathogenic verdict. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, classifies the variant as benign. Overall, the majority of individual predictors and the SGM consensus favor a pathogenic effect, while Foldetta and a subset of benign tools suggest stability preservation. Given the predominance of pathogenic predictions and the absence of ClinVar annotation, the variant is most likely pathogenic and does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -12.110 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.474 | Likely Benign | 0.2271 | 0.5645 | -0.32 | Likely Benign | 0.1 | 0.01 | Likely Benign | -0.16 | Likely Benign | 0.83 | Ambiguous | -4.86 | Deleterious | 0.948 | Possibly Damaging | 0.588 | Possibly Damaging | 5.88 | Benign | 0.01 | Affected | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||
| c.735T>G | N245K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245K is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, Rosetta, and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, the SGM Consensus also indicates Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a Benign effect. Overall, the preponderance of evidence—including the high‑accuracy tools—points to a pathogenic impact for N245K, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -12.110 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.474 | Likely Benign | 0.2271 | 0.5645 | -0.32 | Likely Benign | 0.1 | 0.01 | Likely Benign | -0.16 | Likely Benign | 0.83 | Ambiguous | -4.86 | Deleterious | 0.948 | Possibly Damaging | 0.588 | Possibly Damaging | 5.88 | Benign | 0.01 | Affected | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||
| c.736C>A | L246M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L246M has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include PROVEAN and FATHMM, while a majority (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) are uncertain. High‑accuracy methods 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 is uncertain. Thus no high‑accuracy tool provides a definitive verdict. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict any ClinVar status because no ClinVar record exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.472492 | Structured | 0.302312 | Uncertain | 0.859 | 0.364 | 0.000 | -11.386 | Likely Pathogenic | 0.922 | Likely Pathogenic | Ambiguous | 0.661 | Likely Pathogenic | 0.0710 | 0.3511 | 0.65 | Ambiguous | 0.2 | 0.76 | Ambiguous | 0.71 | Ambiguous | 0.87 | Ambiguous | -1.79 | Neutral | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.72 | Benign | 0.01 | Affected | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||
| c.736C>G | L246V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L246V is reported in gnomAD (variant ID 6‑33435587‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: pathogenic calls are made by SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Only FATHMM predicts a benign outcome. Uncertain results are reported by Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. The overwhelming majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.472492 | Structured | 0.302312 | Uncertain | 0.859 | 0.364 | 0.000 | 6-33435587-C-G | 1 | 6.20e-7 | -12.092 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 0.736 | Likely Pathogenic | 0.1434 | 0.3607 | 2.09 | Destabilizing | 0.1 | 1.52 | Ambiguous | 1.81 | Ambiguous | 1.13 | Destabilizing | -2.60 | Deleterious | 0.930 | Possibly Damaging | 0.504 | Possibly Damaging | 4.71 | Benign | 0.01 | Affected | 3.41 | 14 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||
| c.737T>A | L246Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L246Q missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining tools—SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; Rosetta is uncertain and is not grouped. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Taken together, the overwhelming majority of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.472492 | Structured | 0.302312 | Uncertain | 0.859 | 0.364 | 0.000 | -15.420 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.921 | Likely Pathogenic | 0.1092 | 0.0758 | 2.82 | Destabilizing | 0.3 | 1.79 | Ambiguous | 2.31 | Destabilizing | 1.69 | Destabilizing | -5.43 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.67 | Benign | 0.00 | Affected | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||
| c.737T>C | L246P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L246P is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: the single benign prediction comes from FATHMM, while all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the consensus of these tools, 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 | 0.472492 | Structured | 0.302312 | Uncertain | 0.859 | 0.364 | 0.000 | -16.581 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.944 | Likely Pathogenic | 0.3731 | 0.1582 | 6.42 | Destabilizing | 0.3 | 8.72 | Destabilizing | 7.57 | Destabilizing | 1.79 | Destabilizing | -6.30 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.67 | Benign | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
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