Table of SynGAP1 Isoform α2 (UniProt Q96PV0-1) Missense Variants.
| c.dna | Variant | SGM Consensus | Domain and Structure information: based on WT protein | Annotated databases | Deep learning-based pathogenicity predictions | Folding stability-based pathogenicity predictions | Sequence/structure-based pathogenicity predictions | Phase Separation | Evolutionary/physical properties | Molecular Dynamics-based analysis | DOI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Domain | IUPred2 | ANCHOR2 | AlphaFold | MobiDB | PhosphoSitePlus | ClinVar | gnomAD | ESM1b | AlphaMissense | FoldX | Rosetta | Foldetta | PremPS | REVEL | PROVEAN | PolyPhen-2 HumDiv | PolyPhen-2 HumVar | FATHMM | SIFT | PSMutPred | PAM | Physical | SASA | Normalized B-factor backbone | Normalized B-factor sidechain | SynGAP Structural Annotation | |||||||||||||||||||||||||||||||||||||||||||||
| Score | Prediction | Score | Prediction | pLDDT | disorder | disorder | LTP | HTP | KL | PTM | Clinical Status | Review | Subm. | ID | Allele count | Allele freq. | LLR score | Prediction | Pathogenicity | Class | Optimized | Average ΔΔG | Prediction | StdDev | ΔΔG | Prediction | ΔΔG | Prediction | ΔΔG | Prediction | Score | Prediction | Score | Prediction | pph2_prob | Prediction | pph2_prob | Prediction | Nervous System Score | Prediction | Prediction | Status | Conservation | Sequences | IP RF | SP RF | Prediction | PAM250 | PAM120 | Hydropathy Δ | MW Δ | Average | Δ | Δ | StdDev | Δ | StdDev | Secondary | Tertiary bonds | Inside out | GAP-Ras interface | At membrane | No effect | MD Alert | Verdict | Description | |||||
| c.2496G>C | Q832H 2D  AIThe SynGAP1 missense variant Q832H is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.619913 | Binding | 0.290 | 0.877 | 0.375 | -3.322 | Likely Benign | 0.197 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -1.24 | Neutral | 0.064 | Benign | 0.038 | Benign | 2.76 | Benign | 0.03 | Affected | 0.1263 | 0.3230 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2496G>T | Q832H 2D AIThe SynGAP1 missense variant Q832H is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.619913 | Binding | 0.290 | 0.877 | 0.375 | -3.322 | Likely Benign | 0.197 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -1.24 | Neutral | 0.064 | Benign | 0.038 | Benign | 2.76 | Benign | 0.03 | Affected | 0.1263 | 0.3230 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2638G>A | A880T 2D  AIThe SynGAP1 missense variant A880T 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. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign 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 | 0.703578 | Disordered | 0.621441 | Binding | 0.309 | 0.874 | 0.250 | -4.594 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.75 | Neutral | 0.761 | Possibly Damaging | 0.399 | Benign | 2.61 | Benign | 0.29 | Tolerated | 0.1229 | 0.6396 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2638G>C | A880P 2D  AIThe SynGAP1 missense variant A880P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign 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 | 0.703578 | Disordered | 0.621441 | Binding | 0.309 | 0.874 | 0.250 | -3.671 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.098 | Likely Benign | -0.55 | Neutral | 0.971 | Probably Damaging | 0.693 | Possibly Damaging | 2.61 | Benign | 0.11 | Tolerated | 0.1744 | 0.4106 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2638G>T | A880S 2D  AIThe SynGAP1 missense variant A880S is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.621441 | Binding | 0.309 | 0.874 | 0.250 | -3.149 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -0.33 | Neutral | 0.393 | Benign | 0.187 | Benign | 2.63 | Benign | 0.10 | Tolerated | 0.2504 | 0.5108 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2639C>A | A880D 2D  AIThe SynGAP1 missense variant A880D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicating a likely benign outcome, and no Foldetta stability result is available. Based on the overall consensus of the available predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.621441 | Binding | 0.309 | 0.874 | 0.250 | -4.571 | Likely Benign | 0.493 | Ambiguous | Likely Benign | 0.127 | Likely Benign | -1.29 | Neutral | 0.918 | Possibly Damaging | 0.401 | Benign | 2.60 | Benign | 0.03 | Affected | 0.1664 | 0.1904 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2639C>G | A880G 2D  AIThe SynGAP1 missense variant A880G is catalogued in gnomAD (ID 6‑33443191‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a benign or likely benign outcome. Only SIFT classifies the change as pathogenic, representing a single discordant signal. High‑accuracy assessments confirm the benign prediction: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus likewise reports likely benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the consensus of the majority of tools, including the high‑accuracy methods, 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 | 0.703578 | Disordered | 0.621441 | Binding | 0.309 | 0.874 | 0.250 | 6-33443191-C-G | 2 | 1.24e-6 | -3.283 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -0.14 | Neutral | 0.002 | Benign | 0.007 | Benign | 2.62 | Benign | 0.04 | Affected | 3.77 | 5 | 0.2136 | 0.3841 | 0 | 1 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.2639C>T | A880V 2D  AIThe SynGAP1 missense variant A880V is reported in gnomAD (variant ID 6‑33443191‑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 the change 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 reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign impact for A880V, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.621441 | Binding | 0.309 | 0.874 | 0.250 | 6-33443191-C-T | 1 | 6.20e-7 | -5.440 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.095 | Likely Benign | -0.11 | Neutral | 0.761 | Possibly Damaging | 0.399 | Benign | 2.58 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.0947 | 0.5362 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||
| c.2635G>A | A879T 2D AIThe SynGAP1 missense variant A879T is reported in gnomAD (6-33443187‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign. No Foldetta stability analysis is available, so it does not influence the overall assessment. Taken together, the majority of evidence points to a benign impact for A879T, and this conclusion is not contradicted by any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.622695 | Binding | 0.277 | 0.874 | 0.250 | 6-33443187-G-A | 3 | 1.86e-6 | -5.161 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.042 | Likely Benign | -0.98 | Neutral | 0.872 | Possibly Damaging | 0.580 | Possibly Damaging | 2.66 | Benign | 0.19 | Tolerated | 3.77 | 5 | 0.1292 | 0.6754 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.2635G>C | A879P 2D AIThe SynGAP1 missense variant A879P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that A879P is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.622695 | Binding | 0.277 | 0.874 | 0.250 | -4.317 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.151 | Likely Benign | -1.16 | Neutral | 0.986 | Probably Damaging | 0.825 | Possibly Damaging | 2.61 | Benign | 0.23 | Tolerated | 0.1713 | 0.5004 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2635G>T | A879S 2D AIThe SynGAP1 missense variant A879S 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 Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence supports a benign classification, and this is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.622695 | Binding | 0.277 | 0.874 | 0.250 | -3.406 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -0.26 | Neutral | 0.580 | Possibly Damaging | 0.324 | Benign | 2.68 | Benign | 0.44 | Tolerated | 0.2469 | 0.5266 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2635_2636delinsAA | A879K 2D  AIThe SynGAP1 missense variant A879K is listed in ClinVar (ID 575856.0) as benign and is not reported in gnomAD. Prediction tools that agree on a benign effect include PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this consensus aligns with the ClinVar designation, with no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.622695 | Binding | 0.277 | 0.874 | 0.250 | Likely Benign | 1 | -5.877 | Likely Benign | 0.757 | Likely Pathogenic | Likely Benign | -0.71 | Neutral | 0.969 | Probably Damaging | 0.593 | Possibly Damaging | 2.69 | Benign | 0.21 | Tolerated | 3.77 | 5 | 0.0930 | 0.2569 | -1 | -1 | -5.7 | 57.10 | |||||||||||||||||||||||||||||||||||||
| c.2636C>A | A879E 2D  AIThe SynGAP1 missense variant A879E is reported in gnomAD (variant ID 6‑33443188‑C‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy predictions specifically show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta data is missing. Overall, the majority of evidence points to a benign effect, 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 Benign | 0.608892 | Disordered | 0.622695 | Binding | 0.277 | 0.874 | 0.250 | 6-33443188-C-A | 1 | 6.20e-7 | -3.786 | Likely Benign | 0.503 | Ambiguous | Likely Benign | 0.070 | Likely Benign | -0.27 | Neutral | 0.872 | Possibly Damaging | 0.659 | Possibly Damaging | 2.70 | Benign | 0.27 | Tolerated | 3.77 | 5 | 0.1120 | 0.1903 | -1 | 0 | -5.3 | 58.04 | ||||||||||||||||||||||||||||||||||
| c.2636C>G | A879G 2D AIThe SynGAP1 missense variant A879G is reported in gnomAD (variant ID 6-33443188-C-G) but has no ClinVar entry. Functional prediction tools uniformly classify the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign effect. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available, so they do not influence the assessment. Based on the collective predictions, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.622695 | Binding | 0.277 | 0.874 | 0.250 | 6-33443188-C-G | 1 | 6.20e-7 | -3.924 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.43 | Neutral | 0.001 | Benign | 0.007 | Benign | 2.69 | Benign | 0.43 | Tolerated | 3.77 | 5 | 0.2214 | 0.4362 | 0 | 1 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.2636C>T | A879V 2D AIThe SynGAP1 missense variant A879V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.622695 | Binding | 0.277 | 0.874 | 0.250 | -6.177 | Likely Benign | 0.152 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -1.46 | Neutral | 0.872 | Possibly Damaging | 0.580 | Possibly Damaging | 2.64 | Benign | 0.19 | Tolerated | 0.1003 | 0.6293 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.2497A>C | K833Q 2D  AIThe SynGAP1 missense variant K833Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. 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, reports the variant as likely benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign; Foldetta stability analysis is unavailable. Overall, the consensus of most evidence points to a benign effect, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.625797 | Binding | 0.315 | 0.863 | 0.375 | -1.586 | Likely Benign | 0.215 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -0.34 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.62 | Benign | 0.68 | Tolerated | 0.3744 | 0.1219 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2497A>G | K833E 2D  AIThe SynGAP1 missense variant K833E is evaluated by multiple in silico tools. Benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions are reported by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The AlphaMissense‑Default score is uncertain. The consensus predictor SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus confirms Likely Benign, and Foldetta data are not available. ClinVar contains no entry for this variant, and it is absent from gnomAD, so no external evidence contradicts the computational assessment. Based on the collective predictions, the variant is most likely benign, with no conflict from ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.625797 | Binding | 0.315 | 0.863 | 0.375 | -2.495 | Likely Benign | 0.506 | Ambiguous | Likely Benign | 0.108 | Likely Benign | -0.69 | Neutral | 0.997 | Probably Damaging | 0.925 | Probably Damaging | 2.72 | Benign | 0.04 | Affected | 0.3162 | 0.1039 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.2498A>C | K833T 2D  AIThe SynGAP1 missense variant K833T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic outcome. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized independently predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the aggregate predictions, K833T is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.625797 | Binding | 0.315 | 0.863 | 0.375 | -1.741 | Likely Benign | 0.481 | Ambiguous | Likely Benign | 0.142 | Likely Benign | -1.65 | Neutral | 0.990 | Probably Damaging | 0.921 | Probably Damaging | 2.60 | Benign | 0.02 | Affected | 0.1848 | 0.3335 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||||||
| c.2498A>G | K833R 2D  AIThe SynGAP1 missense variant K833R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that K833R is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.625797 | Binding | 0.315 | 0.863 | 0.375 | -2.158 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -0.83 | Neutral | 0.997 | Probably Damaging | 0.925 | Probably Damaging | 2.61 | Benign | 0.11 | Tolerated | 0.3864 | 0.0945 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||||||||||||
| c.2498A>T | K833M 2D  AIThe SynGAP1 missense variant K833M is not reported 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 evaluated predictors (six benign vs. four pathogenic) support a benign classification. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.625797 | Binding | 0.315 | 0.863 | 0.375 | -3.234 | Likely Benign | 0.685 | Likely Pathogenic | Likely Benign | 0.181 | Likely Benign | -2.05 | Neutral | 0.997 | Probably Damaging | 0.954 | Probably Damaging | 2.55 | Benign | 0.01 | Affected | 0.0867 | 0.3652 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.2499G>C | K833N 2D  AIThe SynGAP1 missense variant K833N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation. This conclusion is consistent with the lack 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 | 0.671169 | Disordered | 0.625797 | Binding | 0.315 | 0.863 | 0.375 | -2.759 | Likely Benign | 0.579 | Likely Pathogenic | Likely Benign | 0.087 | Likely Benign | -1.02 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.61 | Benign | 0.02 | Affected | 0.3088 | 0.1464 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2499G>T | K833N 2D AIThe SynGAP1 missense variant K833N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for K833N, 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 | 0.671169 | Disordered | 0.625797 | Binding | 0.315 | 0.863 | 0.375 | -2.759 | Likely Benign | 0.579 | Likely Pathogenic | Likely Benign | 0.087 | Likely Benign | -1.02 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.61 | Benign | 0.02 | Affected | 0.3088 | 0.1464 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3778A>C | K1260Q 2D AIThe SynGAP1 missense variant K1260Q is listed in ClinVar with no submitted interpretation and is present in gnomAD (ID 6‑33446770‑A‑C). Functional prediction tools cluster into two groups: benign predictions come from REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. ESM1b is uncertain. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts benign, but the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic verdict, and Foldetta results are unavailable. Overall, the majority of evidence points to pathogenicity, and this conclusion does not contradict the ClinVar status, which remains unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.509769 | Disordered | 0.625808 | Binding | 0.890 | 0.575 | 0.250 | 6-33446770-A-C | -7.830 | In-Between | 0.325 | Likely Benign | Likely Benign | 0.367 | Likely Benign | -3.06 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.36 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.3597 | 0.1102 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||||||||
| c.3778A>G | K1260E 2D AIThe SynGAP1 missense variant K1260E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—predict a pathogenic impact, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus remains pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions point to a pathogenic effect, and there is no ClinVar annotation to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.509769 | Disordered | 0.625808 | Binding | 0.890 | 0.575 | 0.250 | -10.913 | Likely Pathogenic | 0.846 | Likely Pathogenic | Ambiguous | 0.462 | Likely Benign | -3.06 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.38 | Pathogenic | 0.00 | Affected | 0.3129 | 0.0877 | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3779A>C | K1260T 2D AIThe SynGAP1 missense variant K1260T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (which is “Likely Pathogenic” based on a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Benign predictions are limited to REVEL and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains pathogenic. No Foldetta stability analysis is available for this variant. Overall, the preponderance of evidence from multiple in‑silico tools indicates that K1260T is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.509769 | Disordered | 0.625808 | Binding | 0.890 | 0.575 | 0.250 | -10.099 | Likely Pathogenic | 0.772 | Likely Pathogenic | Likely Benign | 0.387 | Likely Benign | -4.59 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.33 | Pathogenic | 0.00 | Affected | 0.1859 | 0.3028 | 0 | -1 | 3.2 | -27.07 | ||||||||||||||||||||||||||||||||||||||
| c.3779A>G | K1260R 2D AIThe SynGAP1 missense variant K1260R is catalogued in gnomAD (ID 6‑33446771‑A‑G) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; those that predict pathogenicity are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the collective predictions point to a benign impact, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.509769 | Disordered | 0.625808 | Binding | 0.890 | 0.575 | 0.250 | 6-33446771-A-G | 1 | 6.20e-7 | -6.033 | Likely Benign | 0.135 | Likely Benign | Likely Benign | 0.254 | Likely Benign | -2.29 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.40 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.3655 | 0.0878 | 2 | 3 | -0.6 | 28.01 | |||||||||||||||||||||||||||||||||
| c.3779A>T | K1260M 2D AIThe SynGAP1 missense variant K1260M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the majority of algorithms—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—classify the substitution as pathogenic. High‑accuracy assessments further support a deleterious impact: the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports “Likely Pathogenic”; AlphaMissense‑Optimized yields an uncertain result, and Foldetta’s stability prediction is unavailable. Taken together, the evidence overwhelmingly points to a pathogenic effect for K1260M. 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 Pathogenic | Coiled-coil | 0.509769 | Disordered | 0.625808 | Binding | 0.890 | 0.575 | 0.250 | -10.938 | Likely Pathogenic | 0.887 | Likely Pathogenic | Ambiguous | 0.400 | Likely Benign | -4.72 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.29 | Pathogenic | 0.00 | Affected | 0.0746 | 0.3366 | 0 | -1 | 5.8 | 3.02 | ||||||||||||||||||||||||||||||||||||||
| c.3780G>C | K1260N 2D AIThe SynGAP1 missense variant K1260N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. In contrast, the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all classify the variant as pathogenic or likely pathogenic. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. Based on the consensus of high‑accuracy predictors, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.509769 | Disordered | 0.625808 | Binding | 0.890 | 0.575 | 0.250 | -9.053 | Likely Pathogenic | 0.915 | Likely Pathogenic | Ambiguous | 0.157 | Likely Benign | -3.39 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.42 | Pathogenic | 0.00 | Affected | 0.3064 | 0.1302 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||||
| c.3780G>T | K1260N 2D AIThe SynGAP1 missense variant K1260N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. In contrast, the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all classify the variant as pathogenic or likely pathogenic. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. Based on the consensus of high‑accuracy predictors, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.509769 | Disordered | 0.625808 | Binding | 0.890 | 0.575 | 0.250 | -9.053 | Likely Pathogenic | 0.915 | Likely Pathogenic | Ambiguous | 0.157 | Likely Benign | -3.39 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.42 | Pathogenic | 0.00 | Affected | 0.3064 | 0.1302 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||||
| c.2485G>A | E829K 2D  AIThe SynGAP1 missense variant E829K is listed in ClinVar as Pathogenic (ClinVar ID 1721258.0) and is not reported in gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only REVEL predicts a benign outcome, while ESM1b and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments show the SGM‑Consensus as Likely Pathogenic, AlphaMissense‑Optimized as uncertain, and Foldetta results are unavailable. Overall, the preponderance of evidence indicates that E829K is most likely pathogenic, and this conclusion aligns with the ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.562014 | Disordered | 0.626045 | Binding | 0.326 | 0.882 | 0.375 | Pathogenic | 1 | -7.527 | In-Between | 0.807 | Likely Pathogenic | Ambiguous | 0.194 | Likely Benign | -2.65 | Deleterious | 0.994 | Probably Damaging | 0.900 | Possibly Damaging | 2.27 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2400 | 0.7372 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||
| c.2485G>C | E829Q 2D  AIThe SynGAP1 missense variant E829Q is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of reliable tools predict a benign impact, and there is no ClinVar entry to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.562014 | Disordered | 0.626045 | Binding | 0.326 | 0.882 | 0.375 | -4.985 | Likely Benign | 0.531 | Ambiguous | Likely Benign | 0.225 | Likely Benign | -1.83 | Neutral | 0.994 | Probably Damaging | 0.946 | Probably Damaging | 2.26 | Pathogenic | 0.00 | Affected | 0.1321 | 0.7248 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||||
| c.2486A>C | E829A 2D  AIThe SynGAP1 missense variant E829A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) results are unavailable. Overall, the majority of evidence—including the SGM‑Consensus—points to a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion 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 | 0.626045 | Binding | 0.326 | 0.882 | 0.375 | -4.096 | Likely Benign | 0.574 | Likely Pathogenic | Likely Benign | 0.265 | Likely Benign | -3.75 | Deleterious | 0.994 | Probably Damaging | 0.926 | Probably Damaging | 2.26 | Pathogenic | 0.00 | Affected | 0.4707 | 0.7255 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2486A>G | E829G 2D  AIThe SynGAP1 missense variant E829G is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas the remaining tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and the Foldetta stability analysis is unavailable. Overall, the majority of predictions lean toward pathogenicity, with one high‑accuracy tool suggesting benign. No ClinVar annotation exists, so there is no contradiction with clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.562014 | Disordered | 0.626045 | Binding | 0.326 | 0.882 | 0.375 | -4.152 | Likely Benign | 0.593 | Likely Pathogenic | Likely Benign | 0.316 | Likely Benign | -4.52 | Deleterious | 0.994 | Probably Damaging | 0.927 | Probably Damaging | 2.24 | Pathogenic | 0.00 | Affected | 0.3517 | 0.6557 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.2486A>T | E829V 2D  AIThe SynGAP1 missense variant E829V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority of the four high‑accuracy inputs) remains pathogenic; Foldetta results are unavailable. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.562014 | Disordered | 0.626045 | Binding | 0.326 | 0.882 | 0.375 | -5.142 | Likely Benign | 0.719 | Likely Pathogenic | Likely Benign | 0.296 | Likely Benign | -4.86 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.21 | Pathogenic | 0.00 | Affected | 0.0835 | 0.7984 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.2487G>C | E829D 2D  AIThe SynGAP1 missense variant E829D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence from multiple independent predictors indicates that E829D is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.626045 | Binding | 0.326 | 0.882 | 0.375 | -4.015 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -1.89 | Neutral | 0.217 | Benign | 0.121 | Benign | 2.40 | Pathogenic | 0.00 | Affected | 0.1939 | 0.4964 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2487G>T | E829D 2D AIThe SynGAP1 missense variant E829D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence from multiple independent predictors indicates that E829D is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.626045 | Binding | 0.326 | 0.882 | 0.375 | -4.015 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -1.89 | Neutral | 0.217 | Benign | 0.121 | Benign | 2.40 | Pathogenic | 0.00 | Affected | 0.1939 | 0.4964 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2245C>G | R749G 2D  AIThe SynGAP1 missense variant R749G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for R749G, 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 | 0.675549 | Disordered | 0.626050 | Binding | 0.337 | 0.860 | 0.625 | -3.045 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.161 | Likely Benign | -1.03 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.68 | Benign | 0.02 | Affected | 0.3690 | 0.4196 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2245C>T | R749W 2D  AIThe SynGAP1 missense variant R749W is listed in ClinVar as benign and is observed in gnomAD (ID 6‑33441710‑C‑T). Prediction tools that classify the variant as benign include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also returns benign, and Foldetta stability analysis is unavailable. Overall, the majority of evidence, especially from high‑confidence methods, supports a benign effect. This consensus aligns with the ClinVar designation, so there is no contradiction between the predictions and the reported clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.675549 | Disordered | 0.626050 | Binding | 0.337 | 0.860 | 0.625 | Likely Benign | 1 | 6-33441710-C-T | 3 | 1.86e-6 | -7.647 | In-Between | 0.338 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -2.62 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.59 | Benign | 0.00 | Affected | 4.32 | 2 | 0.1215 | 0.4088 | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||
| c.2246G>A | R749Q 2D  AIThe SynGAP1 missense variant R749Q is listed in ClinVar (ID 793884.0) as Benign and is present in gnomAD (6‑33441711‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a Likely Benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence—including high‑accuracy predictions—supports a benign classification, which is consistent with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.626050 | Binding | 0.337 | 0.860 | 0.625 | Likely Benign | 1 | 6-33441711-G-A | 4 | 2.48e-6 | -3.069 | Likely Benign | 0.212 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -1.00 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 2.64 | Benign | 0.03 | Affected | 4.32 | 2 | 0.3467 | 0.2529 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.2246G>C | R749P 2D  AIThe SynGAP1 missense variant R749P is not reported 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 R749P, 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 | 0.675549 | Disordered | 0.626050 | Binding | 0.337 | 0.860 | 0.625 | -2.467 | Likely Benign | 0.311 | Likely Benign | Likely Benign | 0.170 | Likely Benign | -1.54 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.61 | Benign | 0.02 | Affected | 0.2195 | 0.4878 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2246G>T | R749L 2D  AIThe SynGAP1 missense variant R749L is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster around a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy predictors that are available—AlphaMissense‑Optimized and the SGM‑Consensus—both support a benign classification. Consequently, the overall evidence points to the variant being most likely benign, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.626050 | Binding | 0.337 | 0.860 | 0.625 | -3.926 | Likely Benign | 0.413 | Ambiguous | Likely Benign | 0.168 | Likely Benign | -2.15 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.65 | Benign | 0.01 | Affected | 0.2106 | 0.5154 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2593G>A | A865T 2D AIThe SynGAP1 missense variant A865T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is that the variant is most likely benign, and this conclusion does not contradict any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.626222 | Binding | 0.271 | 0.788 | 0.250 | -4.435 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.026 | Likely Benign | -0.84 | Neutral | 0.440 | Benign | 0.197 | Benign | 2.72 | Benign | 0.29 | Tolerated | 0.1263 | 0.6083 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2593G>C | A865P 2D AIThe SynGAP1 missense variant A865P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.626222 | Binding | 0.271 | 0.788 | 0.250 | -4.178 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -0.66 | Neutral | 0.918 | Possibly Damaging | 0.697 | Possibly Damaging | 2.67 | Benign | 0.27 | Tolerated | 0.1707 | 0.4690 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2593G>T | A865S 2D AIThe SynGAP1 missense variant A865S is reported as “Likely Benign” in SGM‑Consensus and has no ClinVar entry or gnomAD allele. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also benign. Foldetta results are not available. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.626222 | Binding | 0.271 | 0.788 | 0.250 | -3.102 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.050 | Likely Benign | 0.20 | Neutral | 0.009 | Benign | 0.019 | Benign | 2.78 | Benign | 0.52 | Tolerated | 0.2314 | 0.4876 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2594C>A | A865D 2D AIThe SynGAP1 missense variant A865D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this 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 | 0.521092 | Disordered | 0.626222 | Binding | 0.271 | 0.788 | 0.250 | -4.635 | Likely Benign | 0.515 | Ambiguous | Likely Benign | 0.123 | Likely Benign | -0.57 | Neutral | 0.611 | Possibly Damaging | 0.346 | Benign | 2.71 | Benign | 0.36 | Tolerated | 0.1563 | 0.1560 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2594C>G | A865G 2D AIThe SynGAP1 missense variant A865G 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 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 | 0.521092 | Disordered | 0.626222 | Binding | 0.271 | 0.788 | 0.250 | -3.412 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.027 | Likely Benign | -0.74 | Neutral | 0.009 | Benign | 0.019 | Benign | 2.69 | Benign | 0.51 | Tolerated | 0.2344 | 0.4683 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2594C>T | A865V 2D AIThe SynGAP1 missense variant A865V is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only polyPhen‑2 HumDiv predicts it as pathogenic. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. No Foldetta stability analysis is available, so it does not influence the conclusion. Overall, the computational evidence overwhelmingly suggests that A865V is most likely benign, and this assessment 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 | 0.521092 | Disordered | 0.626222 | Binding | 0.271 | 0.788 | 0.250 | -4.639 | Likely Benign | 0.134 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -1.42 | Neutral | 0.611 | Possibly Damaging | 0.419 | Benign | 2.70 | Benign | 0.37 | Tolerated | 0.1145 | 0.6031 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.2509G>A | V837I 2D  AIThe SynGAP1 missense variant V837I is reported in ClinVar as “Not submitted” and is present in gnomAD (variant ID 6-33443061‑G‑A). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict it to be pathogenic. When predictions are grouped by consensus, the benign group contains seven tools, while the pathogenic group contains two. High‑accuracy assessments reinforce the benign view: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. Foldetta results are unavailable. Overall, the majority of evidence indicates that V837I is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.626284 | Binding | 0.318 | 0.871 | 0.125 | 6-33443061-G-A | 1 | 6.19e-7 | -4.299 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.119 | Likely Benign | -0.51 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.63 | Benign | 0.13 | Tolerated | 3.77 | 5 | 0.0833 | 0.3848 | 3 | 4 | 0.3 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2509G>C | V837L 2D  AIThe SynGAP1 missense variant V837L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are not available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.626284 | Binding | 0.318 | 0.871 | 0.125 | -4.895 | Likely Benign | 0.313 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -1.15 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.64 | Benign | 0.17 | Tolerated | 0.1039 | 0.4623 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2509G>T | V837F 2D  AIThe SynGAP1 missense variant V837F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.626284 | Binding | 0.318 | 0.871 | 0.125 | -5.223 | Likely Benign | 0.322 | Likely Benign | Likely Benign | 0.164 | Likely Benign | -1.41 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.60 | Benign | 0.08 | Tolerated | 0.0749 | 0.3744 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||||||||||||
| c.2510T>A | V837D 2D  AIThe SynGAP1 missense variant V837D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.626284 | Binding | 0.318 | 0.871 | 0.125 | -5.712 | Likely Benign | 0.785 | Likely Pathogenic | Ambiguous | 0.127 | Likely Benign | -0.51 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.61 | Benign | 0.85 | Tolerated | 0.1415 | 0.0902 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||||||||||||
| c.2510T>C | V837A 2D  AIThe SynGAP1 missense variant V837A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.626284 | Binding | 0.318 | 0.871 | 0.125 | -1.400 | Likely Benign | 0.370 | Ambiguous | Likely Benign | 0.073 | Likely Benign | -0.41 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.70 | Benign | 1.00 | Tolerated | 0.3058 | 0.2106 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| c.2510T>G | V837G 2D  AIThe SynGAP1 missense variant V837G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are not available, so they do not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.626284 | Binding | 0.318 | 0.871 | 0.125 | -2.599 | Likely Benign | 0.315 | Likely Benign | Likely Benign | 0.187 | Likely Benign | 0.93 | Neutral | 0.997 | Probably Damaging | 0.999 | Probably Damaging | 3.18 | Benign | 1.00 | Tolerated | 0.2260 | 0.2422 | -1 | -3 | -4.6 | -42.08 | |||||||||||||||||||||||||||||||||||||||
| c.2476G>A | D826N 2D  AIThe SynGAP1 missense variant D826N has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on benign effects include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and Foldetta results are unavailable. Given the balance of evidence, the majority of high‑confidence predictions and the SGM consensus favor a benign outcome. Therefore, 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 | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -3.663 | Likely Benign | 0.907 | Likely Pathogenic | Ambiguous | 0.154 | Likely Benign | -2.24 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.54 | Benign | 0.01 | Affected | 0.1520 | 0.8248 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2476G>C | D826H 2D  AIThe SynGAP1 missense variant D826H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. 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 D826H 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 | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -6.437 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.345 | Likely Benign | -3.00 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.49 | Pathogenic | 0.00 | Affected | 0.1757 | 0.8651 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2476G>T | D826Y 2D  AIThe SynGAP1 missense variant D826Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: REVEL classifies it as benign, whereas the remaining predictors—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—label it pathogenic. The consensus score from the SGM framework, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM Consensus also indicates Likely Pathogenic; Foldetta results are not available. Taken together, the overwhelming majority of evidence points to a pathogenic effect for D826Y. Thus, the variant is most likely pathogenic, and this assessment does not contradict the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -8.029 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.336 | Likely Benign | -4.25 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.47 | Pathogenic | 0.00 | Affected | 0.0683 | 0.7410 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| c.2477A>C | D826A 2D  AIThe SynGAP1 D826A 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. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evaluated predictors (six pathogenic vs. three benign) indicate a pathogenic impact. This prediction is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -5.590 | Likely Benign | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.307 | Likely Benign | -3.77 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.53 | Benign | 0.02 | Affected | 0.4463 | 0.7867 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.2477A>G | D826G 2D  AIThe SynGAP1 D826G 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. 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 evaluated predictors (six pathogenic vs. three benign) indicate a pathogenic impact. This prediction is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -6.310 | Likely Benign | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.323 | Likely Benign | -2.94 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.51 | Benign | 0.01 | Affected | 0.4251 | 0.7480 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2477A>T | D826V 2D  AIThe SynGAP1 missense variant D826V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, 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 D826V, and this conclusion does not conflict with ClinVar, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -6.918 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.428 | Likely Benign | -4.64 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 0.1017 | 0.8023 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.2478C>A | D826E 2D  AIThe SynGAP1 missense variant D826E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -4.172 | Likely Benign | 0.859 | Likely Pathogenic | Ambiguous | 0.164 | Likely Benign | -0.66 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.92 | Benign | 0.56 | Tolerated | 0.1795 | 0.7687 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2478C>G | D826E 2D AIThe SynGAP1 missense variant D826E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -4.172 | Likely Benign | 0.859 | Likely Pathogenic | Ambiguous | 0.164 | Likely Benign | -0.66 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.92 | Benign | 0.56 | Tolerated | 0.1795 | 0.7687 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2467A>C | S823R 2D  AIThe SynGAP1 missense variant S823R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all indicate likely pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus also reports it as likely pathogenic. Foldetta results are not available for this variant. Overall, the preponderance of evidence from both general and high‑accuracy prediction tools points to a pathogenic effect for S823R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.685117 | Disordered | 0.627336 | Binding | 0.358 | 0.884 | 0.750 | -6.612 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.293 | Likely Benign | -3.47 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.93 | Pathogenic | 0.00 | Affected | 0.0893 | 0.4046 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2467A>G | S823G 2D  AIThe SynGAP1 missense variant S823G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and the Foldetta stability analysis is 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 | 0.685117 | Disordered | 0.627336 | Binding | 0.358 | 0.884 | 0.750 | -6.034 | Likely Benign | 0.822 | Likely Pathogenic | Ambiguous | 0.202 | Likely Benign | -2.59 | Deleterious | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.96 | Pathogenic | 0.00 | Affected | 0.2855 | 0.5287 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2467A>T | S823C 2D  AIThe SynGAP1 missense variant S823C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Two tools give uncertain results: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Pathogenic, while AlphaMissense‑Optimized remains uncertain. No Foldetta stability prediction is available, so it does not contribute to the assessment. Overall, the preponderance of evidence points to a pathogenic effect for S823C, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.685117 | Disordered | 0.627336 | Binding | 0.358 | 0.884 | 0.750 | -7.881 | In-Between | 0.911 | Likely Pathogenic | Ambiguous | 0.332 | Likely Benign | -3.80 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.91 | Pathogenic | 0.00 | Affected | 0.1019 | 0.6137 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2468G>A | S823N 2D  AIThe SynGAP1 missense variant S823N is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b. Tools that agree on a pathogenic effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic, two benign votes). 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 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. | 0.685117 | Disordered | 0.627336 | Binding | 0.358 | 0.884 | 0.750 | -6.880 | Likely Benign | 0.974 | Likely Pathogenic | Likely Pathogenic | 0.170 | Likely Benign | -1.76 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.93 | Pathogenic | 0.00 | Affected | 0.1370 | 0.5172 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2468G>C | S823T 2D  AIThe SynGAP1 missense variant S823T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus (SGM Consensus) derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN is inconclusive (two benign, two pathogenic). AlphaMissense‑Optimized predicts benign, while Foldetta (combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the majority of standard predictors indicate a pathogenic effect, and this assessment does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.685117 | Disordered | 0.627336 | Binding | 0.358 | 0.884 | 0.750 | -6.036 | Likely Benign | 0.717 | Likely Pathogenic | Likely Benign | 0.165 | Likely Benign | -2.02 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.05 | Pathogenic | 0.00 | Affected | 0.1453 | 0.6580 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2468G>T | S823I 2D  AIThe SynGAP1 missense variant S823I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only REVEL predicts a benign outcome, while ESM1b remains uncertain. High‑accuracy assessments reinforce the pathogenic signal: 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 consensus of the majority of prediction tools 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 | 0.685117 | Disordered | 0.627336 | Binding | 0.358 | 0.884 | 0.750 | -7.332 | In-Between | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.287 | Likely Benign | -4.26 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.92 | Pathogenic | 0.00 | Affected | 0.0964 | 0.5848 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2469C>A | S823R 2D AIThe SynGAP1 missense variant S823R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.685117 | Disordered | 0.627336 | Binding | 0.358 | 0.884 | 0.750 | -6.612 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.196 | Likely Benign | -3.47 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.93 | Pathogenic | 0.00 | Affected | 0.0893 | 0.4046 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2469C>G | S823R 2D AIThe SynGAP1 missense variant S823R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.685117 | Disordered | 0.627336 | Binding | 0.358 | 0.884 | 0.750 | -6.612 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.196 | Likely Benign | -3.47 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.93 | Pathogenic | 0.00 | Affected | 0.0893 | 0.4046 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2632A>C | T878P 2D  AIThe SynGAP1 missense variant T878P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, 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 | 0.622677 | Disordered | 0.628767 | Binding | 0.288 | 0.878 | 0.250 | -3.130 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -1.41 | Neutral | 0.761 | Possibly Damaging | 0.478 | Possibly Damaging | 2.96 | Benign | 0.01 | Affected | 0.2026 | 0.5538 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2632A>G | T878A 2D  AIThe SynGAP1 missense variant T878A is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). No tool in the dataset predicts a pathogenic outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign,” and a Foldetta stability analysis is unavailable. Overall, the evidence strongly supports a benign classification, and this does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.628767 | Binding | 0.288 | 0.878 | 0.250 | Uncertain | 2 | -2.154 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -0.67 | Neutral | 0.003 | Benign | 0.006 | Benign | 2.73 | Benign | 0.18 | Tolerated | 3.77 | 5 | 0.4312 | 0.4625 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.2632A>T | T878S 2D  AIThe SynGAP1 missense variant T878S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.628767 | Binding | 0.288 | 0.878 | 0.250 | -2.493 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.073 | Likely Benign | -0.06 | Neutral | 0.009 | Benign | 0.012 | Benign | 2.82 | Benign | 0.03 | Affected | 0.3557 | 0.4867 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2633C>A | T878K 2D  AIThe SynGAP1 missense variant T878K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, SGM‑Consensus indicates likely benign, and Foldetta results are unavailable. Taken together, the majority of evidence points to a benign impact for T878K, and this conclusion does not contradict the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.628767 | Binding | 0.288 | 0.878 | 0.250 | -5.694 | Likely Benign | 0.592 | Likely Pathogenic | Likely Benign | 0.099 | Likely Benign | -1.51 | Neutral | 0.611 | Possibly Damaging | 0.196 | Benign | 2.66 | Benign | 0.00 | Affected | 0.1168 | 0.3300 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||||
| c.2633C>G | T878R 2D  AIThe SynGAP1 missense variant T878R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.628767 | Binding | 0.288 | 0.878 | 0.250 | -4.289 | Likely Benign | 0.496 | Ambiguous | Likely Benign | 0.119 | Likely Benign | -1.39 | Neutral | 0.611 | Possibly Damaging | 0.398 | Benign | 2.64 | Benign | 0.00 | Affected | 0.1006 | 0.2920 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||||||||||||
| c.2633C>T | T878I 2D  AIThe SynGAP1 missense variant T878I is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect. **Benign:** REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized. **Pathogenic:** polyPhen‑2 HumDiv, SIFT. AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are unavailable. Overall, the computational evidence overwhelmingly points to a benign effect, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.628767 | Binding | 0.288 | 0.878 | 0.250 | -6.247 | Likely Benign | 0.459 | Ambiguous | Likely Benign | 0.055 | Likely Benign | -1.99 | Neutral | 0.761 | Possibly Damaging | 0.398 | Benign | 2.63 | Benign | 0.00 | Affected | 0.0980 | 0.6502 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.2641T>A | L881M 2D  AIThe SynGAP1 missense variant L881M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign based on current computational evidence, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.629350 | Binding | 0.299 | 0.874 | 0.250 | -4.419 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.31 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.49 | Pathogenic | 0.03 | Affected | 0.0807 | 0.3997 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2641T>G | L881V 2D  AIThe SynGAP1 missense variant L881V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect. The variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.629350 | Binding | 0.299 | 0.874 | 0.250 | -3.961 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -0.29 | Neutral | 0.790 | Possibly Damaging | 0.266 | Benign | 2.60 | Benign | 0.39 | Tolerated | 0.1599 | 0.3053 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2642T>C | L881S 2D  AIThe SynGAP1 missense variant L881S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for the L881S variant, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.629350 | Binding | 0.299 | 0.874 | 0.250 | -3.063 | Likely Benign | 0.169 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -0.49 | Neutral | 0.068 | Benign | 0.012 | Benign | 2.49 | Pathogenic | 0.00 | Affected | 0.3363 | 0.0850 | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2642T>G | L881W 2D  AIThe SynGAP1 missense variant L881W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.629350 | Binding | 0.299 | 0.874 | 0.250 | -6.646 | Likely Benign | 0.231 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -0.96 | Neutral | 0.014 | Benign | 0.008 | Benign | 2.44 | Pathogenic | 0.00 | Affected | 0.0662 | 0.3288 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||||||||||||
| c.2643G>C | L881F 2D  AIThe SynGAP1 missense variant L881F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for L881F, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.629350 | Binding | 0.299 | 0.874 | 0.250 | -5.759 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.87 | Neutral | 0.818 | Possibly Damaging | 0.360 | Benign | 2.48 | Pathogenic | 0.02 | Affected | 0.0711 | 0.3415 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2643G>T | L881F 2D AIThe SynGAP1 missense variant L881F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for L881F, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.629350 | Binding | 0.299 | 0.874 | 0.250 | -5.759 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.87 | Neutral | 0.818 | Possibly Damaging | 0.360 | Benign | 2.48 | Pathogenic | 0.02 | Affected | 0.0711 | 0.3415 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2626T>A | S876T 2D AIThe SynGAP1 missense variant S876T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.631130 | Binding | 0.280 | 0.872 | 0.250 | -5.158 | Likely Benign | 0.183 | Likely Benign | Likely Benign | 0.121 | Likely Benign | -1.91 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.60 | Benign | 0.11 | Tolerated | 0.1380 | 0.6790 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2626T>C | S876P 2D  AIThe SynGAP1 missense variant S876P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the consensus of the available predictions indicates that S876P is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.631130 | Binding | 0.280 | 0.872 | 0.250 | -5.002 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.171 | Likely Benign | -2.04 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.56 | Benign | 0.35 | Tolerated | 0.1979 | 0.6928 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2626T>G | S876A 2D  AIThe SynGAP1 missense variant S876A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.631130 | Binding | 0.280 | 0.872 | 0.250 | -4.228 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -1.43 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.63 | Benign | 0.54 | Tolerated | 0.4495 | 0.5889 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2627C>G | S876W 2D  AIThe SynGAP1 missense variant S876W is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID: 6‑33443179‑C‑G). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). The high‑accuracy AlphaMissense‑Optimized result is uncertain, and the SGM‑Consensus indicates a likely pathogenic classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the preponderance of pathogenic predictions and the SGM‑Consensus, the variant is most likely pathogenic; this assessment does not contradict ClinVar status, as no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.549308 | Disordered | 0.631130 | Binding | 0.280 | 0.872 | 0.250 | 6-33443179-C-G | 1 | 6.20e-7 | -9.305 | Likely Pathogenic | 0.829 | Likely Pathogenic | Ambiguous | 0.291 | Likely Benign | -3.72 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.54 | Benign | 0.01 | Affected | 3.77 | 5 | 0.0964 | 0.6700 | -3 | -2 | -0.1 | 99.14 | ||||||||||||||||||||||||||||||||||
| c.2627C>T | S876L 2D  AISynGAP1 variant S876L 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, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign effect; the SGM Consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive and therefore unavailable; Foldetta stability analysis is also unavailable. Overall, the majority of available predictions favor a benign impact, suggesting the variant is most likely benign. This conclusion does not conflict with the ClinVar uncertain status, which reflects the current lack of definitive evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.549308 | Disordered | 0.631130 | Binding | 0.280 | 0.872 | 0.250 | Uncertain | 2 | -5.856 | Likely Benign | 0.489 | Ambiguous | Likely Benign | 0.249 | Likely Benign | -3.56 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 2.57 | Benign | 0.05 | Affected | 3.77 | 5 | 0.1268 | 0.6053 | -2 | -3 | 4.6 | 26.08 | ||||||||||||||||||||||||||||||||||||
| c.2482A>C | T828P 2D AIThe SynGAP1 missense variant T828P is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain. The SGM Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to benign (2 benign vs. 1 pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) is unavailable. Overall, the preponderance of evidence points to a benign impact for T828P, 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. | 0.604312 | Disordered | 0.631236 | Binding | 0.321 | 0.879 | 0.500 | -3.902 | Likely Benign | 0.466 | Ambiguous | Likely Benign | 0.280 | Likely Benign | -2.53 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.61 | Benign | 0.12 | Tolerated | 0.1898 | 0.4424 | 0 | -1 | -0.9 | -3.99 | ||||||||||||||||||||||||||||||||||||||||
| c.2482A>G | T828A 2D AIThe SynGAP1 missense variant T828A is reported in gnomAD (variant ID 6‑33443034‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign. No Foldetta stability analysis is available, so it does not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.604312 | Disordered | 0.631236 | Binding | 0.321 | 0.879 | 0.500 | 6-33443034-A-G | 1 | 6.20e-7 | -2.974 | Likely Benign | 0.340 | Likely Benign | Likely Benign | 0.197 | Likely Benign | -2.13 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.67 | Benign | 0.24 | Tolerated | 3.77 | 5 | 0.4039 | 0.3861 | 0 | 1 | 2.5 | -30.03 | ||||||||||||||||||||||||||||||||||
| c.2482A>T | T828S 2D AIThe SynGAP1 missense variant T828S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that T828S is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.604312 | Disordered | 0.631236 | Binding | 0.321 | 0.879 | 0.500 | -2.851 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -0.49 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.67 | Benign | 0.52 | Tolerated | 0.3332 | 0.3913 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2483C>A | T828K 2D AIThe SynGAP1 missense variant T828K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, while the SGM‑Consensus (majority vote) remains Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, 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 | 0.604312 | Disordered | 0.631236 | Binding | 0.321 | 0.879 | 0.500 | -5.466 | Likely Benign | 0.853 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | -0.88 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.68 | Benign | 0.39 | Tolerated | 0.0924 | 0.2886 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||||
| c.2483C>G | T828R 2D AIThe SynGAP1 missense variant T828R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for T828R, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.604312 | Disordered | 0.631236 | Binding | 0.321 | 0.879 | 0.500 | -4.887 | Likely Benign | 0.773 | Likely Pathogenic | Likely Benign | 0.184 | Likely Benign | -1.38 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.64 | Benign | 0.47 | Tolerated | 0.0815 | 0.2530 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||||||||||||
| c.2483C>T | T828I 2D AISynGAP1 missense variant T828I is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM, whereas tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a 2‑to‑2 split and therefore unavailable; Foldetta predictions are not provided. Consequently, the computational evidence is evenly divided between benign and pathogenic, with no clear direction. The variant is therefore not clearly benign or pathogenic based on current predictions, and this lack of consensus does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.604312 | Disordered | 0.631236 | Binding | 0.321 | 0.879 | 0.500 | -4.971 | Likely Benign | 0.893 | Likely Pathogenic | Ambiguous | 0.139 | Likely Benign | -3.40 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.61 | Benign | 0.06 | Tolerated | 0.0767 | 0.5262 | 0 | -1 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||||||||||||
| c.292C>A | H98N 2D  AIThe SynGAP1 missense variant H98N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.631713 | Binding | 0.348 | 0.872 | 0.625 | -3.855 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.103 | Likely Benign | -0.35 | Neutral | 0.115 | Benign | 0.012 | Benign | 4.24 | Benign | 0.00 | Affected | 0.2003 | 0.3759 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.292C>G | H98D 2D  AIThe SynGAP1 missense variant H98D is reported in gnomAD (variant ID 6‑33425900‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all classify the change as benign. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is “Likely Benign.” No Foldetta stability result is available, so it does not influence the assessment. Overall, the consensus of the available predictions indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.631713 | Binding | 0.348 | 0.872 | 0.625 | 6-33425900-C-G | 1 | 6.20e-7 | -1.739 | Likely Benign | 0.167 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -0.42 | Neutral | 0.115 | Benign | 0.012 | Benign | 4.24 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2732 | 0.3018 | -1 | 1 | -0.3 | -22.05 | ||||||||||||||||||||||||||||||||||
| c.292C>T | H98Y 2D  AIThe SynGAP1 missense variant H98Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.631713 | Binding | 0.348 | 0.872 | 0.625 | -4.050 | Likely Benign | 0.135 | Likely Benign | Likely Benign | 0.112 | Likely Benign | -0.86 | Neutral | 0.444 | Benign | 0.024 | Benign | 4.19 | Benign | 0.00 | Affected | 0.0950 | 0.5024 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.293A>C | H98P 2D  AIThe SynGAP1 missense variant H98P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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. There is no ClinVar classification to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.631713 | Binding | 0.348 | 0.872 | 0.625 | -1.460 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.275 | Likely Benign | -0.83 | Neutral | 0.659 | Possibly Damaging | 0.024 | Benign | 4.20 | Benign | 0.00 | Affected | 0.2062 | 0.4669 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.293A>G | H98R 2D  AIThe SynGAP1 missense variant H98R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this 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 | 0.733139 | Disordered | 0.631713 | Binding | 0.348 | 0.872 | 0.625 | -2.772 | Likely Benign | 0.180 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -0.39 | Neutral | 0.115 | Benign | 0.006 | Benign | 4.27 | Benign | 0.00 | Affected | 0.2271 | 0.3022 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.293A>T | H98L 2D  AIThe SynGAP1 H98L missense variant is reported in gnomAD (ID 6‑33425901‑A‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is likely benign, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for H98L, 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 | 0.733139 | Disordered | 0.631713 | Binding | 0.348 | 0.872 | 0.625 | 6-33425901-A-T | 1 | 6.32e-7 | -1.804 | Likely Benign | 0.113 | Likely Benign | Likely Benign | 0.194 | Likely Benign | -0.51 | Neutral | 0.115 | Benign | 0.012 | Benign | 4.24 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1125 | 0.6291 | -3 | -2 | 7.0 | -23.98 | ||||||||||||||||||||||||||||||||||
| c.294T>A | H98Q 2D  AIThe SynGAP1 missense variant H98Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.631713 | Binding | 0.348 | 0.872 | 0.625 | -2.749 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -0.47 | Neutral | 0.002 | Benign | 0.000 | Benign | 4.26 | Benign | 0.00 | Affected | 0.1831 | 0.4347 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.294T>G | H98Q 2D AIThe SynGAP1 missense variant H98Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.631713 | Binding | 0.348 | 0.872 | 0.625 | -2.749 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -0.47 | Neutral | 0.002 | Benign | 0.000 | Benign | 4.26 | Benign | 0.00 | Affected | 0.1831 | 0.4347 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2623G>A | A875T 2D AIThe SynGAP1 missense variant A875T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443175‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.545602 | Disordered | 0.632173 | Binding | 0.273 | 0.872 | 0.250 | Uncertain | 1 | 6-33443175-G-A | 1 | 6.20e-7 | -3.793 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.110 | Likely Benign | -1.56 | Neutral | 0.972 | Probably Damaging | 0.864 | Possibly Damaging | 2.72 | Benign | 0.26 | Tolerated | 3.77 | 5 | 0.1438 | 0.7518 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||
| c.2623G>C | A875P 2D AIThe SynGAP1 missense variant A875P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). In contrast, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar all predict a pathogenic impact. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the overall assessment. Overall, the majority of evidence points to a benign effect for A875P, 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 | 0.545602 | Disordered | 0.632173 | Binding | 0.273 | 0.872 | 0.250 | -3.799 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.154 | Likely Benign | -2.53 | Deleterious | 0.997 | Probably Damaging | 0.959 | Probably Damaging | 2.66 | Benign | 0.09 | Tolerated | 0.1750 | 0.5688 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2623G>T | A875S 2D AIThe SynGAP1 missense variant A875S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that A875S is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.545602 | Disordered | 0.632173 | Binding | 0.273 | 0.872 | 0.250 | -2.719 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -1.07 | Neutral | 0.945 | Possibly Damaging | 0.767 | Possibly Damaging | 2.78 | Benign | 0.08 | Tolerated | 0.2607 | 0.6338 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2624C>A | A875D 2D AIThe SynGAP1 missense variant A875D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2) and Foldetta data are unavailable. Overall, the majority of standard tools (5 pathogenic vs 4 benign) lean toward a pathogenic interpretation, but the high‑accuracy predictions are mixed or missing. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.545602 | Disordered | 0.632173 | Binding | 0.273 | 0.872 | 0.250 | -3.268 | Likely Benign | 0.645 | Likely Pathogenic | Likely Benign | 0.149 | Likely Benign | -2.78 | Deleterious | 0.992 | Probably Damaging | 0.913 | Probably Damaging | 2.68 | Benign | 0.02 | Affected | 0.1648 | 0.2035 | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.2624C>G | A875G 2D AIThe SynGAP1 missense variant A875G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. Foldetta, 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, 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 | 0.545602 | Disordered | 0.632173 | Binding | 0.273 | 0.872 | 0.250 | -2.904 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.22 | Neutral | 0.022 | Benign | 0.048 | Benign | 2.68 | Benign | 0.04 | Affected | 0.2308 | 0.5046 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2624C>T | A875V 2D AIThe SynGAP1 missense variant A875V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this 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 | 0.545602 | Disordered | 0.632173 | Binding | 0.273 | 0.872 | 0.250 | -4.946 | Likely Benign | 0.255 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -1.17 | Neutral | 0.991 | Probably Damaging | 0.904 | Possibly Damaging | 2.74 | Benign | 1.00 | Tolerated | 0.1099 | 0.6605 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.2644G>A | G882R 2D  AIThe SynGAP1 missense variant G882R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive because it yields a 2‑to‑2 split. Foldetta results are unavailable. Overall, the majority of predictions lean toward a benign impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.690604 | Disordered | 0.632888 | Binding | 0.306 | 0.878 | 0.250 | -4.715 | Likely Benign | 0.758 | Likely Pathogenic | Likely Benign | 0.051 | Likely Benign | -1.48 | Neutral | 0.001 | Benign | 0.003 | Benign | 2.04 | Pathogenic | 0.01 | Affected | 0.0905 | 0.4126 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.2644G>C | G882R 2D AIThe SynGAP1 missense variant G882R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta results are unavailable. Overall, the majority of predictions (six benign vs three pathogenic) support a benign classification. This consensus does not contradict any ClinVar status, as the variant is not yet catalogued there. Thus, the variant is most likely benign based on current predictive evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.690604 | Disordered | 0.632888 | Binding | 0.306 | 0.878 | 0.250 | -4.715 | Likely Benign | 0.758 | Likely Pathogenic | Likely Benign | 0.051 | Likely Benign | -1.48 | Neutral | 0.001 | Benign | 0.003 | Benign | 2.04 | Pathogenic | 0.01 | Affected | 0.0905 | 0.4126 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.2644G>T | G882W 2D  AIThe SynGAP1 missense variant G882W has no ClinVar entry and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains pathogenic; Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion does not conflict with the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.690604 | Disordered | 0.632888 | Binding | 0.306 | 0.878 | 0.250 | -8.637 | Likely Pathogenic | 0.606 | Likely Pathogenic | Likely Benign | 0.166 | Likely Benign | -2.35 | Neutral | 0.983 | Probably Damaging | 0.813 | Possibly Damaging | 2.01 | Pathogenic | 0.00 | Affected | 0.0829 | 0.4616 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.2645G>A | G882E 2D  AIThe SynGAP1 missense variant G882E is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split; Foldetta results are unavailable. Overall, more tools (six) predict benign than pathogenic (three), and no ClinVar evidence contradicts this assessment. Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.690604 | Disordered | 0.632888 | Binding | 0.306 | 0.878 | 0.250 | -4.246 | Likely Benign | 0.613 | Likely Pathogenic | Likely Benign | 0.079 | Likely Benign | -1.16 | Neutral | 0.004 | Benign | 0.005 | Benign | 2.04 | Pathogenic | 0.01 | Affected | 0.1263 | 0.3244 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.2645G>C | G882A 2D  AIThe SynGAP1 missense variant G882A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, whereas only FATHMM predicts pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence indicates the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.632888 | Binding | 0.306 | 0.878 | 0.250 | -3.876 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -1.05 | Neutral | 0.004 | Benign | 0.002 | Benign | 2.14 | Pathogenic | 0.79 | Tolerated | 0.3345 | 0.5268 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2645G>T | G882V 2D  AIThe SynGAP1 missense variant G882V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation—there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.632888 | Binding | 0.306 | 0.878 | 0.250 | -5.893 | Likely Benign | 0.257 | Likely Benign | Likely Benign | 0.115 | Likely Benign | -2.41 | Neutral | 0.224 | Benign | 0.066 | Benign | 2.06 | Pathogenic | 0.02 | Affected | 0.1178 | 0.4717 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.2629C>A | L877M 2D AIThe SynGAP1 missense variant L877M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the two polyPhen‑2 scores (HumDiv and HumVar) predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.634010 | Binding | 0.265 | 0.875 | 0.250 | -6.266 | Likely Benign | 0.134 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -0.55 | Neutral | 0.922 | Possibly Damaging | 0.776 | Possibly Damaging | 2.58 | Benign | 0.15 | Tolerated | 0.0813 | 0.3532 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2629C>G | L877V 2D AIThe SynGAP1 missense variant L877V is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence strongly supports a benign classification, and this 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 | 0.653063 | Disordered | 0.634010 | Binding | 0.265 | 0.875 | 0.250 | -5.063 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.022 | Likely Benign | -0.10 | Neutral | 0.232 | Benign | 0.109 | Benign | 2.71 | Benign | 0.26 | Tolerated | 0.1726 | 0.3178 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2630T>A | L877Q 2D  AIThe SynGAP1 missense variant L877Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic impact. AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is Likely Benign, and Foldetta (which integrates FoldX‑MD and Rosetta outputs) is not available for this variant. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.634010 | Binding | 0.265 | 0.875 | 0.250 | -5.919 | Likely Benign | 0.460 | Ambiguous | Likely Benign | 0.152 | Likely Benign | -1.58 | Neutral | 0.986 | Probably Damaging | 0.876 | Possibly Damaging | 2.57 | Benign | 0.03 | Affected | 0.1208 | 0.0919 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2630T>C | L877P 2D  AIThe SynGAP1 missense variant L877P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.634010 | Binding | 0.265 | 0.875 | 0.250 | -4.960 | Likely Benign | 0.312 | Likely Benign | Likely Benign | 0.154 | Likely Benign | -1.57 | Neutral | 0.986 | Probably Damaging | 0.876 | Possibly Damaging | 2.59 | Benign | 0.03 | Affected | 0.3899 | 0.1543 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2630T>G | L877R 2D  AIThe SynGAP1 missense variant L877R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict the ClinVar status, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.634010 | Binding | 0.265 | 0.875 | 0.250 | -6.678 | Likely Benign | 0.673 | Likely Pathogenic | Likely Benign | 0.148 | Likely Benign | -1.82 | Neutral | 0.986 | Probably Damaging | 0.876 | Possibly Damaging | 2.57 | Benign | 0.02 | Affected | 0.1218 | 0.0761 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2506A>C | S836R 2D AIThe SynGAP1 missense variant S836R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, whereas the SGM‑Consensus remains benign; Foldetta results are unavailable. Overall, the balance of evidence (five benign versus three pathogenic predictions, with the high‑accuracy consensus leaning benign) indicates that the variant is most likely benign. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | -6.050 | Likely Benign | 0.935 | Likely Pathogenic | Ambiguous | 0.120 | Likely Benign | -2.06 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.54 | Benign | 0.08 | Tolerated | 0.0731 | 0.3210 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2506A>G | S836G 2D AIThe SynGAP1 missense variant S836G is listed in ClinVar (ID 537003.0) with an uncertain significance annotation and is observed in the gnomAD database (variant ID 6‑33443058‑A‑G). Consensus from multiple in silico predictors indicates a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Benign. Foldetta, a protein‑folding stability predictor, did not return a result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign classification, which does not conflict with the ClinVar uncertain designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | Uncertain | 1 | 6-33443058-A-G | 4 | 2.48e-6 | -4.749 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -1.65 | Neutral | 0.006 | Benign | 0.019 | Benign | 2.54 | Benign | 0.39 | Tolerated | 3.77 | 5 | 0.2567 | 0.4089 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||
| c.2506A>T | S836C 2D AIThe SynGAP1 missense variant S836C 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT; ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields 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 annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | -7.859 | In-Between | 0.208 | Likely Benign | Likely Benign | 0.184 | Likely Benign | -2.66 | Deleterious | 0.997 | Probably Damaging | 0.923 | Probably Damaging | 2.50 | Benign | 0.04 | Affected | 0.0834 | 0.5468 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.2507G>A | S836N 2D AIThe SynGAP1 missense variant S836N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the lack of ClinVar annotation. Thus, the variant is most likely benign and does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | -3.881 | Likely Benign | 0.269 | Likely Benign | Likely Benign | 0.116 | Likely Benign | 0.75 | Neutral | 0.901 | Possibly Damaging | 0.636 | Possibly Damaging | 2.89 | Benign | 0.85 | Tolerated | 0.1053 | 0.3831 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| c.2507G>C | S836T 2D AIThe SynGAP1 missense variant S836T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | -3.871 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -1.28 | Neutral | 0.901 | Possibly Damaging | 0.535 | Possibly Damaging | 2.56 | Benign | 0.36 | Tolerated | 0.1161 | 0.5326 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2507G>T | S836I 2D AIThe SynGAP1 missense variant S836I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Consensus from standard in silico predictors shows five tools (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Optimized) predict a benign effect, while two tools (PROVEAN, SIFT) predict pathogenicity. Two additional predictors (ESM1b, AlphaMissense‑Default) return uncertain results. High‑accuracy assessment further indicates a benign prediction from AlphaMissense‑Optimized; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (one benign, one pathogenic, two uncertain). Foldetta stability analysis is unavailable. Overall, the balance of evidence favors a benign classification, and this conclusion does not conflict with the absence of a ClinVar annotation. Therefore, 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. | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | -7.751 | In-Between | 0.517 | Ambiguous | Likely Benign | 0.149 | Likely Benign | -3.33 | Deleterious | 0.057 | Benign | 0.053 | Benign | 2.51 | Benign | 0.03 | Affected | 0.0756 | 0.5023 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2508T>A | S836R 2D AIThe SynGAP1 missense variant S836R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus (majority vote) as Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | -6.050 | Likely Benign | 0.935 | Likely Pathogenic | Ambiguous | 0.159 | Likely Benign | -2.06 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.54 | Benign | 0.08 | Tolerated | 0.0731 | 0.3210 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2508T>G | S836R 2D AIThe SynGAP1 missense variant S836R is not reported in ClinVar and has no gnomAD entry. Consensus from multiple in silico predictors shows a split: benign calls come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Grouping by agreement, the benign‑predicating tools outnumber the pathogenic ones. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized returns an uncertain result, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is classified as Likely Benign, and no Foldetta stability data are available. Overall, the preponderance of evidence leans toward a benign effect for S836R, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | -6.050 | Likely Benign | 0.935 | Likely Pathogenic | Ambiguous | 0.159 | Likely Benign | -2.06 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.54 | Benign | 0.08 | Tolerated | 0.0731 | 0.3210 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2620C>A | Q874K 2D  AIThe SynGAP1 missense variant Q874K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for this variant. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.490133 | Structured | 0.635258 | Binding | 0.289 | 0.873 | 0.250 | -6.379 | Likely Benign | 0.604 | Likely Pathogenic | Likely Benign | 0.169 | Likely Benign | -2.35 | Neutral | 0.963 | Probably Damaging | 0.973 | Probably Damaging | 2.73 | Benign | 0.00 | Affected | 0.2008 | 0.4893 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2620C>G | Q874E 2D  AIThe SynGAP1 missense variant Q874E is not reported 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta’s protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for Q874E, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.490133 | Structured | 0.635258 | Binding | 0.289 | 0.873 | 0.250 | -4.576 | Likely Benign | 0.197 | Likely Benign | Likely Benign | 0.193 | Likely Benign | -1.95 | Neutral | 0.963 | Probably Damaging | 0.973 | Probably Damaging | 2.73 | Benign | 0.00 | Affected | 0.1489 | 0.3577 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2621A>C | Q874P 2D  AIThe SynGAP1 missense variant Q874P is reported in gnomAD (ID 6‑33443173‑A‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar classification (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.490133 | Structured | 0.635258 | Binding | 0.289 | 0.873 | 0.250 | 6-33443173-A-C | 9 | 5.58e-6 | -4.622 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.219 | Likely Benign | -2.89 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.77 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2373 | 0.5911 | -1 | 0 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||||||
| c.2621A>G | Q874R 2D  AIThe SynGAP1 missense variant Q874R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized independently predicts a benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.490133 | Structured | 0.635258 | Binding | 0.289 | 0.873 | 0.250 | -4.834 | Likely Benign | 0.527 | Ambiguous | Likely Benign | 0.200 | Likely Benign | -2.33 | Neutral | 0.985 | Probably Damaging | 0.982 | Probably Damaging | 2.69 | Benign | 0.00 | Affected | 0.1619 | 0.2924 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.2621A>T | Q874L 2D  AIThe SynGAP1 missense variant Q874L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs four benign) lean toward pathogenicity. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar status because the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.490133 | Structured | 0.635258 | Binding | 0.289 | 0.873 | 0.250 | -6.084 | Likely Benign | 0.608 | Likely Pathogenic | Likely Benign | 0.199 | Likely Benign | -3.39 | Deleterious | 0.985 | Probably Damaging | 0.982 | Probably Damaging | 2.67 | Benign | 0.00 | Affected | 0.0828 | 0.6595 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||||||||||||
| c.2622G>C | Q874H 2D AIThe SynGAP1 missense variant Q874H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta results are unavailable. Overall, the balance of evidence from both general and high‑accuracy predictors 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. | 0.490133 | Structured | 0.635258 | Binding | 0.289 | 0.873 | 0.250 | -4.658 | Likely Benign | 0.543 | Ambiguous | Likely Benign | 0.236 | Likely Benign | -2.90 | Deleterious | 0.996 | Probably Damaging | 0.995 | Probably Damaging | 2.65 | Benign | 0.00 | Affected | 0.1588 | 0.5088 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||||
| c.2622G>T | Q874H 2D AIThe SynGAP1 missense variant Q874H has no ClinVar record and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, while PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT all predict a pathogenic outcome; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority, and Foldetta data are unavailable. Overall, the balance of evidence leans toward a benign impact, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.490133 | Structured | 0.635258 | Binding | 0.289 | 0.873 | 0.250 | -4.658 | Likely Benign | 0.543 | Ambiguous | Likely Benign | 0.236 | Likely Benign | -2.90 | Deleterious | 0.996 | Probably Damaging | 0.995 | Probably Damaging | 2.65 | Benign | 0.00 | Affected | 0.1588 | 0.5088 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||||
| c.2653C>A | P885T 2D  AIThe SynGAP1 missense variant P885T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Based on the 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 | 0.690604 | Disordered | 0.636133 | Binding | 0.344 | 0.917 | 0.250 | -5.152 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -1.44 | Neutral | 0.369 | Benign | 0.171 | Benign | 2.78 | Benign | 0.00 | Affected | 0.1438 | 0.6484 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2653C>G | P885A 2D  AIThe SynGAP1 missense variant P885A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.636133 | Binding | 0.344 | 0.917 | 0.250 | -3.908 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -1.29 | Neutral | 0.112 | Benign | 0.084 | Benign | 2.80 | Benign | 0.00 | Affected | 0.3425 | 0.5481 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2653C>T | P885S 2D  AIThe SynGAP1 missense variant P885S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.636133 | Binding | 0.344 | 0.917 | 0.250 | -4.089 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.037 | Likely Benign | -1.10 | Neutral | 0.369 | Benign | 0.222 | Benign | 2.87 | Benign | 0.00 | Affected | 0.3363 | 0.5881 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2654C>A | P885H 2D  AIThe SynGAP1 missense variant P885H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence, including the high‑accuracy tools, points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.636133 | Binding | 0.344 | 0.917 | 0.250 | -5.239 | Likely Benign | 0.171 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -1.68 | Neutral | 0.938 | Possibly Damaging | 0.749 | Possibly Damaging | 2.74 | Benign | 0.00 | Affected | 0.1552 | 0.5280 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2654C>G | P885R 2D  AIThe SynGAP1 missense variant P885R is reported in gnomAD (ID 6‑33443206‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.636133 | Binding | 0.344 | 0.917 | 0.250 | 6-33443206-C-G | 1 | 6.20e-7 | -4.166 | Likely Benign | 0.308 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -1.99 | Neutral | 0.586 | Possibly Damaging | 0.377 | Benign | 2.84 | Benign | 0.00 | Affected | 4.32 | 4 | 0.1311 | 0.3505 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||
| c.2654C>T | P885L 2D  AIThe SynGAP1 missense variant P885L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.636133 | Binding | 0.344 | 0.917 | 0.250 | -4.352 | Likely Benign | 0.150 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -1.99 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.75 | Benign | 0.00 | Affected | 0.2138 | 0.6951 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2479A>C | I827L 2D  AIThe SynGAP1 missense variant I827L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.590140 | Disordered | 0.636272 | Binding | 0.383 | 0.884 | 0.625 | -2.535 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.120 | Likely Benign | -0.64 | Neutral | 0.981 | Probably Damaging | 0.970 | Probably Damaging | 2.71 | Benign | 0.43 | Tolerated | 0.0711 | 0.2901 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.2479A>G | I827V 2D  AIThe SynGAP1 missense variant I827V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence indicates that the I827V variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.590140 | Disordered | 0.636272 | Binding | 0.383 | 0.884 | 0.625 | -3.590 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.129 | Likely Benign | 0.05 | Neutral | 0.958 | Probably Damaging | 0.970 | Probably Damaging | 2.70 | Benign | 1.00 | Tolerated | 0.1011 | 0.2536 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2479A>T | I827F 2D  AIThe SynGAP1 missense variant I827F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy methods give a benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign, with no Foldetta data. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.590140 | Disordered | 0.636272 | Binding | 0.383 | 0.884 | 0.625 | -4.799 | Likely Benign | 0.517 | Ambiguous | Likely Benign | 0.155 | Likely Benign | -1.30 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.65 | Benign | 0.09 | Tolerated | 0.0490 | 0.2306 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2480T>A | I827N 2D  AIThe SynGAP1 missense variant I827N is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while 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, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, whereas the SGM‑Consensus (majority vote) supports a benign prediction. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. 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 | 0.590140 | Disordered | 0.636272 | Binding | 0.383 | 0.884 | 0.625 | -4.860 | Likely Benign | 0.804 | Likely Pathogenic | Ambiguous | 0.114 | Likely Benign | -1.69 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.66 | Benign | 0.11 | Tolerated | 0.0876 | 0.0342 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.2480T>C | I827T 2D  AIThe SynGAP1 missense variant I827T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.590140 | Disordered | 0.636272 | Binding | 0.383 | 0.884 | 0.625 | -4.586 | Likely Benign | 0.874 | Likely Pathogenic | Ambiguous | 0.147 | Likely Benign | -0.47 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.74 | Benign | 0.40 | Tolerated | 0.1002 | 0.0685 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||||||||||||
| c.2480T>G | I827S 2D  AIThe SynGAP1 missense variant I827S is not reported 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) is Likely Benign, and AlphaMissense‑Optimized is classified as 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 the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.590140 | Disordered | 0.636272 | Binding | 0.383 | 0.884 | 0.625 | -3.693 | Likely Benign | 0.849 | Likely Pathogenic | Ambiguous | 0.140 | Likely Benign | -0.42 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.70 | Benign | 0.29 | Tolerated | 0.2891 | 0.0512 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2481C>G | I827M 2D  AIThe SynGAP1 missense variant I827M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.590140 | Disordered | 0.636272 | Binding | 0.383 | 0.884 | 0.625 | -4.910 | Likely Benign | 0.282 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -0.61 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.65 | Benign | 0.13 | Tolerated | 0.0642 | 0.2560 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2401G>A | G801S 2D  AIThe SynGAP1 missense variant G801S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All available in‑silico predictors classify the change as benign: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this benign prediction: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant. Overall, the evidence strongly supports a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.874069 | Disordered | 0.636323 | Binding | 0.320 | 0.892 | 0.625 | Uncertain | 1 | -3.665 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -0.41 | Neutral | 0.009 | Benign | 0.019 | Benign | 2.76 | Benign | 0.48 | Tolerated | 4.32 | 2 | 0.2325 | 0.4755 | 0 | 1 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.2401G>C | G801R 2D AIThe SynGAP1 missense variant G801R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM‑Consensus also indicates a benign outcome; Foldetta data are not available. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.874069 | Disordered | 0.636323 | Binding | 0.320 | 0.892 | 0.625 | -4.226 | Likely Benign | 0.424 | Ambiguous | Likely Benign | 0.045 | Likely Benign | -0.18 | Neutral | 0.846 | Possibly Damaging | 0.624 | Possibly Damaging | 2.73 | Benign | 0.64 | Tolerated | 0.0850 | 0.3793 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.2401G>T | G801C 2D  AIThe SynGAP1 missense variant G801C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM‑Consensus also indicates a benign outcome; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, and this does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.874069 | Disordered | 0.636323 | Binding | 0.320 | 0.892 | 0.625 | -7.542 | In-Between | 0.125 | Likely Benign | Likely Benign | 0.156 | Likely Benign | -1.83 | Neutral | 0.992 | Probably Damaging | 0.873 | Possibly Damaging | 2.67 | Benign | 0.06 | Tolerated | 0.1039 | 0.4021 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||||
| c.2402G>A | G801D 2D  AIThe SynGAP1 missense variant G801D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic call comes from polyPhen‑2 HumDiv. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates likely benign. Foldetta results are not available, so they do not influence the assessment. Overall, the majority of evidence points to a benign effect, 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 | SH3-binding motif | 0.874069 | Disordered | 0.636323 | Binding | 0.320 | 0.892 | 0.625 | -5.312 | Likely Benign | 0.414 | Ambiguous | Likely Benign | 0.066 | Likely Benign | -0.69 | Neutral | 0.611 | Possibly Damaging | 0.346 | Benign | 2.84 | Benign | 0.25 | Tolerated | 0.1631 | 0.1835 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||
| c.2402G>C | G801A 2D AIThe SynGAP1 missense variant G801A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are not available, so they do not influence the assessment. **Overall, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.874069 | Disordered | 0.636323 | Binding | 0.320 | 0.892 | 0.625 | -3.747 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.025 | Likely Benign | -0.61 | Neutral | 0.025 | Benign | 0.034 | Benign | 2.83 | Benign | 0.50 | Tolerated | 0.3458 | 0.4681 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2402G>T | G801V 2D AIThe SynGAP1 missense variant G801V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags the variant as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that G801V is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.874069 | Disordered | 0.636323 | Binding | 0.320 | 0.892 | 0.625 | -4.781 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.098 | Likely Benign | -1.64 | Neutral | 0.611 | Possibly Damaging | 0.272 | Benign | 2.70 | Benign | 0.11 | Tolerated | 0.1041 | 0.4230 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||
| c.2596G>A | V866I 2D AIThe SynGAP1 missense variant V866I is listed in ClinVar with an “Uncertain” status (ClinVar ID 536995.0) and is present in gnomAD (6‑33443148‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.638070 | Binding | 0.266 | 0.788 | 0.250 | Conflicting | 3 | 6-33443148-G-A | 5 | 3.10e-6 | -4.652 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 0.059 | Likely Benign | -0.39 | Neutral | 0.957 | Probably Damaging | 0.541 | Possibly Damaging | 2.69 | Benign | 0.27 | Tolerated | 3.82 | 4 | 0.0699 | 0.4004 | 4 | 3 | 0.3 | 14.03 | ||||||||||||||||||||||||||||||||
| c.2596G>C | V866L 2D AIThe SynGAP1 missense variant V866L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification—there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.638070 | Binding | 0.266 | 0.788 | 0.250 | -3.352 | Likely Benign | 0.148 | Likely Benign | Likely Benign | 0.046 | Likely Benign | -0.97 | Neutral | 0.217 | Benign | 0.229 | Benign | 2.71 | Benign | 0.21 | Tolerated | 3.82 | 4 | 0.0836 | 0.4660 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.2596G>T | V866L 2D AIThe SynGAP1 missense variant V866L is listed in ClinVar (ID 469150.0) with an “Uncertain” clinical significance and is present in gnomAD (6‑33443148‑G‑T). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic outcome. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the computational evidence strongly supports a benign effect, and this conclusion does not contradict the current ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.638070 | Binding | 0.266 | 0.788 | 0.250 | Uncertain | 1 | 6-33443148-G-T | 1 | 6.20e-7 | -3.352 | Likely Benign | 0.148 | Likely Benign | Likely Benign | 0.046 | Likely Benign | -0.97 | Neutral | 0.217 | Benign | 0.229 | Benign | 2.71 | Benign | 0.21 | Tolerated | 3.82 | 4 | 0.0836 | 0.4660 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||
| c.2597T>A | V866E 2D  AIThe SynGAP1 missense variant V866E 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, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic impact. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized 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—including the SGM consensus and AlphaMissense‑Optimized—points to a benign effect, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.638070 | Binding | 0.266 | 0.788 | 0.250 | -3.917 | Likely Benign | 0.422 | Ambiguous | Likely Benign | 0.157 | Likely Benign | -2.09 | Neutral | 0.998 | Probably Damaging | 0.939 | Probably Damaging | 2.72 | Benign | 0.05 | Affected | 0.0996 | 0.1629 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||||||||||||
| c.2597T>C | V866A 2D AIThe SynGAP1 missense variant V866A is reported in gnomAD (ID 6‑33443149‑T‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict it to be pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments 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 preponderance of evidence points to a benign impact, and this assessment does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.638070 | Binding | 0.266 | 0.788 | 0.250 | 6-33443149-T-C | 1 | 6.20e-7 | -1.805 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -1.27 | Neutral | 0.889 | Possibly Damaging | 0.682 | Possibly Damaging | 2.87 | Benign | 0.37 | Tolerated | 3.82 | 4 | 0.3441 | 0.2512 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||||||||||
| c.2597T>G | V866G 2D AIThe SynGAP1 missense variant V866G is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods points to a benign impact for V866G, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.599170 | Disordered | 0.638070 | Binding | 0.266 | 0.788 | 0.250 | -1.519 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -2.30 | Neutral | 0.912 | Possibly Damaging | 0.993 | Probably Damaging | 2.69 | Benign | 0.07 | Tolerated | 0.2548 | 0.2157 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.337G>A | G113R 2D AIThe SynGAP1 missense variant G113R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default, while AlphaMissense‑Optimized returns an uncertain result. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.639486 | Binding | 0.350 | 0.870 | 0.750 | -3.904 | Likely Benign | 0.791 | Likely Pathogenic | Ambiguous | 0.087 | Likely Benign | -1.50 | Neutral | 0.267 | Benign | 0.080 | Benign | 4.16 | Benign | 0.03 | Affected | 0.1025 | 0.4138 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.337G>C | G113R 2D AIThe SynGAP1 missense variant G113R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM all classify it as benign. In contrast, SIFT and AlphaMissense‑Default predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized score is uncertain, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as likely benign. Protein‑folding stability analysis via Foldetta is unavailable for this residue. Overall, the preponderance of evidence points to a benign effect, and this assessment does not conflict with the absence of a ClinVar classification. Thus, the variant is most likely benign, and this conclusion is consistent with the lack of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.639486 | Binding | 0.350 | 0.870 | 0.750 | -3.904 | Likely Benign | 0.791 | Likely Pathogenic | Ambiguous | 0.088 | Likely Benign | -1.50 | Neutral | 0.267 | Benign | 0.080 | Benign | 4.16 | Benign | 0.03 | Affected | 0.1025 | 0.4138 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.337G>T | G113W 2D AIThe SynGAP1 missense variant G113W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence (six benign versus four pathogenic predictions) supports a benign classification. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.639486 | Binding | 0.350 | 0.870 | 0.750 | -5.635 | Likely Benign | 0.620 | Likely Pathogenic | Likely Benign | 0.162 | Likely Benign | -2.44 | Neutral | 0.983 | Probably Damaging | 0.717 | Possibly Damaging | 4.10 | Benign | 0.01 | Affected | 0.0700 | 0.4462 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.338G>A | G113E 2D AIThe SynGAP1 missense variant G113E is not reported in ClinVar (ClinVar ID: None) but is present in gnomAD (ID 6‑33432203‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) also as benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.639486 | Binding | 0.350 | 0.870 | 0.750 | 6-33432203-G-A | 1 | 6.20e-7 | -3.169 | Likely Benign | 0.669 | Likely Pathogenic | Likely Benign | 0.092 | Likely Benign | -0.34 | Neutral | 0.028 | Benign | 0.006 | Benign | 4.21 | Benign | 0.05 | Affected | 3.61 | 5 | 0.1464 | 0.4035 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| c.338G>C | G113A 2D AIThe SynGAP1 missense variant G113A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign. Foldetta results are not available for this variant. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.639486 | Binding | 0.350 | 0.870 | 0.750 | -3.552 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.61 | Neutral | 0.131 | Benign | 0.039 | Benign | 4.20 | Benign | 0.22 | Tolerated | 0.4059 | 0.4684 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.338G>T | G113V 2D AIThe SynGAP1 missense variant G113V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.639486 | Binding | 0.350 | 0.870 | 0.750 | -3.752 | Likely Benign | 0.188 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -1.77 | Neutral | 0.838 | Possibly Damaging | 0.145 | Benign | 4.18 | Benign | 0.05 | Affected | 0.1316 | 0.4002 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| 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 | -1.22 | Neutral | 0.993 | Probably Damaging | 0.967 | Probably Damaging | 3.73 | Benign | 0.00 | Affected | 0.0932 | 0.3102 | 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 | -1.75 | Neutral | 0.993 | Probably Damaging | 0.967 | Probably Damaging | 3.73 | Benign | 0.00 | Affected | 0.1533 | 0.2612 | 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 | -3.43 | Deleterious | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 3.60 | Benign | 0.00 | Affected | 0.1137 | 0.1049 | -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 | -3.77 | Deleterious | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 3.59 | Benign | 0.00 | Affected | 0.3620 | 0.1177 | -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 | -3.50 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 3.60 | Benign | 0.00 | Affected | 0.1300 | 0.0691 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.334G>A | G112R 2D AIThe SynGAP1 missense variant G112R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. High‑accuracy assessments are less definitive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of standard predictors lean toward a benign impact, and this is not contradicted by any ClinVar annotation. Thus, based on current predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.728858 | Disordered | 0.640153 | Binding | 0.332 | 0.867 | 0.750 | -3.680 | Likely Benign | 0.866 | Likely Pathogenic | Ambiguous | 0.141 | Likely Benign | -3.31 | Deleterious | 0.002 | Benign | 0.004 | Benign | 3.94 | Benign | 0.00 | Affected | 0.0983 | 0.3978 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.334G>C | G112R 2D AIThe SynGAP1 missense variant G112R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. High‑accuracy assessments are less definitive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of standard predictors lean toward a benign impact, and this is not contradicted by any ClinVar annotation. Thus, based on current predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.728858 | Disordered | 0.640153 | Binding | 0.332 | 0.867 | 0.750 | -3.680 | Likely Benign | 0.866 | Likely Pathogenic | Ambiguous | 0.142 | Likely Benign | -3.31 | Deleterious | 0.002 | Benign | 0.004 | Benign | 3.94 | Benign | 0.00 | Affected | 0.0983 | 0.3978 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.334G>T | G112W 2D AIThe SynGAP1 missense variant G112W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs. 2 benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic interpretation. This conclusion is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.728858 | Disordered | 0.640153 | Binding | 0.332 | 0.867 | 0.750 | -6.382 | Likely Benign | 0.720 | Likely Pathogenic | Likely Benign | 0.190 | Likely Benign | -3.98 | Deleterious | 0.983 | Probably Damaging | 0.778 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 0.0631 | 0.4212 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||||||
| c.335G>A | G112E 2D AIThe SynGAP1 missense variant G112E is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split; Foldetta predictions are not available. Overall, the majority of evidence (five benign vs. three pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.728858 | Disordered | 0.640153 | Binding | 0.332 | 0.867 | 0.750 | -3.470 | Likely Benign | 0.818 | Likely Pathogenic | Ambiguous | 0.134 | Likely Benign | -3.30 | Deleterious | 0.421 | Benign | 0.146 | Benign | 3.96 | Benign | 0.00 | Affected | 0.1330 | 0.3814 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.335G>C | G112A 2D AIThe SynGAP1 missense variant G112A is listed in ClinVar with an uncertain significance (ClinVar ID 1425533.0) and is present in gnomAD (6‑33432200‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also benign. Foldetta results are unavailable. Overall, the majority of computational evidence indicates that the variant is most likely benign, which is consistent with its ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.640153 | Binding | 0.332 | 0.867 | 0.750 | Uncertain | 1 | 6-33432200-G-C | 15 | 9.30e-6 | -2.456 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.114 | Likely Benign | -2.34 | Neutral | 0.231 | Benign | 0.054 | Benign | 4.07 | Benign | 0.00 | Affected | 3.61 | 5 | 0.3817 | 0.4429 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||
| c.335G>T | G112V 2D AIThe SynGAP1 missense variant G112V is not 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 | 0.728858 | Disordered | 0.640153 | Binding | 0.332 | 0.867 | 0.750 | -2.411 | Likely Benign | 0.230 | Likely Benign | Likely Benign | 0.159 | Likely Benign | -3.39 | Deleterious | 0.421 | Benign | 0.108 | Benign | 3.96 | Benign | 0.00 | Affected | 0.1225 | 0.4218 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.2500A>C | M834L 2D  AIThe SynGAP1 missense variant M834L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.585406 | Disordered | 0.640801 | Binding | 0.258 | 0.863 | 0.375 | -1.926 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -0.97 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.05 | Benign | 0.00 | Affected | 0.1087 | 0.3331 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2500A>G | M834V 2D  AIThe SynGAP1 missense variant M834V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.585406 | Disordered | 0.640801 | Binding | 0.258 | 0.863 | 0.375 | -2.345 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.059 | Likely Benign | -1.10 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.53 | Benign | 0.00 | Affected | 0.2562 | 0.2705 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||||||||||||
| c.2500A>T | M834L 2D AIThe SynGAP1 missense variant M834L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.585406 | Disordered | 0.640801 | Binding | 0.258 | 0.863 | 0.375 | -1.926 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -0.97 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.05 | Benign | 0.00 | Affected | 0.1087 | 0.3331 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2501T>A | M834K 2D  AIThe SynGAP1 missense variant M834K is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.585406 | Disordered | 0.640801 | Binding | 0.258 | 0.863 | 0.375 | -3.154 | Likely Benign | 0.453 | Ambiguous | Likely Benign | 0.154 | Likely Benign | -2.21 | Neutral | 0.369 | Benign | 0.150 | Benign | 2.43 | Pathogenic | 0.00 | Affected | 0.1131 | 0.0688 | 0 | -1 | -5.8 | -3.02 | ||||||||||||||||||||||||||||||||||||||||
| c.2501T>C | M834T 2D  AIThe SynGAP1 missense variant M834T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for M834T, 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 | 0.585406 | Disordered | 0.640801 | Binding | 0.258 | 0.863 | 0.375 | -1.525 | Likely Benign | 0.332 | Likely Benign | Likely Benign | 0.137 | Likely Benign | -2.03 | Neutral | 0.224 | Benign | 0.085 | Benign | 2.45 | Pathogenic | 0.00 | Affected | 0.1757 | 0.1799 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||||||||||||
| c.2501T>G | M834R 2D  AIThe SynGAP1 missense variant M834R is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) leans toward benign (2 benign vs. 1 pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence indicates a benign impact, and this conclusion does not contradict any ClinVar annotation, as none exists for M834R. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.585406 | Disordered | 0.640801 | Binding | 0.258 | 0.863 | 0.375 | -2.621 | Likely Benign | 0.449 | Ambiguous | Likely Benign | 0.148 | Likely Benign | -2.44 | Neutral | 0.812 | Possibly Damaging | 0.284 | Benign | 2.43 | Pathogenic | 0.00 | Affected | 0.1310 | 0.0837 | 0 | -1 | -6.4 | 24.99 | ||||||||||||||||||||||||||||||||||||||||
| c.2502G>A | M834I 2D  AIThe SynGAP1 missense variant M834I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.585406 | Disordered | 0.640801 | Binding | 0.258 | 0.863 | 0.375 | -3.377 | Likely Benign | 0.291 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -1.21 | Neutral | 0.026 | Benign | 0.009 | Benign | 2.56 | Benign | 0.00 | Affected | 4.32 | 4 | 0.0976 | 0.2456 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.2502G>C | M834I 2D AIThe SynGAP1 missense variant M834I is listed in ClinVar (ID 3007819.0) with an uncertain significance designation and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only SIFT classifies the change as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority‑vote) is likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the collective predictions indicate that M834I is most likely benign, which is consistent with its ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.585406 | Disordered | 0.640801 | Binding | 0.258 | 0.863 | 0.375 | Uncertain | 1 | -3.377 | Likely Benign | 0.291 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -1.21 | Neutral | 0.026 | Benign | 0.009 | Benign | 2.56 | Benign | 0.00 | Affected | 4.32 | 4 | 0.0976 | 0.2456 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||
| c.2502G>T | M834I 2D AIThe SynGAP1 missense variant M834I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect; there is no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.585406 | Disordered | 0.640801 | Binding | 0.258 | 0.863 | 0.375 | -3.377 | Likely Benign | 0.291 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -1.21 | Neutral | 0.026 | Benign | 0.009 | Benign | 2.56 | Benign | 0.00 | Affected | 4.32 | 4 | 0.0976 | 0.2456 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.2650C>G | R884G 2D AIThe SynGAP1 missense variant R884G is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population evidence. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign status. Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.641526 | Binding | 0.305 | 0.898 | 0.250 | -1.332 | Likely Benign | 0.183 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -0.58 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.64 | Benign | 0.27 | Tolerated | 0.3502 | 0.3655 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2650C>T | R884W 2D AIThe SynGAP1 missense variant R884W is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (gnomAD ID 6‑33443202‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. No Foldetta (protein‑folding stability) result is available for this variant. Overall, the majority of computational predictions, including the high‑accuracy tools, indicate that R884W is most likely benign, which is consistent with the ClinVar “Uncertain” status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.641526 | Binding | 0.305 | 0.898 | 0.250 | Uncertain | 1 | 6-33443202-C-T | 5 | 3.10e-6 | -3.785 | Likely Benign | 0.332 | Likely Benign | Likely Benign | 0.151 | Likely Benign | 0.26 | Neutral | 0.995 | Probably Damaging | 0.812 | Possibly Damaging | 2.56 | Benign | 0.05 | Affected | 4.32 | 4 | 0.1223 | 0.3304 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||
| c.2651G>A | R884Q 2D AIThe SynGAP1 missense variant R884Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443203‑G‑A). All available in silico predictors agree on a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not reported, so they are unavailable. Overall, the computational evidence strongly supports a benign classification, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.641526 | Binding | 0.305 | 0.898 | 0.250 | Uncertain | 2 | 6-33443203-G-A | 5 | 3.10e-6 | -3.785 | Likely Benign | 0.128 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.42 | Neutral | 0.012 | Benign | 0.004 | Benign | 2.62 | Benign | 0.36 | Tolerated | 4.32 | 4 | 0.2874 | 0.2332 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.2651G>C | R884P 2D AIThe SynGAP1 missense variant R884P is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors classify the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the computational evidence strongly supports a benign classification, and this is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.641526 | Binding | 0.305 | 0.898 | 0.250 | -1.882 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.188 | Likely Benign | -1.28 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.58 | Benign | 0.20 | Tolerated | 0.2186 | 0.4337 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2651G>T | R884L 2D AIThe SynGAP1 missense variant R884L 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 | 0.720929 | Disordered | 0.641526 | Binding | 0.305 | 0.898 | 0.250 | -3.482 | Likely Benign | 0.280 | Likely Benign | Likely Benign | 0.095 | Likely Benign | -1.08 | Neutral | 0.300 | Benign | 0.191 | Benign | 2.63 | Benign | 0.24 | Tolerated | 0.1809 | 0.4177 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2647C>A | L883I 2D AIThe SynGAP1 missense variant L883I 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, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. Foldetta, a protein‑folding stability method 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 | 0.716283 | Disordered | 0.641952 | Binding | 0.334 | 0.886 | 0.250 | -5.046 | Likely Benign | 0.102 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -0.26 | Neutral | 0.802 | Possibly Damaging | 0.355 | Benign | 2.66 | Benign | 0.35 | Tolerated | 0.0970 | 0.4093 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.2647C>G | L883V 2D AIThe SynGAP1 missense variant L883V is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification—there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.716283 | Disordered | 0.641952 | Binding | 0.334 | 0.886 | 0.250 | -4.075 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.059 | Likely Benign | -0.28 | Neutral | 0.451 | Benign | 0.157 | Benign | 2.67 | Benign | 0.28 | Tolerated | 0.1611 | 0.3744 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2648T>A | L883Q 2D AIThe SynGAP1 missense variant L883Q is reported in gnomAD (6‑33443200‑T‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The variant is therefore 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 | 0.716283 | Disordered | 0.641952 | Binding | 0.334 | 0.886 | 0.250 | 6-33443200-T-A | 3 | 1.86e-6 | -3.559 | Likely Benign | 0.123 | Likely Benign | Likely Benign | 0.129 | Likely Benign | -0.51 | Neutral | 0.934 | Possibly Damaging | 0.637 | Possibly Damaging | 2.66 | Benign | 0.11 | Tolerated | 4.32 | 4 | 0.1119 | 0.1505 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||
| c.2648T>C | L883P 2D AIThe SynGAP1 missense variant L883P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence supports a benign classification for this variant, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.716283 | Disordered | 0.641952 | Binding | 0.334 | 0.886 | 0.250 | -2.572 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -0.58 | Neutral | 0.934 | Possibly Damaging | 0.516 | Possibly Damaging | 2.62 | Benign | 0.21 | Tolerated | 0.3462 | 0.1658 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2648T>G | L883R 2D AIThe SynGAP1 missense variant L883R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact for the L883R variant, 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 | 0.716283 | Disordered | 0.641952 | Binding | 0.334 | 0.886 | 0.250 | -3.026 | Likely Benign | 0.286 | Likely Benign | Likely Benign | 0.110 | Likely Benign | -0.83 | Neutral | 0.934 | Possibly Damaging | 0.435 | Benign | 2.73 | Benign | 0.11 | Tolerated | 0.1237 | 0.1147 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2503C>A | L835M 2D AIThe SynGAP1 missense variant L835M is listed in ClinVar (ID 2731331) with an uncertain significance designation and is not reported in gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral 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) classify the substitution as pathogenic. High‑accuracy tools further support a benign interpretation: AlphaMissense‑Optimized reports benign, and the SGM‑Consensus (majority vote) is likely benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.642742 | Binding | 0.319 | 0.863 | 0.125 | Conflicting | 2 | -4.153 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -0.45 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.67 | Benign | 0.12 | Tolerated | 3.77 | 5 | 0.0724 | 0.3839 | 2 | 4 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||
| c.2503C>G | L835V 2D AIThe SynGAP1 missense variant L835V is reported in gnomAD (variant ID 6‑33443055‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict the variant to be pathogenic. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence from multiple prediction algorithms and high‑accuracy tools indicates that 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 | 0.608892 | Disordered | 0.642742 | Binding | 0.319 | 0.863 | 0.125 | 6-33443055-C-G | 1 | 6.19e-7 | -3.439 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.073 | Likely Benign | -0.70 | Neutral | 0.995 | Probably Damaging | 0.926 | Probably Damaging | 2.72 | Benign | 0.17 | Tolerated | 3.77 | 5 | 0.1492 | 0.2886 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.2504T>A | L835Q 2D AIThe SynGAP1 missense variant L835Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. Foldetta results are not available, so they do not influence the overall assessment. Based on the majority of predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.642742 | Binding | 0.319 | 0.863 | 0.125 | -4.788 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -0.84 | Neutral | 0.996 | Probably Damaging | 0.967 | Probably Damaging | 2.70 | Benign | 0.02 | Affected | 0.1033 | 0.1162 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2504T>C | L835P 2D AIThe SynGAP1 missense variant L835P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the overall assessment. Overall, the majority of evidence points to the variant being most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.642742 | Binding | 0.319 | 0.863 | 0.125 | -3.024 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.144 | Likely Benign | 0.03 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.78 | Benign | 0.04 | Affected | 0.3455 | 0.1079 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2504T>G | L835R 2D AIThe SynGAP1 missense variant L835R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic outcome. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized independently predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, 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 | 0.608892 | Disordered | 0.642742 | Binding | 0.319 | 0.863 | 0.125 | -4.749 | Likely Benign | 0.381 | Ambiguous | Likely Benign | 0.126 | Likely Benign | -1.05 | Neutral | 0.996 | Probably Damaging | 0.955 | Probably Damaging | 2.70 | Benign | 0.02 | Affected | 0.1239 | 0.0804 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2716C>A | L906I 2D AIThe SynGAP1 missense variant L906I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; no Foldetta stability result is available. Overall, the majority of evidence points to a benign impact for this variant. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.604312 | Disordered | 0.644316 | Binding | 0.315 | 0.920 | 0.250 | -5.882 | Likely Benign | 0.174 | Likely Benign | Likely Benign | 0.036 | Likely Benign | -0.50 | Neutral | 0.905 | Possibly Damaging | 0.545 | Possibly Damaging | 2.45 | Pathogenic | 0.32 | Tolerated | 0.1060 | 0.4093 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.2716C>G | L906V 2D AIThe SynGAP1 missense variant L906V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as tolerated or benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a damaging or pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields 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 conclusion does not conflict with ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.604312 | Disordered | 0.644316 | Binding | 0.315 | 0.920 | 0.250 | -5.105 | Likely Benign | 0.206 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -0.64 | Neutral | 0.981 | Probably Damaging | 0.832 | Possibly Damaging | 2.46 | Pathogenic | 0.21 | Tolerated | 0.1632 | 0.3744 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2716C>T | L906F 2D AIThe SynGAP1 missense variant L906F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for the variant. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.604312 | Disordered | 0.644316 | Binding | 0.315 | 0.920 | 0.250 | -4.700 | Likely Benign | 0.304 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -1.79 | Neutral | 0.999 | Probably Damaging | 0.979 | Probably Damaging | 2.22 | Pathogenic | 0.18 | Tolerated | 0.0753 | 0.3342 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2717T>A | L906H 2D  AIThe SynGAP1 missense variant L906H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two benign vs. two pathogenic votes) and Foldetta results are unavailable. Overall, the majority of standard predictors lean toward pathogenicity, but the most reliable high‑accuracy tool suggests a benign outcome and the consensus is unresolved. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.604312 | Disordered | 0.644316 | Binding | 0.315 | 0.920 | 0.250 | -4.367 | Likely Benign | 0.732 | Likely Pathogenic | Likely Benign | 0.124 | Likely Benign | -1.01 | Neutral | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.18 | Pathogenic | 0.02 | Affected | 0.1125 | 0.1073 | -2 | -3 | -7.0 | 23.98 | ||||||||||||||||||||||||||||||||||||||||
| c.2717T>C | L906P 2D AIThe SynGAP1 missense variant L906P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors a benign outcome. Foldetta, which would provide a protein‑folding stability estimate, is unavailable for this variant. Overall, the preponderance of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.604312 | Disordered | 0.644316 | Binding | 0.315 | 0.920 | 0.250 | -3.662 | Likely Benign | 0.478 | Ambiguous | Likely Benign | 0.150 | Likely Benign | 0.08 | Neutral | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 2.18 | Pathogenic | 0.10 | Tolerated | 0.3430 | 0.1458 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2717T>G | L906R 2D AIThe SynGAP1 missense variant L906R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of standard predictors (5 vs 4) lean toward pathogenicity, while the high‑accuracy AlphaMissense‑Optimized predicts benign and the consensus remains unresolved. Thus, the variant is most likely pathogenic based on the current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.604312 | Disordered | 0.644316 | Binding | 0.315 | 0.920 | 0.250 | -3.440 | Likely Benign | 0.769 | Likely Pathogenic | Likely Benign | 0.160 | Likely Benign | -0.26 | Neutral | 1.000 | Probably Damaging | 0.990 | Probably Damaging | 2.18 | Pathogenic | 0.04 | Affected | 0.1228 | 0.0947 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.295G>A | E99K 2D AIThe SynGAP1 E99K missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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 (majority vote) also as benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar reporting, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.645246 | Binding | 0.325 | 0.874 | 0.500 | -4.746 | Likely Benign | 0.678 | Likely Pathogenic | Likely Benign | 0.071 | Likely Benign | -0.88 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.14 | Benign | 0.00 | Affected | 0.2752 | 0.8149 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.295G>C | E99Q 2D AIThe SynGAP1 missense variant E99Q is reported in gnomAD (6-33425903‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact for E99Q, and this conclusion is not contradicted by any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.645246 | Binding | 0.325 | 0.874 | 0.500 | 6-33425903-G-C | 1 | 6.20e-7 | -3.675 | Likely Benign | 0.325 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -0.82 | Neutral | 0.001 | Benign | 0.000 | Benign | 4.10 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1672 | 0.7727 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||
| c.296A>C | E99A 2D AIThe SynGAP1 E99A missense change is not reported in ClinVar and has no entry in gnomAD. Consensus‑based predictors cluster around a benign interpretation: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all score the variant as benign, while only SIFT predicts it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” verdict. AlphaMissense‑Default remains uncertain, and no Foldetta stability assessment is available. High‑accuracy tools therefore converge on a benign prediction: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta data are missing. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.645246 | Binding | 0.325 | 0.874 | 0.500 | -3.173 | Likely Benign | 0.347 | Ambiguous | Likely Benign | 0.127 | Likely Benign | -1.49 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.07 | Benign | 0.00 | Affected | 0.4245 | 0.7548 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.296A>G | E99G 2D AIThe SynGAP1 missense variant E99G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.645246 | Binding | 0.325 | 0.874 | 0.500 | -3.031 | Likely Benign | 0.259 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -1.69 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.04 | Benign | 0.00 | Affected | 0.3048 | 0.6399 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.296A>T | E99V 2D AIThe SynGAP1 missense variant E99V 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 a benign interpretation: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus likewise reports Likely Benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign effect for E99V, 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 | 0.795062 | Disordered | 0.645246 | Binding | 0.325 | 0.874 | 0.500 | -3.628 | Likely Benign | 0.544 | Ambiguous | Likely Benign | 0.208 | Likely Benign | -1.69 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.02 | Benign | 0.00 | Affected | 0.1109 | 0.8175 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.297A>C | E99D 2D AIThe SynGAP1 missense variant E99D is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that E99D is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.645246 | Binding | 0.325 | 0.874 | 0.500 | -3.323 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -0.78 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.09 | Benign | 0.00 | Affected | 0.2360 | 0.5200 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.297A>T | E99D 2D AIThe SynGAP1 missense variant E99D is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that E99D is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.645246 | Binding | 0.325 | 0.874 | 0.500 | -3.323 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -0.78 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.09 | Benign | 0.00 | Affected | 0.2360 | 0.5200 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2248G>A | G750R 2D AIThe SynGAP1 missense variant G750R is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33441713‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (five pathogenic vs four benign) lean toward a pathogenic impact. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.618285 | Disordered | 0.646832 | Binding | 0.348 | 0.866 | 0.625 | 6-33441713-G-A | 17 | 1.05e-5 | -3.861 | Likely Benign | 0.619 | Likely Pathogenic | Likely Benign | 0.179 | Likely Benign | -2.09 | Neutral | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 3.99 | 5 | 0.0960 | 0.4015 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.2248G>C | G750R 2D AIThe SynGAP1 missense variant G750R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments are mixed: AlphaMissense‑Optimized predicts benign, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2), and Foldetta data are unavailable. Overall, the majority of standard predictors (5 pathogenic vs 4 benign) lean toward pathogenicity, and no ClinVar annotation contradicts this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.618285 | Disordered | 0.646832 | Binding | 0.348 | 0.866 | 0.625 | -3.861 | Likely Benign | 0.619 | Likely Pathogenic | Likely Benign | 0.179 | Likely Benign | -2.09 | Neutral | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 3.99 | 5 | 0.0960 | 0.4015 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.2248G>T | G750W 2D AIThe SynGAP1 missense variant G750W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized, while the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all classify the variant as damaging. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Overall, the preponderance of evidence from multiple in silico predictors indicates that G750W is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.618285 | Disordered | 0.646832 | Binding | 0.348 | 0.866 | 0.625 | -8.433 | Likely Pathogenic | 0.427 | Ambiguous | Likely Benign | 0.135 | Likely Benign | -3.30 | Deleterious | 1.000 | Probably Damaging | 0.994 | Probably Damaging | 2.41 | Pathogenic | 0.00 | Affected | 0.0738 | 0.4009 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.2249G>A | G750E 2D AISynGAP1 missense variant G750E is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.618285 | Disordered | 0.646832 | Binding | 0.348 | 0.866 | 0.625 | Uncertain | 1 | -2.618 | Likely Benign | 0.413 | Ambiguous | Likely Benign | 0.146 | Likely Benign | -2.27 | Neutral | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 2.49 | Pathogenic | 0.01 | Affected | 3.99 | 5 | 0.1326 | 0.3768 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||
| c.2249G>C | G750A 2D AIThe SynGAP1 missense variant G750A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.646832 | Binding | 0.348 | 0.866 | 0.625 | -3.263 | Likely Benign | 0.124 | Likely Benign | Likely Benign | 0.106 | Likely Benign | -1.65 | Neutral | 0.996 | Probably Damaging | 0.887 | Possibly Damaging | 2.52 | Benign | 0.04 | Affected | 0.3683 | 0.4792 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2249G>T | G750V 2D AIThe SynGAP1 missense variant G750V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy predictions therefore show AlphaMissense‑Optimized as benign, while the remaining high‑confidence tools (PROVEAN, polyPhen‑2, SIFT, FATHMM) all indicate pathogenicity. Overall, the majority of evidence (five pathogenic vs four benign) points to a pathogenic effect. 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. | 0.618285 | Disordered | 0.646832 | Binding | 0.348 | 0.866 | 0.625 | -4.512 | Likely Benign | 0.134 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -2.54 | Deleterious | 0.984 | Probably Damaging | 0.850 | Possibly Damaging | 2.45 | Pathogenic | 0.01 | Affected | 0.1270 | 0.4212 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.340A>C | K114Q 2D AIThe SynGAP1 missense variant K114Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign. Pathogenic predictions come from polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is Likely Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and there is no ClinVar annotation to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.649749 | Binding | 0.381 | 0.879 | 0.750 | -3.221 | Likely Benign | 0.467 | Ambiguous | Likely Benign | 0.058 | Likely Benign | -1.33 | Neutral | 0.608 | Possibly Damaging | 0.108 | Benign | 3.98 | Benign | 0.00 | Affected | 0.5476 | 0.1530 | Weaken | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||||||||||
| c.340A>G | K114E 2D AISynGAP1 missense variant K114E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default, while AlphaMissense‑Optimized 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 uncertain, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation, as none exists for K114E. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.649749 | Binding | 0.381 | 0.879 | 0.750 | -2.648 | Likely Benign | 0.885 | Likely Pathogenic | Ambiguous | 0.093 | Likely Benign | -1.27 | Neutral | 0.005 | Benign | 0.003 | Benign | 4.01 | Benign | 0.00 | Affected | 0.4815 | 0.1340 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.341A>C | K114T 2D AIThe SynGAP1 missense variant K114T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which collectively indicate a likely benign outcome. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, the SGM‑Consensus score is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the overall distribution of predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.649749 | Binding | 0.381 | 0.879 | 0.750 | -3.366 | Likely Benign | 0.804 | Likely Pathogenic | Ambiguous | 0.091 | Likely Benign | -1.48 | Neutral | 0.759 | Possibly Damaging | 0.190 | Benign | 3.95 | Benign | 0.00 | Affected | 0.2796 | 0.3391 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||||||
| c.341A>G | K114R 2D AIThe SynGAP1 missense variant K114R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect; there is no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.649749 | Binding | 0.381 | 0.879 | 0.750 | -1.861 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -1.02 | Neutral | 0.005 | Benign | 0.003 | Benign | 4.09 | Benign | 0.00 | Affected | 0.5668 | 0.1498 | Weaken | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||||||||||
| c.341A>T | K114M 2D AIThe SynGAP1 missense variant K114M is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Overall, the majority of evidence points toward a benign effect, and there is no ClinVar entry to contradict this conclusion. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.649749 | Binding | 0.381 | 0.879 | 0.750 | -3.953 | Likely Benign | 0.877 | Likely Pathogenic | Ambiguous | 0.120 | Likely Benign | -1.89 | Neutral | 0.992 | Probably Damaging | 0.615 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 0.1809 | 0.4075 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.342G>C | K114N 2D AIThe SynGAP1 missense variant K114N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus remains likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.649749 | Binding | 0.381 | 0.879 | 0.750 | -3.851 | Likely Benign | 0.937 | Likely Pathogenic | Ambiguous | 0.045 | Likely Benign | -1.41 | Neutral | 0.608 | Possibly Damaging | 0.190 | Benign | 3.95 | Benign | 0.00 | Affected | 0.4590 | 0.1877 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.342G>T | K114N 2D AIThe SynGAP1 missense variant K114N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.649749 | Binding | 0.381 | 0.879 | 0.750 | -3.851 | Likely Benign | 0.937 | Likely Pathogenic | Ambiguous | 0.045 | Likely Benign | -1.41 | Neutral | 0.608 | Possibly Damaging | 0.190 | Benign | 3.95 | Benign | 0.00 | Affected | 0.4590 | 0.1877 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2617A>C | S873R 2D AIThe SynGAP1 missense variant S873R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the balance of evidence (five pathogenic vs four benign predictions) suggests the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | -5.856 | Likely Benign | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.218 | Likely Benign | -2.74 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.67 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0.0970 | 0.3667 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.2617A>G | S873G 2D AIThe SynGAP1 missense variant S873G is catalogued in gnomAD (ID 6‑33443169‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | 6-33443169-A-G | 4 | 2.48e-6 | -5.702 | Likely Benign | 0.219 | Likely Benign | Likely Benign | 0.120 | Likely Benign | -1.88 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.68 | Benign | 0.75 | Tolerated | 3.77 | 5 | 0.2897 | 0.5270 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||
| c.2617A>T | S873C 2D AIThe SynGAP1 missense variant S873C 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, FATHMM, and AlphaMissense‑Optimized, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b) predict a pathogenic impact; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a pathogenic view: AlphaMissense‑Optimized predicts benign, while the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence leans toward pathogenicity, and this conclusion does not contradict the ClinVar status, which currently contains no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | -8.293 | Likely Pathogenic | 0.502 | Ambiguous | Likely Benign | 0.224 | Likely Benign | -2.71 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.62 | Benign | 0.04 | Affected | 0.1124 | 0.5887 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.2618G>A | S873N 2D AIThe SynGAP1 missense variant S873N is 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 further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S873N, 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 | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | -6.453 | Likely Benign | 0.706 | Likely Pathogenic | Likely Benign | 0.180 | Likely Benign | -1.88 | Neutral | 0.991 | Probably Damaging | 0.988 | Probably Damaging | 2.66 | Benign | 0.12 | Tolerated | 0.1440 | 0.4612 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| c.2618G>C | S873T 2D AIThe SynGAP1 missense variant S873T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | -6.364 | Likely Benign | 0.301 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -1.77 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.68 | Benign | 0.11 | Tolerated | 0.1514 | 0.6288 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2618G>T | S873I 2D AIThe SynGAP1 missense variant S873I has no ClinVar record and is not reported in gnomAD. Functional prediction tools that agree on a benign effect are 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 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 outputs) has no available prediction for this residue. High‑accuracy assessment therefore points to a Likely Pathogenic status from SGM‑Consensus, with AlphaMissense‑Optimized inconclusive and Foldetta missing. Overall, the preponderance of evidence suggests 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 | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | -9.412 | Likely Pathogenic | 0.945 | Likely Pathogenic | Ambiguous | 0.305 | Likely Benign | -3.44 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 2.66 | Benign | 0.02 | Affected | 0.1012 | 0.5560 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2619C>A | S873R 2D AIThe SynGAP1 missense variant S873R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the balance of evidence (five pathogenic vs. four benign predictions, with a pathogenic high‑accuracy tool) suggests the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as the variant has not yet been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | -5.856 | Likely Benign | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.192 | Likely Benign | -2.74 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.67 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0.0970 | 0.3667 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.2619C>G | S873R 2D AIThe SynGAP1 missense variant S873R is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443171‑C‑G). Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, ESM1b, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic versus two benign votes), and Foldetta stability analysis is unavailable. Overall, the balance of evidence favors a pathogenic effect, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | Uncertain | 1 | 6-33443171-C-G | 1 | 6.20e-7 | -5.856 | Likely Benign | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.192 | Likely Benign | -2.74 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.67 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0.0970 | 0.3667 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||
| c.331C>A | P111T 2D AIThe SynGAP1 missense variant P111T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.650020 | Binding | 0.438 | 0.858 | 0.750 | -2.800 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -1.44 | Neutral | 0.421 | Benign | 0.050 | Benign | 4.11 | Benign | 0.02 | Affected | 0.1650 | 0.5402 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.331C>G | P111A 2D AIThe SynGAP1 missense variant P111A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.650020 | Binding | 0.438 | 0.858 | 0.750 | -2.726 | Likely Benign | 0.163 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -1.42 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.26 | Benign | 0.04 | Affected | 0.3520 | 0.4825 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.331C>T | P111S 2D AIThe SynGAP1 missense variant P111S 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 also support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Overall, the collective predictions strongly suggest that P111S is most likely benign, and this conclusion is not contradicted by any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.650020 | Binding | 0.438 | 0.858 | 0.750 | -2.773 | Likely Benign | 0.307 | Likely Benign | Likely Benign | 0.033 | Likely Benign | -1.03 | Neutral | 0.131 | Benign | 0.026 | Benign | 4.21 | Benign | 0.29 | Tolerated | 0.3515 | 0.4973 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.332C>A | P111Q 2D  AIThe SynGAP1 missense variant P111Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign status. High‑accuracy assessments further support this view: AlphaMissense‑Optimized indicates benign, SGM‑Consensus confirms likely benign, and Foldetta data are unavailable. Taken together, the preponderance of evidence points to a benign effect for P111Q, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.650020 | Binding | 0.438 | 0.858 | 0.750 | -4.726 | Likely Benign | 0.543 | Ambiguous | Likely Benign | 0.079 | Likely Benign | -2.10 | Neutral | 0.421 | Benign | 0.054 | Benign | 4.06 | Benign | 0.00 | Affected | 0.1593 | 0.4232 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||||
| c.332C>G | P111R 2D AIThe SynGAP1 missense variant P111R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are unavailable for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.650020 | Binding | 0.438 | 0.858 | 0.750 | -4.811 | Likely Benign | 0.782 | Likely Pathogenic | Likely Benign | 0.100 | Likely Benign | -2.34 | Neutral | 0.421 | Benign | 0.075 | Benign | 4.06 | Benign | 0.00 | Affected | 0.1578 | 0.3015 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.332C>T | P111L 2D AIThe SynGAP1 missense variant P111L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also yields a benign prediction (2 benign vs. 1 pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions indicates that P111L is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.707965 | Disordered | 0.650020 | Binding | 0.438 | 0.858 | 0.750 | -4.430 | Likely Benign | 0.486 | Ambiguous | Likely Benign | 0.089 | Likely Benign | -2.81 | Deleterious | 0.421 | Benign | 0.055 | Benign | 4.06 | Benign | 0.00 | Affected | 0.2355 | 0.7085 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2464A>C | T822P 2D AIThe SynGAP1 missense variant T822P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for T822P. 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 Benign | 0.724957 | Disordered | 0.651624 | Binding | 0.295 | 0.881 | 0.750 | -3.961 | Likely Benign | 0.737 | Likely Pathogenic | Likely Benign | 0.145 | Likely Benign | -2.29 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.50 | Benign | 0.09 | Tolerated | 0.2437 | 0.5044 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2464A>G | T822A 2D AIThe SynGAP1 T822A missense variant has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and the SGM‑Consensus (majority vote) remains Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.651624 | Binding | 0.295 | 0.881 | 0.750 | -3.695 | Likely Benign | 0.788 | Likely Pathogenic | Ambiguous | 0.122 | Likely Benign | -1.55 | Neutral | 0.987 | Probably Damaging | 0.891 | Possibly Damaging | 2.60 | Benign | 0.17 | Tolerated | 0.4566 | 0.4456 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2464A>T | T822S 2D AIThe SynGAP1 missense variant T822S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for T822S, 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 | 0.724957 | Disordered | 0.651624 | Binding | 0.295 | 0.881 | 0.750 | -1.710 | Likely Benign | 0.655 | Likely Pathogenic | Likely Benign | 0.107 | Likely Benign | -0.54 | Neutral | 0.998 | Probably Damaging | 0.949 | Probably Damaging | 3.08 | Benign | 0.74 | Tolerated | 0.3794 | 0.4547 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2465C>A | T822K 2D AIThe SynGAP1 missense variant T822K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, whereas the SGM‑Consensus remains benign; Foldetta results are unavailable. Overall, the majority of conventional tools lean toward a benign interpretation, but the high‑accuracy AlphaMissense‑Optimized prediction contradicts this. Because ClinVar has no entry for this variant, there is no existing clinical classification to conflict with; thus, the variant is most likely benign based on the preponderance of evidence, though high‑accuracy predictions remain inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.651624 | Binding | 0.295 | 0.881 | 0.750 | -1.814 | Likely Benign | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.215 | Likely Benign | -2.25 | Neutral | 1.000 | Probably Damaging | 0.988 | Probably Damaging | 2.51 | Benign | 0.07 | Tolerated | 0.1369 | 0.3552 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||||
| c.2465C>G | T822R 2D AIThe SynGAP1 missense variant T822R is not 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, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a 2‑vs‑2 tie and therefore unavailable; Foldetta predictions are not provided. Overall, the balance of evidence (five pathogenic versus three benign predictions) suggests 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. | 0.724957 | Disordered | 0.651624 | Binding | 0.295 | 0.881 | 0.750 | 0.414 | Likely Benign | 0.952 | Likely Pathogenic | Ambiguous | 0.237 | Likely Benign | -2.74 | Deleterious | 1.000 | Probably Damaging | 0.992 | Probably Damaging | 2.50 | Benign | 0.05 | Affected | 0.1182 | 0.3439 | -1 | -1 | -3.8 | 55.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2465C>T | T822M 2D  AIThe SynGAP1 missense variant T822M is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443017‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive because it yields a 2‑to‑2 split. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (five pathogenic vs. three benign) lean toward pathogenicity. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.724957 | Disordered | 0.651624 | Binding | 0.295 | 0.881 | 0.750 | 6-33443017-C-T | 5 | 3.10e-6 | -4.525 | Likely Benign | 0.833 | Likely Pathogenic | Ambiguous | 0.239 | Likely Benign | -2.11 | Neutral | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 2.48 | Pathogenic | 0.03 | Affected | 3.77 | 5 | 0.1580 | 0.6379 | -1 | -1 | 2.6 | 30.09 | |||||||||||||||||||||||||||||||||||
| c.3517A>C | I1173L 2D AIThe SynGAP1 missense variant I1173L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign effect. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and there is no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.501700 | Disordered | 0.653145 | Binding | 0.521 | 0.756 | 0.375 | -1.792 | Likely Benign | 0.202 | Likely Benign | Likely Benign | 0.218 | Likely Benign | -0.30 | Neutral | 0.152 | Benign | 0.102 | Benign | 5.41 | Benign | 0.97 | Tolerated | 0.0745 | 0.3004 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||||||||||
| c.3517A>G | I1173V 2D AIThe SynGAP1 missense variant I1173V is observed in gnomAD (ID 6‑33444552‑A‑G) and has no ClinVar entry. Consensus from multiple in‑silico predictors classifies the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a benign effect, while no tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign, and Foldetta results are unavailable. Thus, based on current predictions, the variant is most likely benign and does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.501700 | Disordered | 0.653145 | Binding | 0.521 | 0.756 | 0.375 | 6-33444552-A-G | 1 | 6.20e-7 | -3.564 | Likely Benign | 0.160 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -0.16 | Neutral | 0.011 | Benign | 0.006 | Benign | 5.55 | Benign | 0.36 | Tolerated | 4.32 | 4 | 0.1023 | 0.2439 | 3 | 4 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||
| c.3517A>T | I1173F 2D AIThe SynGAP1 missense variant I1173F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (both HumDiv and HumVar) predict a pathogenic outcome. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for I1173F, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.501700 | Disordered | 0.653145 | Binding | 0.521 | 0.756 | 0.375 | -3.635 | Likely Benign | 0.491 | Ambiguous | Likely Benign | 0.365 | Likely Benign | -0.87 | Neutral | 0.934 | Possibly Damaging | 0.636 | Possibly Damaging | 5.39 | Benign | 0.13 | Tolerated | 0.0567 | 0.2108 | 1 | 0 | -1.7 | 34.02 | ||||||||||||||||||||||||||||||||||||||
| c.3518T>A | I1173N 2D AIThe SynGAP1 missense variant I1173N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also leans benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Taken together, the preponderance of evidence points to a benign impact for I1173N, 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 | Coiled-coil | 0.501700 | Disordered | 0.653145 | Binding | 0.521 | 0.756 | 0.375 | -4.130 | Likely Benign | 0.691 | Likely Pathogenic | Likely Benign | 0.443 | Likely Benign | -1.46 | Neutral | 0.925 | Possibly Damaging | 0.611 | Possibly Damaging | 5.34 | Benign | 0.02 | Affected | 0.0920 | 0.0142 | -2 | -3 | -8.0 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3518T>C | I1173T 2D AIThe SynGAP1 missense variant I1173T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for I1173T, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.501700 | Disordered | 0.653145 | Binding | 0.521 | 0.756 | 0.375 | -3.162 | Likely Benign | 0.441 | Ambiguous | Likely Benign | 0.405 | Likely Benign | -1.18 | Neutral | 0.451 | Benign | 0.265 | Benign | 5.46 | Benign | 0.05 | Affected | 0.1016 | 0.0821 | 0 | -1 | -5.2 | -12.05 | ||||||||||||||||||||||||||||||||||||||
| c.3518T>G | I1173S 2D AIThe SynGAP1 missense variant I1173S is not reported 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 polyPhen‑2 HumVar, while those that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for I1173S, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.501700 | Disordered | 0.653145 | Binding | 0.521 | 0.756 | 0.375 | -2.416 | Likely Benign | 0.557 | Ambiguous | Likely Benign | 0.455 | Likely Benign | -1.18 | Neutral | 0.625 | Possibly Damaging | 0.265 | Benign | 5.45 | Benign | 0.02 | Affected | 0.2796 | 0.0512 | -1 | -2 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||||||||||
| c.3519C>G | I1173M 2D AIThe SynGAP1 missense variant I1173M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.501700 | Disordered | 0.653145 | Binding | 0.521 | 0.756 | 0.375 | -3.301 | Likely Benign | 0.196 | Likely Benign | Likely Benign | 0.327 | Likely Benign | -0.61 | Neutral | 0.973 | Probably Damaging | 0.830 | Possibly Damaging | 5.37 | Benign | 0.15 | Tolerated | 0.0676 | 0.2295 | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||||||||||||||
| c.2356C>A | L786I 2D AIThe SynGAP1 missense variant L786I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence, especially from the high‑accuracy methods, points to a benign 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. | Likely Benign | SH3-binding motif | 0.882776 | Disordered | 0.655253 | Binding | 0.341 | 0.895 | 0.750 | -5.464 | Likely Benign | 0.215 | Likely Benign | Likely Benign | 0.087 | Likely Benign | -1.12 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.93 | Pathogenic | 0.00 | Affected | 0.1056 | 0.4199 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||||||||||
| c.2356C>G | L786V 2D AIThe SynGAP1 missense variant L786V is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict the ClinVar status, which currently has no classification for L786V. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.882776 | Disordered | 0.655253 | Binding | 0.341 | 0.895 | 0.750 | -4.607 | Likely Benign | 0.310 | Likely Benign | Likely Benign | 0.099 | Likely Benign | -1.66 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.00 | Pathogenic | 0.00 | Affected | 0.1683 | 0.4049 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2356C>T | L786F 2D AIThe SynGAP1 missense variant L786F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; Foldetta results are unavailable. Overall, the balance of evidence leans toward pathogenicity, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.882776 | Disordered | 0.655253 | Binding | 0.341 | 0.895 | 0.750 | -4.949 | Likely Benign | 0.578 | Likely Pathogenic | Likely Benign | 0.112 | Likely Benign | -2.53 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.83 | Pathogenic | 0.00 | Affected | 0.0765 | 0.3847 | 2 | 0 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||||||||
| c.2357T>A | L786H 2D AIThe SynGAP1 missense variant L786H is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign calls come from REVEL and ESM1b, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. Grouping by agreement, two tools predict benign, seven predict pathogenic, and AlphaMissense‑Optimized remains uncertain. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, but the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.882776 | Disordered | 0.655253 | Binding | 0.341 | 0.895 | 0.750 | -5.892 | Likely Benign | 0.836 | Likely Pathogenic | Ambiguous | 0.168 | Likely Benign | -3.72 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.79 | Pathogenic | 0.00 | Affected | 0.1309 | 0.1214 | -2 | -3 | -7.0 | 23.98 | ||||||||||||||||||||||||||||||||||||||
| c.2357T>C | L786P 2D AISynGAP1 missense variant L786P is reported in gnomAD (ID 6‑33442909‑T‑C) but has no ClinVar entry. Functional prediction tools show discordant results: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further highlight this split: AlphaMissense‑Optimized reports a benign effect, SGM‑Consensus confirms a likely pathogenic outcome, and Foldetta results are unavailable. Overall, the majority of conventional tools and the SGM‑Consensus support a pathogenic interpretation, while one high‑accuracy tool suggests benign. No ClinVar status is present, 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 | SH3-binding motif | 0.882776 | Disordered | 0.655253 | Binding | 0.341 | 0.895 | 0.750 | 6-33442909-T-C | -3.217 | Likely Benign | 0.656 | Likely Pathogenic | Likely Benign | 0.219 | Likely Benign | -4.06 | Deleterious | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 1.79 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.3343 | 0.1814 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||
| c.2357T>G | L786R 2D AIThe SynGAP1 missense variant L786R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. The high‑accuracy consensus from SGM (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) favors pathogenicity, and the lack of a Foldetta result does not alter this conclusion. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant has not yet been catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.882776 | Disordered | 0.655253 | Binding | 0.341 | 0.895 | 0.750 | -4.989 | Likely Benign | 0.842 | Likely Pathogenic | Ambiguous | 0.169 | Likely Benign | -3.07 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.79 | Pathogenic | 0.00 | Affected | 0.1403 | 0.1288 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||
| c.343C>A | Q115K 2D AIThe SynGAP1 missense variant Q115K is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign interpretation: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign, while the majority of other predictors (polyPhen‑2 HumDiv and HumVar) indicate pathogenic. When predictions are grouped by agreement, the benign‑oriented tools outnumber the pathogenic ones, and the single uncertain call from AlphaMissense‑Default does not alter the overall trend. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Based on the preponderance of benign predictions and the high‑accuracy consensus, the variant is most likely benign; this conclusion is consistent with the absence of a ClinVar pathogenic claim. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.657256 | Binding | 0.327 | 0.878 | 0.750 | -3.365 | Likely Benign | 0.507 | Ambiguous | Likely Benign | 0.101 | Likely Benign | -0.49 | Neutral | 0.924 | Possibly Damaging | 0.857 | Possibly Damaging | 4.18 | Benign | 0.40 | Tolerated | 0.1704 | 0.3678 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.343C>G | Q115E 2D AIThe SynGAP1 missense variant Q115E is reported in gnomAD (variant ID 6‑33432208‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. When predictions are grouped by consensus, the benign group contains seven tools, whereas the pathogenic group contains two. High‑accuracy assessments reinforce the benign view: AlphaMissense‑Optimized reports a benign outcome, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. No Foldetta stability analysis is available, so it does not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion 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 | 0.784345 | Disordered | 0.657256 | Binding | 0.327 | 0.878 | 0.750 | 6-33432208-C-G | 1 | 6.20e-7 | -3.465 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.096 | Likely Benign | -0.40 | Neutral | 0.924 | Possibly Damaging | 0.857 | Possibly Damaging | 4.18 | Benign | 0.42 | Tolerated | 3.61 | 5 | 0.1377 | 0.1832 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||
| c.344A>C | Q115P 2D AIThe SynGAP1 missense variant Q115P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this assessment does not conflict with the absence of a ClinVar claim. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.657256 | Binding | 0.327 | 0.878 | 0.750 | -2.766 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.175 | Likely Benign | -0.71 | Neutral | 0.990 | Probably Damaging | 0.954 | Probably Damaging | 4.08 | Benign | 0.46 | Tolerated | 0.2418 | 0.4778 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.344A>G | Q115R 2D AIThe SynGAP1 missense variant Q115R is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of high‑accuracy predictors—AlphaMissense‑Optimized and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—also support a benign classification. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact, and AlphaMissense‑Default remains uncertain. No Foldetta stability analysis is available. Overall, the preponderance of evidence from both general and high‑accuracy tools points to a benign effect for Q115R. This assessment is consistent with the absence of a ClinVar claim, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.657256 | Binding | 0.327 | 0.878 | 0.750 | -1.429 | Likely Benign | 0.497 | Ambiguous | Likely Benign | 0.109 | Likely Benign | -0.46 | Neutral | 0.967 | Probably Damaging | 0.901 | Possibly Damaging | 4.12 | Benign | 0.24 | Tolerated | 0.1469 | 0.1507 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.344A>T | Q115L 2D AIThe SynGAP1 missense variant Q115L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for Q115L, 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 | 0.784345 | Disordered | 0.657256 | Binding | 0.327 | 0.878 | 0.750 | -3.281 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -1.25 | Neutral | 0.967 | Probably Damaging | 0.901 | Possibly Damaging | 4.10 | Benign | 0.10 | Tolerated | 0.0710 | 0.5452 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.345G>C | Q115H 2D AIThe SynGAP1 missense variant Q115H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q115H, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.657256 | Binding | 0.327 | 0.878 | 0.750 | -3.888 | Likely Benign | 0.277 | Likely Benign | Likely Benign | 0.156 | Likely Benign | -0.99 | Neutral | 0.990 | Probably Damaging | 0.969 | Probably Damaging | 4.08 | Benign | 0.17 | Tolerated | 0.1248 | 0.3383 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.345G>T | Q115H 2D AIThe SynGAP1 missense variant Q115H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic effect. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence from multiple prediction algorithms and consensus methods points to a benign classification for Q115H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.657256 | Binding | 0.327 | 0.878 | 0.750 | -3.888 | Likely Benign | 0.277 | Likely Benign | Likely Benign | 0.156 | Likely Benign | -0.99 | Neutral | 0.990 | Probably Damaging | 0.969 | Probably Damaging | 4.08 | Benign | 0.17 | Tolerated | 0.1248 | 0.3383 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.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 | -3.46 | Deleterious | 0.487 | Possibly Damaging | 0.211 | Benign | 3.47 | Benign | 0.00 | Affected | 0.3581 | 0.3585 | -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 | -4.71 | Deleterious | 0.965 | Probably Damaging | 0.416 | Benign | 3.45 | Benign | 0.00 | Affected | 3.61 | 5 | 0.1189 | 0.3827 | 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 | -2.26 | Neutral | 0.957 | Probably Damaging | 0.342 | Benign | 3.52 | Benign | 0.01 | Affected | 3.61 | 5 | 0.3171 | 0.2460 | 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 | -3.72 | Deleterious | 0.910 | Possibly Damaging | 0.578 | Possibly Damaging | 3.47 | Benign | 0.00 | Affected | 3.61 | 5 | 0.2063 | 0.4426 | 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 | -4.19 | Deleterious | 0.190 | Benign | 0.037 | Benign | 3.48 | Benign | 0.01 | Affected | 3.61 | 5 | 0.1718 | 0.4475 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||
| c.2599G>A | G867R 2D AIThe SynGAP1 missense variant G867R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.657954 | Binding | 0.285 | 0.801 | 0.250 | -3.569 | Likely Benign | 0.755 | Likely Pathogenic | Likely Benign | 0.131 | Likely Benign | -1.76 | Neutral | 0.997 | Probably Damaging | 0.943 | Probably Damaging | 2.70 | Benign | 0.05 | Affected | 3.82 | 4 | 0.0886 | 0.4494 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.2599G>C | G867R 2D AIThe SynGAP1 missense variant G867R is catalogued in gnomAD (6‑33443151‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score, whereas pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized reports a benign effect, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign status. No Foldetta stability analysis is available for this residue. Overall, the majority of evidence points to a benign effect for G867R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.657954 | Binding | 0.285 | 0.801 | 0.250 | 6-33443151-G-C | 1 | 6.20e-7 | -3.569 | Likely Benign | 0.755 | Likely Pathogenic | Likely Benign | 0.131 | Likely Benign | -1.76 | Neutral | 0.997 | Probably Damaging | 0.943 | Probably Damaging | 2.70 | Benign | 0.05 | Affected | 3.82 | 4 | 0.0886 | 0.4494 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||
| c.2599G>T | G867W 2D AIThe SynGAP1 missense variant G867W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains pathogenic; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.517562 | Disordered | 0.657954 | Binding | 0.285 | 0.801 | 0.250 | -8.983 | Likely Pathogenic | 0.776 | Likely Pathogenic | Likely Benign | 0.163 | Likely Benign | -2.95 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.64 | Benign | 0.01 | Affected | 0.0726 | 0.4584 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.2600G>A | G867E 2D AIThe SynGAP1 missense variant G867E is catalogued in gnomAD (6‑33443152‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions are reported by polyPhen‑2 HumDiv and polyPhen‑2 HumVar, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.657954 | Binding | 0.285 | 0.801 | 0.250 | 6-33443152-G-A | 3 | 1.86e-6 | -5.204 | Likely Benign | 0.492 | Ambiguous | Likely Benign | 0.105 | Likely Benign | -1.57 | Neutral | 0.994 | Probably Damaging | 0.943 | Probably Damaging | 2.74 | Benign | 0.07 | Tolerated | 3.82 | 4 | 0.1305 | 0.3880 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| c.2600G>C | G867A 2D AIThe SynGAP1 missense variant G867A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.657954 | Binding | 0.285 | 0.801 | 0.250 | -4.638 | Likely Benign | 0.172 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -1.18 | Neutral | 0.990 | Probably Damaging | 0.828 | Possibly Damaging | 2.79 | Benign | 0.94 | Tolerated | 0.3666 | 0.5534 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2600G>T | G867V 2D AIThe SynGAP1 missense variant G867V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Two tools—ESM1b and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑to‑2 split between benign and uncertain calls. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the balance of evidence (five benign predictions versus two pathogenic predictions, with no decisive high‑accuracy support for pathogenicity) indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.517562 | Disordered | 0.657954 | Binding | 0.285 | 0.801 | 0.250 | -7.049 | In-Between | 0.441 | Ambiguous | Likely Benign | 0.111 | Likely Benign | -2.23 | Neutral | 0.999 | Probably Damaging | 0.958 | Probably Damaging | 2.70 | Benign | 0.10 | Tolerated | 0.1125 | 0.4613 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.358G>A | G120S 2D AIThe SynGAP1 missense variant G120S is reported in gnomAD (variant ID 6-33432223‑G‑A) but has no ClinVar entry. Functional prediction tools uniformly classify the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability predictor, was not available for this variant. Overall, the evidence strongly supports a benign classification, and there is no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.659993 | Binding | 0.359 | 0.887 | 0.750 | 6-33432223-G-A | 1 | 6.20e-7 | -3.558 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.034 | Likely Benign | 0.07 | Neutral | 0.020 | Benign | 0.012 | Benign | 4.29 | Benign | 0.91 | Tolerated | 3.61 | 5 | 0.2841 | 0.4713 | 0 | 1 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.358G>C | G120R 2D AIThe SynGAP1 missense variant G120R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. Only AlphaMissense‑Default predicts a pathogenic outcome. When predictions are grouped, the benign consensus includes eight tools, whereas the pathogenic consensus contains a single tool. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign effect, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a likely benign classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that G120R is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.659993 | Binding | 0.359 | 0.887 | 0.750 | -4.406 | Likely Benign | 0.745 | Likely Pathogenic | Likely Benign | 0.022 | Likely Benign | -0.33 | Neutral | 0.089 | Benign | 0.047 | Benign | 4.26 | Benign | 0.14 | Tolerated | 0.1050 | 0.4345 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.358G>T | G120C 2D AIThe SynGAP1 missense variant G120C is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.659993 | Binding | 0.359 | 0.887 | 0.750 | -5.979 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -0.73 | Neutral | 0.410 | Benign | 0.146 | Benign | 4.20 | Benign | 0.10 | Tolerated | 0.1376 | 0.4225 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.359G>A | G120D 2D AIThe SynGAP1 missense variant G120D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence overwhelmingly supports a benign classification, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.659993 | Binding | 0.359 | 0.887 | 0.750 | -3.483 | Likely Benign | 0.465 | Ambiguous | Likely Benign | 0.037 | Likely Benign | -0.57 | Neutral | 0.165 | Benign | 0.034 | Benign | 4.25 | Benign | 0.21 | Tolerated | 0.1847 | 0.2024 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.359G>C | G120A 2D AIThe SynGAP1 missense variant G120A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.659993 | Binding | 0.359 | 0.887 | 0.750 | -3.477 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.027 | Likely Benign | 0.29 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.37 | Benign | 1.00 | Tolerated | 0.4003 | 0.4565 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.359G>T | G120V 2D AIThe SynGAP1 missense variant G120V is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is not contradicted by any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.659993 | Binding | 0.359 | 0.887 | 0.750 | -4.571 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.036 | Likely Benign | -0.68 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.28 | Benign | 0.19 | Tolerated | 0.1321 | 0.3883 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.361G>A | A121T 2D AIThe SynGAP1 missense variant A121T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. The prediction is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.779859 | Disordered | 0.661304 | Binding | 0.362 | 0.888 | 0.750 | -3.955 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.059 | Likely Benign | -0.25 | Neutral | 0.063 | Benign | 0.026 | Benign | 4.10 | Benign | 0.05 | Affected | 0.1792 | 0.7305 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.361G>C | A121P 2D AIThe SynGAP1 missense variant A121P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that A121P is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.779859 | Disordered | 0.661304 | Binding | 0.362 | 0.888 | 0.750 | -3.210 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.062 | Likely Benign | 0.95 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.18 | Benign | 0.03 | Affected | 0.2197 | 0.6196 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.361G>T | A121S 2D AIThe SynGAP1 missense variant A121S 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 also support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Overall, the collective predictions strongly suggest that the variant is most likely benign, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.779859 | Disordered | 0.661304 | Binding | 0.362 | 0.888 | 0.750 | -3.027 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.06 | Neutral | 0.002 | Benign | 0.002 | Benign | 4.18 | Benign | 0.40 | Tolerated | 0.2805 | 0.5817 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.362C>A | A121D 2D AIThe SynGAP1 missense variant A121D is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.779859 | Disordered | 0.661304 | Binding | 0.362 | 0.888 | 0.750 | -3.626 | Likely Benign | 0.595 | Likely Pathogenic | Likely Benign | 0.096 | Likely Benign | -0.89 | Neutral | 0.244 | Benign | 0.050 | Benign | 4.06 | Benign | 0.03 | Affected | 0.1876 | 0.1945 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.362C>G | A121G 2D AIThe SynGAP1 missense variant A121G is catalogued in gnomAD (ID 6‑33432227‑C‑G) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool examined—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classifies the substitution as benign. No pathogenic predictions are reported. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status remains unavailable. Overall, the evidence strongly supports a benign effect for A121G, and this conclusion does not contradict any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.779859 | Disordered | 0.661304 | Binding | 0.362 | 0.888 | 0.750 | 6-33432227-C-G | 4 | 2.48e-6 | -3.123 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.073 | Likely Benign | -0.52 | Neutral | 0.118 | Benign | 0.026 | Benign | 4.06 | Benign | 0.07 | Tolerated | 3.61 | 5 | 0.2407 | 0.5271 | 0 | 1 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.362C>T | A121V 2D AIThe SynGAP1 missense variant A121V is reported in gnomAD (ID 6‑33432227‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, while only SIFT predicts it as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence supports a benign classification for A121V, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.779859 | Disordered | 0.661304 | Binding | 0.362 | 0.888 | 0.750 | 6-33432227-C-T | 3 | 1.86e-6 | -3.818 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.046 | Likely Benign | -1.44 | Neutral | 0.213 | Benign | 0.050 | Benign | 4.04 | Benign | 0.02 | Affected | 3.61 | 5 | 0.1450 | 0.6898 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||
| c.2719A>C | S907R 2D AIThe SynGAP1 missense variant S907R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, while the SGM‑Consensus (a majority vote of the same four high‑accuracy tools) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.661854 | Binding | 0.336 | 0.920 | 0.250 | -3.852 | Likely Benign | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.082 | Likely Benign | -0.71 | Neutral | 0.998 | Probably Damaging | 0.951 | Probably Damaging | 2.73 | Benign | 0.34 | Tolerated | 0.0964 | 0.3441 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2719A>G | S907G 2D AIThe SynGAP1 missense variant S907G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.661854 | Binding | 0.336 | 0.920 | 0.250 | -3.018 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.23 | Neutral | 0.942 | Possibly Damaging | 0.788 | Possibly Damaging | 2.63 | Benign | 0.04 | Affected | 0.2625 | 0.5134 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2719A>T | S907C 2D AIThe SynGAP1 missense variant S907C is listed in ClinVar as Benign (ClinVar ID 1502069.0) and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign effect, aligning with the ClinVar classification and indicating no contradiction with the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.661854 | Binding | 0.336 | 0.920 | 0.250 | Likely Benign | 1 | -6.685 | Likely Benign | 0.298 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -2.34 | Neutral | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 2.60 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1023 | 0.5951 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||
| c.2720G>A | S907N 2D AIThe SynGAP1 missense variant S907N is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority‑vote SGM‑Consensus also reports a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy evaluations further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely benign, with no Foldetta data to contradict this. Overall, the preponderance of evidence points to a benign effect, 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 Benign | 0.637480 | Disordered | 0.661854 | Binding | 0.336 | 0.920 | 0.250 | -4.520 | Likely Benign | 0.430 | Ambiguous | Likely Benign | 0.140 | Likely Benign | -0.26 | Neutral | 0.951 | Possibly Damaging | 0.803 | Possibly Damaging | 2.66 | Benign | 0.08 | Tolerated | 0.1312 | 0.4585 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| c.2720G>C | S907T 2D AIThe SynGAP1 missense variant S907T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.661854 | Binding | 0.336 | 0.920 | 0.250 | -4.794 | Likely Benign | 0.220 | Likely Benign | Likely Benign | 0.178 | Likely Benign | -0.53 | Neutral | 0.992 | Probably Damaging | 0.846 | Possibly Damaging | 2.66 | Benign | 0.93 | Tolerated | 0.1324 | 0.6352 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2720G>T | S907I 2D AIThe SynGAP1 missense variant S907I is not reported 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, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus (majority vote) as Likely Benign, and Foldetta results are unavailable. Based on the overall balance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.661854 | Binding | 0.336 | 0.920 | 0.250 | -6.082 | Likely Benign | 0.795 | Likely Pathogenic | Ambiguous | 0.229 | Likely Benign | -2.20 | Neutral | 0.998 | Probably Damaging | 0.967 | Probably Damaging | 2.62 | Benign | 0.03 | Affected | 0.1006 | 0.5853 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2721C>A | S907R 2D AIThe SynGAP1 missense variant S907R has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic outcome. AlphaMissense‑Optimized also classifies the variant as pathogenic, whereas the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely benign. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus as benign; Foldetta results are unavailable. Overall, the majority of tools (five benign vs. four pathogenic) lean toward a benign interpretation, and there is no ClinVar evidence contradicting this assessment. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.661854 | Binding | 0.336 | 0.920 | 0.250 | -3.852 | Likely Benign | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.089 | Likely Benign | -0.71 | Neutral | 0.998 | Probably Damaging | 0.951 | Probably Damaging | 2.73 | Benign | 0.34 | Tolerated | 0.0964 | 0.3441 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2721C>G | S907R 2D AIThe SynGAP1 missense variant S907R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, whereas the SGM‑Consensus remains benign; Foldetta results are unavailable. Overall, the predictions are mixed but lean toward a benign interpretation, with no conflict with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.661854 | Binding | 0.336 | 0.920 | 0.250 | -3.852 | Likely Benign | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.089 | Likely Benign | -0.71 | Neutral | 0.998 | Probably Damaging | 0.951 | Probably Damaging | 2.73 | Benign | 0.34 | Tolerated | 0.0964 | 0.3441 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.355G>A | E119K 2D AIThe SynGAP1 missense variant E119K is not reported in ClinVar (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, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. Overall, the majority of high‑accuracy predictors (including the SGM‑Consensus) indicate a benign impact, and there is no conflict with ClinVar status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.661946 | Binding | 0.346 | 0.881 | 0.750 | -6.741 | Likely Benign | 0.922 | Likely Pathogenic | Ambiguous | 0.122 | Likely Benign | -1.95 | Neutral | 0.012 | Benign | 0.006 | Benign | 3.85 | Benign | 0.01 | Affected | 0.2633 | 0.7739 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.355G>C | E119Q 2D AIThe SynGAP1 missense variant E119Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that converge on a benign outcome include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments therefore favor a benign effect: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence indicates that E119Q is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.661946 | Binding | 0.346 | 0.881 | 0.750 | -5.839 | Likely Benign | 0.676 | Likely Pathogenic | Likely Benign | 0.136 | Likely Benign | -1.38 | Neutral | 0.596 | Possibly Damaging | 0.143 | Benign | 3.84 | Benign | 0.02 | Affected | 0.1627 | 0.7886 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.356A>C | E119A 2D AIThe SynGAP1 missense variant E119A is not 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, while those that predict a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs. 2 pathogenic), and Foldetta results are unavailable. Overall, the balance of evidence (five benign versus three pathogenic predictions) suggests the variant is most likely benign. This conclusion does not contradict ClinVar status, as the variant has no existing ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.690604 | Disordered | 0.661946 | Binding | 0.346 | 0.881 | 0.750 | -4.881 | Likely Benign | 0.647 | Likely Pathogenic | Likely Benign | 0.108 | Likely Benign | -2.52 | Deleterious | 0.231 | Benign | 0.074 | Benign | 3.84 | Benign | 0.01 | Affected | 0.4374 | 0.7514 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.356A>G | E119G 2D AIThe SynGAP1 missense variant E119G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status because no ClinVar claim exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.661946 | Binding | 0.346 | 0.881 | 0.750 | -4.349 | Likely Benign | 0.584 | Likely Pathogenic | Likely Benign | 0.143 | Likely Benign | -2.40 | Neutral | 0.421 | Benign | 0.055 | Benign | 3.82 | Benign | 0.01 | Affected | 0.3246 | 0.6405 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.356A>T | E119V 2D AISynGAP1 missense variant E119V 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, ESM1b, FATHMM, and polyPhen‑2 HumVar, while pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. High‑accuracy methods are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a tie and is therefore unavailable, and Foldetta results are not provided. Consequently, the evidence does not strongly support either outcome. The variant is most likely inconclusive; it does not clearly favor benign or pathogenic status, and this lack of consensus does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.690604 | Disordered | 0.661946 | Binding | 0.346 | 0.881 | 0.750 | -5.696 | Likely Benign | 0.842 | Likely Pathogenic | Ambiguous | 0.151 | Likely Benign | -2.78 | Deleterious | 0.596 | Possibly Damaging | 0.189 | Benign | 3.79 | Benign | 0.00 | Affected | 0.1152 | 0.7753 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||||
| c.357G>C | E119D 2D AIThe SynGAP1 missense variant E119D is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are 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 | 0.690604 | Disordered | 0.661946 | Binding | 0.346 | 0.881 | 0.750 | -3.258 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.07 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.08 | Benign | 0.32 | Tolerated | 3.61 | 5 | 0.2180 | 0.5759 | 2 | 3 | 0.0 | -14.03 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||||||||||||
| c.357G>T | E119D 2D AIThe SynGAP1 missense variant E119D is reported in gnomAD (variant ID 6‑33432222‑G‑T) but has no ClinVar entry. All available in silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments concur: AlphaMissense‑Optimized indicates a benign effect, 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, did not provide a result for this variant. Overall, the evidence strongly supports a benign classification, 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 | 0.690604 | Disordered | 0.661946 | Binding | 0.346 | 0.881 | 0.750 | 6-33432222-G-T | 3 | 1.86e-6 | -3.258 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.07 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.08 | Benign | 0.32 | Tolerated | 3.61 | 5 | 0.2180 | 0.5759 | 2 | 3 | 0.0 | -14.03 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||||
| c.2614T>A | S872T 2D AIThe SynGAP1 missense variant S872T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for S872T, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.662664 | Binding | 0.262 | 0.865 | 0.125 | -5.129 | Likely Benign | 0.189 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -1.20 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.65 | Benign | 0.17 | Tolerated | 0.1738 | 0.6234 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2614T>C | S872P 2D AIThe SynGAP1 missense variant S872P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also predicts Likely Benign. Foldetta results are not available for this variant. Overall, the majority of evidence indicates that S872P is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.662664 | Binding | 0.262 | 0.865 | 0.125 | -4.291 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.187 | Likely Benign | -1.91 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.59 | Benign | 0.13 | Tolerated | 0.2321 | 0.5581 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2614T>G | S872A 2D AIThe SynGAP1 missense variant S872A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments further support a benign prediction: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for S872A, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.662664 | Binding | 0.262 | 0.865 | 0.125 | -4.574 | Likely Benign | 0.170 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -0.91 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.77 | Benign | 0.28 | Tolerated | 0.5351 | 0.4945 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.2615C>T | S872L 2D AIThe SynGAP1 missense variant S872L is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact, and AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus likewise favors a benign classification; Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign effect for S872L, 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 Benign | 0.486429 | Structured | 0.662664 | Binding | 0.262 | 0.865 | 0.125 | -6.450 | Likely Benign | 0.555 | Ambiguous | Likely Benign | 0.178 | Likely Benign | -2.28 | Neutral | 0.991 | Probably Damaging | 0.991 | Probably Damaging | 2.61 | Benign | 0.04 | Affected | 0.1168 | 0.5283 | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.316A>G | R106G 2D AIThe SynGAP1 missense variant R106G is listed in gnomAD (ID 6‑33432181‑A‑G) but has no ClinVar entry. 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. AlphaMissense‑Optimized is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar classification to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.663409 | Binding | 0.345 | 0.862 | 0.875 | 6-33432181-A-G | 1 | 6.20e-7 | -2.617 | Likely Benign | 0.835 | Likely Pathogenic | Ambiguous | 0.161 | Likely Benign | -2.21 | Neutral | 0.421 | Benign | 0.050 | Benign | 3.65 | Benign | 0.00 | Affected | 4.05 | 3 | 0.3680 | 0.3980 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||
| c.316A>T | R106W 2D AIThe SynGAP1 missense variant R106W is not 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, 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 (5) than benign (3), 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. | 0.675549 | Disordered | 0.663409 | Binding | 0.345 | 0.862 | 0.875 | -5.350 | Likely Benign | 0.875 | Likely Pathogenic | Ambiguous | 0.240 | Likely Benign | -3.31 | Deleterious | 0.983 | Probably Damaging | 0.624 | Possibly Damaging | 3.62 | Benign | 0.00 | Affected | 0.1369 | 0.3995 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.317G>A | R106K 2D  AIThe SynGAP1 missense variant R106K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus indicates Likely Benign, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for R106K, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.663409 | Binding | 0.345 | 0.862 | 0.875 | -4.312 | Likely Benign | 0.513 | Ambiguous | Likely Benign | 0.150 | Likely Benign | -1.25 | Neutral | 0.004 | Benign | 0.001 | Benign | 3.82 | Benign | 0.00 | Affected | 0.5602 | 0.4129 | Weaken | 3 | 2 | 0.6 | -28.01 | ||||||||||||||||||||||||||||||||||||||
| c.317G>C | R106T 2D  AIThe SynGAP1 missense variant R106T is not reported 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, and no Foldetta stability assessment is available. Separately, the high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, while AlphaMissense‑Optimized remains uncertain and Foldetta data are missing. Based on the overall pattern of 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 | 0.675549 | Disordered | 0.663409 | Binding | 0.345 | 0.862 | 0.875 | -4.197 | Likely Benign | 0.950 | Likely Pathogenic | Ambiguous | 0.229 | Likely Benign | -2.30 | Neutral | 0.004 | Benign | 0.002 | Benign | 3.67 | Benign | 0.00 | Affected | 0.1941 | 0.4742 | -1 | -1 | 3.8 | -55.08 | |||||||||||||||||||||||||||||||||||||||
| c.317G>T | R106M 2D  AIThe SynGAP1 missense variant R106M is not 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 methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2), and Foldetta data are unavailable. Because the majority of tools (five of nine) predict pathogenicity and the most accurate predictor (AlphaMissense‑Optimized) also indicates pathogenicity, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as the variant has not yet been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.675549 | Disordered | 0.663409 | Binding | 0.345 | 0.862 | 0.875 | -4.804 | Likely Benign | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.184 | Likely Benign | -2.65 | Deleterious | 0.940 | Possibly Damaging | 0.360 | Benign | 3.64 | Benign | 0.00 | Affected | 0.1971 | 0.4146 | 0 | -1 | 6.4 | -24.99 | ||||||||||||||||||||||||||||||||||||||||
| c.318G>C | R106S 2D  AIThe SynGAP1 missense variant R106S is not reported 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as benign, and the Foldetta stability analysis is unavailable. Overall, the majority of predictions lean toward a benign impact, but the high‑accuracy tools provide conflicting evidence. Thus, 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 | 0.675549 | Disordered | 0.663409 | Binding | 0.345 | 0.862 | 0.875 | -2.651 | Likely Benign | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.093 | Likely Benign | -1.87 | Neutral | 0.131 | Benign | 0.026 | Benign | 3.68 | Benign | 0.00 | Affected | 0.3050 | 0.4129 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.318G>T | R106S 2D AIThe SynGAP1 missense variant R106S is not reported 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as benign, and the Foldetta stability analysis is unavailable. Overall, the majority of predictions lean toward a benign impact, but the high‑accuracy tools provide conflicting evidence. Thus, 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 | 0.675549 | Disordered | 0.663409 | Binding | 0.345 | 0.862 | 0.875 | -2.651 | Likely Benign | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.093 | Likely Benign | -1.87 | Neutral | 0.131 | Benign | 0.026 | Benign | 3.68 | Benign | 0.00 | Affected | 0.3050 | 0.4129 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.319A>G | R107G 2D AIThe SynGAP1 missense variant R107G is not 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, and FATHMM, while those that predict a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a tie and thus unavailable, and Foldetta stability analysis is missing. Overall, the majority of tools (five benign vs. three pathogenic) suggest a benign impact, but the lack of consensus from the most accurate predictors means the variant’s effect remains uncertain. This assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.663448 | Binding | 0.331 | 0.863 | 0.875 | -3.486 | Likely Benign | 0.948 | Likely Pathogenic | Ambiguous | 0.180 | Likely Benign | -3.15 | Deleterious | 0.421 | Benign | 0.050 | Benign | 2.98 | Benign | 0.00 | Affected | 0.3280 | 0.4000 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.319A>T | R107W 2D AIThe SynGAP1 missense variant R107W is not 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 predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (two pathogenic vs two benign), and Foldetta results are unavailable. Overall, the majority of evidence (six pathogenic vs three benign) points to a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.663448 | Binding | 0.331 | 0.863 | 0.875 | -4.963 | Likely Benign | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.328 | Likely Benign | -2.99 | Deleterious | 0.983 | Probably Damaging | 0.624 | Possibly Damaging | 2.95 | Benign | 0.00 | Affected | 0.1146 | 0.4228 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.320G>A | R107K 2D AIThe SynGAP1 missense variant R107K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for R107K, 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 | 0.666105 | Disordered | 0.663448 | Binding | 0.331 | 0.863 | 0.875 | -3.941 | Likely Benign | 0.758 | Likely Pathogenic | Likely Benign | 0.153 | Likely Benign | -1.33 | Neutral | 0.004 | Benign | 0.001 | Benign | 3.07 | Benign | 0.00 | Affected | 0.5618 | 0.4185 | Weaken | 3 | 2 | 0.6 | -28.01 | ||||||||||||||||||||||||||||||||||||||
| c.320G>C | R107T 2D AIThe SynGAP1 missense variant R107T is not 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 classifying the variant as pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs. 2 benign) and Foldetta results are unavailable. Overall, the majority of predictions (five benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign based on current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.663448 | Binding | 0.331 | 0.863 | 0.875 | -2.902 | Likely Benign | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.191 | Likely Benign | -2.63 | Deleterious | 0.421 | Benign | 0.050 | Benign | 2.98 | Benign | 0.00 | Affected | 0.1549 | 0.4761 | -1 | -1 | 3.8 | -55.08 | ||||||||||||||||||||||||||||||||||||||||
| c.320G>T | R107M 2D AIThe SynGAP1 missense variant R107M is not 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, 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, and Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not conflict with the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.663448 | Binding | 0.331 | 0.863 | 0.875 | -4.873 | Likely Benign | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.233 | Likely Benign | -2.65 | Deleterious | 0.028 | Benign | 0.011 | Benign | 2.96 | Benign | 0.00 | Affected | 0.1605 | 0.4415 | 0 | -1 | 6.4 | -24.99 | ||||||||||||||||||||||||||||||||||||||||
| c.321G>C | R107S 2D AIThe SynGAP1 missense variant R107S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the majority of predictions lean toward a benign impact, and this is not contradicted by any ClinVar annotation. Thus, the variant is most likely benign, although high‑accuracy tools provide conflicting evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.666105 | Disordered | 0.663448 | Binding | 0.331 | 0.863 | 0.875 | -1.162 | Likely Benign | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.147 | Likely Benign | -2.37 | Neutral | 0.231 | Benign | 0.037 | Benign | 2.99 | Benign | 0.00 | Affected | 0.2771 | 0.4148 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.321G>T | R107S 2D AIThe SynGAP1 missense variant R107S is 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the majority of predictions lean toward a benign impact, but the high‑accuracy tools provide conflicting evidence. Thus, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.666105 | Disordered | 0.663448 | Binding | 0.331 | 0.863 | 0.875 | -1.162 | Likely Benign | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.147 | Likely Benign | -2.37 | Neutral | 0.231 | Benign | 0.037 | Benign | 2.99 | Benign | 0.00 | Affected | 0.2771 | 0.4148 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.328G>A | V110I 2D AIThe SynGAP1 missense variant V110I is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population evidence. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.665934 | Binding | 0.347 | 0.860 | 0.750 | -4.409 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.10 | Neutral | 0.012 | Benign | 0.006 | Benign | 4.26 | Benign | 0.52 | Tolerated | 0.0875 | 0.4485 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.328G>C | V110L 2D AIThe SynGAP1 missense variant V110L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence overwhelmingly supports a benign impact for V110L, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.665934 | Binding | 0.347 | 0.860 | 0.750 | -3.024 | Likely Benign | 0.357 | Ambiguous | Likely Benign | 0.058 | Likely Benign | -0.71 | Neutral | 0.158 | Benign | 0.025 | Benign | 4.20 | Benign | 0.50 | Tolerated | 0.1165 | 0.5145 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.328G>T | V110F 2D AIThe SynGAP1 missense variant V110F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, SGM‑Consensus is Likely Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.665934 | Binding | 0.347 | 0.860 | 0.750 | -4.872 | Likely Benign | 0.397 | Ambiguous | Likely Benign | 0.042 | Likely Benign | -1.63 | Neutral | 0.006 | Benign | 0.003 | Benign | 4.13 | Benign | 0.01 | Affected | 0.0794 | 0.4027 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||||||||||||
| c.329T>A | V110D 2D AIThe SynGAP1 missense variant V110D is not 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 pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evaluated tools (seven pathogenic vs. three benign) indicate a pathogenic effect. This prediction is consistent with the lack of ClinVar reporting and does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.622677 | Disordered | 0.665934 | Binding | 0.347 | 0.860 | 0.750 | -4.536 | Likely Benign | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.189 | Likely Benign | -2.84 | Deleterious | 0.978 | Probably Damaging | 0.500 | Possibly Damaging | 4.04 | Benign | 0.00 | Affected | 0.1849 | 0.1115 | -2 | -3 | -7.7 | 15.96 | ||||||||||||||||||||||||||||||||||||||||
| c.329T>C | V110A 2D AIThe SynGAP1 missense variant V110A is reported as “Likely Benign” in ClinVar and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the consensus of the available predictions points to a benign impact for V110A, 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 | 0.622677 | Disordered | 0.665934 | Binding | 0.347 | 0.860 | 0.750 | -2.971 | Likely Benign | 0.717 | Likely Pathogenic | Likely Benign | 0.075 | Likely Benign | -1.35 | Neutral | 0.462 | Possibly Damaging | 0.122 | Benign | 4.14 | Benign | 0.13 | Tolerated | 0.3196 | 0.2872 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| c.329T>G | V110G 2D AIThe SynGAP1 missense variant V110G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence points toward a benign impact, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.622677 | Disordered | 0.665934 | Binding | 0.347 | 0.860 | 0.750 | -4.012 | Likely Benign | 0.724 | Likely Pathogenic | Likely Benign | 0.162 | Likely Benign | -2.87 | Deleterious | 0.377 | Benign | 0.928 | Probably Damaging | 4.06 | Benign | 0.00 | Affected | 0.2302 | 0.2671 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2251C>A | P751T 2D AIThe SynGAP1 missense variant P751T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Taken together, 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 | 0.618285 | Disordered | 0.667683 | Binding | 0.386 | 0.866 | 0.625 | -5.111 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.100 | Likely Benign | -1.65 | Neutral | 0.679 | Possibly Damaging | 0.348 | Benign | 2.71 | Benign | 1.00 | Tolerated | 0.1613 | 0.5704 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2251C>G | P751A 2D AIThe SynGAP1 missense variant P751A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the collective evidence strongly supports a benign classification, and this conclusion 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 | 0.618285 | Disordered | 0.667683 | Binding | 0.386 | 0.866 | 0.625 | -4.612 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -1.42 | Neutral | 0.028 | Benign | 0.009 | Benign | 2.73 | Benign | 0.26 | Tolerated | 0.3592 | 0.5487 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2251C>T | P751S 2D AIThe SynGAP1 missense variant P751S 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 Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions indicate that P751S 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 | 0.618285 | Disordered | 0.667683 | Binding | 0.386 | 0.866 | 0.625 | -4.157 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.109 | Likely Benign | -0.80 | Neutral | 0.514 | Possibly Damaging | 0.216 | Benign | 2.70 | Benign | 0.33 | Tolerated | 0.3446 | 0.5837 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2252C>A | P751Q 2D AIThe SynGAP1 missense variant P751Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.667683 | Binding | 0.386 | 0.866 | 0.625 | -5.273 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.079 | Likely Benign | -2.07 | Neutral | 0.837 | Possibly Damaging | 0.531 | Possibly Damaging | 2.68 | Benign | 0.05 | Affected | 0.1488 | 0.5073 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2252C>G | P751R 2D AIThe SynGAP1 missense variant P751R is catalogued in gnomAD (ID 6‑33441717‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are PROVEAN and polyPhen‑2 HumDiv. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.667683 | Binding | 0.386 | 0.866 | 0.625 | 6-33441717-C-G | 1 | 6.20e-7 | -5.646 | Likely Benign | 0.296 | Likely Benign | Likely Benign | 0.157 | Likely Benign | -2.61 | Deleterious | 0.719 | Possibly Damaging | 0.295 | Benign | 2.68 | Benign | 0.06 | Tolerated | 3.99 | 5 | 0.1390 | 0.3644 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||
| c.2252C>T | P751L 2D AIThe SynGAP1 missense variant P751L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this trend: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.667683 | Binding | 0.386 | 0.866 | 0.625 | -3.558 | Likely Benign | 0.143 | Likely Benign | Likely Benign | 0.207 | Likely Benign | -1.62 | Neutral | 0.316 | Benign | 0.062 | Benign | 2.94 | Benign | 0.24 | Tolerated | 0.2318 | 0.6451 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.313T>A | S105T 2D AIThe SynGAP1 missense variant S105T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a benign effect. AlphaMissense‑Optimized independently scores the variant as benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.669201 | Binding | 0.364 | 0.870 | 0.625 | -4.166 | Likely Benign | 0.132 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.54 | Neutral | 0.012 | Benign | 0.007 | Benign | 4.06 | Benign | 0.00 | Affected | 0.1583 | 0.5212 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.313T>C | S105P 2D AIThe SynGAP1 missense variant S105P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only two tools—polyPhen‑2 HumDiv and SIFT—predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates likely benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.669201 | Binding | 0.364 | 0.870 | 0.625 | Uncertain | 1 | -3.631 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.204 | Likely Benign | 0.03 | Neutral | 0.808 | Possibly Damaging | 0.212 | Benign | 4.00 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2236 | 0.4584 | -1 | 1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.313T>G | S105A 2D AIThe SynGAP1 missense variant S105A is not reported in ClinVar (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 predictions do not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.669201 | Binding | 0.364 | 0.870 | 0.625 | -3.779 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.046 | Likely Benign | -0.67 | Neutral | 0.012 | Benign | 0.002 | Benign | 4.11 | Benign | 0.00 | Affected | 0.5299 | 0.4214 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.314C>G | S105W 2D AIThe SynGAP1 missense variant S105W is catalogued in gnomAD (ID 6‑33432179‑C‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” status, reflecting the majority of benign calls. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also leans benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.669201 | Binding | 0.364 | 0.870 | 0.625 | 6-33432179-C-G | 2 | 1.24e-6 | -5.600 | Likely Benign | 0.606 | Likely Pathogenic | Likely Benign | 0.177 | Likely Benign | -2.28 | Neutral | 0.998 | Probably Damaging | 0.844 | Possibly Damaging | 3.97 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0705 | 0.4984 | -3 | -2 | -0.1 | 99.14 | ||||||||||||||||||||||||||||||||||
| c.314C>T | S105L 2D AIThe SynGAP1 missense variant S105L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33432179‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy methods both support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.669201 | Binding | 0.364 | 0.870 | 0.625 | Uncertain | 2 | 6-33432179-C-T | 4 | 2.48e-6 | -3.710 | Likely Benign | 0.233 | Likely Benign | Likely Benign | 0.095 | Likely Benign | -1.52 | Neutral | 0.828 | Possibly Damaging | 0.048 | Benign | 4.06 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1161 | 0.5023 | -3 | -2 | 4.6 | 26.08 | ||||||||||||||||||||||||||||||||
| c.325A>C | S109R 2D AIThe SynGAP1 missense variant S109R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM, whereas pathogenic calls come from SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments highlight that AlphaMissense‑Optimized predicts pathogenicity, whereas the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts benign impact; Foldetta data are unavailable. Overall, the balance of evidence leans toward a benign effect for S109R, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.669335 | Binding | 0.328 | 0.864 | 0.750 | -4.830 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.225 | Likely Benign | -1.80 | Neutral | 0.002 | Benign | 0.001 | Benign | 3.48 | Benign | 0.00 | Affected | 0.0884 | 0.2700 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.325A>G | S109G 2D AIThe SynGAP1 missense variant S109G is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority of the four high‑accuracy tools) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.669335 | Binding | 0.328 | 0.864 | 0.750 | -3.918 | Likely Benign | 0.549 | Ambiguous | Likely Benign | 0.132 | Likely Benign | -1.95 | Neutral | 0.378 | Benign | 0.067 | Benign | 3.51 | Benign | 0.00 | Affected | 0.2686 | 0.3779 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.325A>T | S109C 2D AIThe SynGAP1 missense variant S109C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus (majority vote) also as 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 | 0.622677 | Disordered | 0.669335 | Binding | 0.328 | 0.864 | 0.750 | -6.268 | Likely Benign | 0.761 | Likely Pathogenic | Likely Benign | 0.217 | Likely Benign | -2.19 | Neutral | 0.983 | Probably Damaging | 0.431 | Benign | 3.46 | Benign | 0.00 | Affected | 0.1084 | 0.5354 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.326G>A | S109N 2D AIThe SynGAP1 missense variant S109N is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM, while pathogenic calls come from polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to a likely benign verdict. High‑accuracy assessments further support this: AlphaMissense‑Optimized is uncertain, and Foldetta data are unavailable. Overall, 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 | 0.622677 | Disordered | 0.669335 | Binding | 0.328 | 0.864 | 0.750 | -5.509 | Likely Benign | 0.863 | Likely Pathogenic | Ambiguous | 0.116 | Likely Benign | -1.45 | Neutral | 0.596 | Possibly Damaging | 0.074 | Benign | 3.49 | Benign | 0.00 | Affected | 0.1350 | 0.3717 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| c.326G>C | S109T 2D AIThe SynGAP1 missense variant S109T is catalogued in gnomAD (6‑33432191‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all report benign or likely benign. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments confirm the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus, derived from the majority of the high‑accuracy predictors, is benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that S109T is most likely benign, and this assessment does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.669335 | Binding | 0.328 | 0.864 | 0.750 | 6-33432191-G-C | 2 | 1.24e-6 | -4.065 | Likely Benign | 0.449 | Ambiguous | Likely Benign | 0.090 | Likely Benign | -1.19 | Neutral | 0.231 | Benign | 0.050 | Benign | 3.59 | Benign | 0.00 | Affected | 3.61 | 5 | 0.1519 | 0.5212 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.326G>T | S109I 2D AIThe SynGAP1 missense variant S109I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie, and Foldetta data are unavailable. Overall, the majority of evidence (five benign vs. three pathogenic predictions) points toward a benign impact. This conclusion does not contradict ClinVar, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.622677 | Disordered | 0.669335 | Binding | 0.328 | 0.864 | 0.750 | -5.195 | Likely Benign | 0.927 | Likely Pathogenic | Ambiguous | 0.200 | Likely Benign | -2.56 | Deleterious | 0.267 | Benign | 0.039 | Benign | 3.47 | Benign | 0.00 | Affected | 0.0910 | 0.4930 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.327T>A | S109R 2D AIThe SynGAP1 missense variant S109R has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) remains benign; Foldetta stability analysis is unavailable. Overall, the majority of predictions lean toward a benign impact, and this is not contradicted by any ClinVar status. Thus, the variant is most likely benign based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.669335 | Binding | 0.328 | 0.864 | 0.750 | -4.830 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.198 | Likely Benign | -1.80 | Neutral | 0.002 | Benign | 0.001 | Benign | 3.48 | Benign | 0.00 | Affected | 0.0884 | 0.2700 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.327T>G | S109R 2D AIThe SynGAP1 missense variant S109R has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict pathogenicity are SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give mixed results: AlphaMissense‑Optimized reports a pathogenic effect, whereas the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome; Foldetta stability analysis is unavailable. Overall, the majority of predictions lean toward a benign impact, with one high‑accuracy tool suggesting pathogenicity, and there is no ClinVar status to contradict these findings. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.669335 | Binding | 0.328 | 0.864 | 0.750 | -4.830 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.198 | Likely Benign | -1.80 | Neutral | 0.002 | Benign | 0.001 | Benign | 3.48 | Benign | 0.00 | Affected | 0.0884 | 0.2700 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.346T>A | Y116N 2D  AIThe SynGAP1 missense variant Y116N is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.670235 | Binding | 0.381 | 0.878 | 0.625 | -1.706 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.108 | Likely Benign | 0.21 | Neutral | 0.137 | Benign | 0.021 | Benign | 4.27 | Benign | 1.00 | Tolerated | 0.2592 | 0.0545 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||||||||||||
| c.346T>C | Y116H 2D  AIThe SynGAP1 missense variant Y116H is listed in gnomAD (ID 6‑33432211‑T‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑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 outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments confirm the benign trend: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus also reports it as likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.670235 | Binding | 0.381 | 0.878 | 0.625 | 6-33432211-T-C | 7 | 4.34e-6 | -1.512 | Likely Benign | 0.378 | Ambiguous | Likely Benign | 0.080 | Likely Benign | 0.11 | Neutral | 0.539 | Possibly Damaging | 0.085 | Benign | 4.21 | Benign | 0.40 | Tolerated | 3.61 | 5 | 0.2691 | 0.0485 | 2 | 0 | -1.9 | -26.03 | ||||||||||||||||||||||||||||||||||
| c.346T>G | Y116D 2D  AIThe SynGAP1 missense variant Y116D is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The 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, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions strongly suggests that Y116D is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.670235 | Binding | 0.381 | 0.878 | 0.625 | 0.542 | Likely Benign | 0.524 | Ambiguous | Likely Benign | 0.302 | Likely Benign | -0.14 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.24 | Benign | 0.83 | Tolerated | 0.4603 | 0.0545 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||||||||||||
| c.347A>C | Y116S 2D  AIThe SynGAP1 missense variant Y116S is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population evidence. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions strongly suggests that Y116S is most likely benign, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.670235 | Binding | 0.381 | 0.878 | 0.625 | -0.249 | Likely Benign | 0.269 | Likely Benign | Likely Benign | 0.178 | Likely Benign | -0.05 | Neutral | 0.033 | Benign | 0.013 | Benign | 4.31 | Benign | 0.58 | Tolerated | 0.5111 | 0.1694 | Weaken | -3 | -2 | 0.5 | -76.10 | ||||||||||||||||||||||||||||||||||||||
| c.347A>G | Y116C 2D  AIThe SynGAP1 missense variant Y116C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.670235 | Binding | 0.381 | 0.878 | 0.625 | -2.822 | Likely Benign | 0.197 | Likely Benign | Likely Benign | 0.160 | Likely Benign | -0.90 | Neutral | 0.804 | Possibly Damaging | 0.187 | Benign | 4.19 | Benign | 0.11 | Tolerated | 0.3208 | 0.2105 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||||||||||||
| c.347A>T | Y116F 2D  AIThe SynGAP1 missense variant Y116F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign likelihood. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign 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 | 0.661982 | Disordered | 0.670235 | Binding | 0.381 | 0.878 | 0.625 | -2.911 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -0.71 | Neutral | 0.539 | Possibly Damaging | 0.042 | Benign | 4.21 | Benign | 0.33 | Tolerated | 0.2632 | 0.3069 | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3781A>C | S1261R 2D AIThe SynGAP1 missense variant S1261R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is likely pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect for S1261R, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.501700 | Disordered | 0.671500 | Binding | 0.889 | 0.574 | 0.250 | -4.363 | Likely Benign | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.152 | Likely Benign | -2.97 | Deleterious | 0.996 | Probably Damaging | 0.898 | Possibly Damaging | 2.21 | Pathogenic | 0.04 | Affected | 0.0661 | 0.2642 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3781A>G | S1261G 2D AIThe SynGAP1 missense variant S1261G is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates benign; Foldetta results are not available. Overall, the majority of evidence supports a benign impact for S1261G, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.501700 | Disordered | 0.671500 | Binding | 0.889 | 0.574 | 0.250 | -5.042 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -0.46 | Neutral | 0.005 | Benign | 0.013 | Benign | 2.32 | Pathogenic | 0.65 | Tolerated | 0.2063 | 0.3477 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||||||
| c.3781A>T | S1261C 2D AIThe SynGAP1 missense variant S1261C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all classify the variant as damaging. The SGM‑Consensus, which aggregates these predictions, reports the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized remains benign, but the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is 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 prediction algorithms indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.501700 | Disordered | 0.671500 | Binding | 0.889 | 0.574 | 0.250 | -8.275 | Likely Pathogenic | 0.322 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -3.51 | Deleterious | 0.999 | Probably Damaging | 0.947 | Probably Damaging | 2.20 | Pathogenic | 0.04 | Affected | 0.0760 | 0.4580 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||
| c.3782G>A | S1261N 2D AIThe SynGAP1 missense variant S1261N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate a benign or likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports likely benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for S1261N, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.501700 | Disordered | 0.671500 | Binding | 0.889 | 0.574 | 0.250 | -4.850 | Likely Benign | 0.294 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -0.92 | Neutral | 0.959 | Probably Damaging | 0.551 | Possibly Damaging | 2.23 | Pathogenic | 0.12 | Tolerated | 0.0917 | 0.2820 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||||
| c.3782G>C | S1261T 2D AIThe SynGAP1 missense variant S1261T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate a benign or likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports likely benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for S1261T, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.501700 | Disordered | 0.671500 | Binding | 0.889 | 0.574 | 0.250 | -4.800 | Likely Benign | 0.203 | Likely Benign | Likely Benign | 0.109 | Likely Benign | -2.01 | Neutral | 0.906 | Possibly Damaging | 0.629 | Possibly Damaging | 2.27 | Pathogenic | 0.11 | Tolerated | 0.1007 | 0.4249 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3782G>T | S1261I 2D AIThe SynGAP1 missense variant S1261I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and AlphaMissense‑Optimized, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score indicates a benign effect, whereas the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely pathogenic. No Foldetta stability assessment is available for this residue. Overall, the preponderance of evidence from standard and high‑accuracy predictors points to a pathogenic impact for S1261I. This conclusion is not contradicted by ClinVar status, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.501700 | Disordered | 0.671500 | Binding | 0.889 | 0.574 | 0.250 | -8.835 | Likely Pathogenic | 0.761 | Likely Pathogenic | Likely Benign | 0.244 | Likely Benign | -4.20 | Deleterious | 0.996 | Probably Damaging | 0.898 | Possibly Damaging | 2.21 | Pathogenic | 0.02 | Affected | 0.0631 | 0.4410 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||
| c.3783C>A | S1261R 2D AIThe SynGAP1 missense variant S1261R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence from multiple in silico tools points to a pathogenic classification, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.501700 | Disordered | 0.671500 | Binding | 0.889 | 0.574 | 0.250 | -4.363 | Likely Benign | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.190 | Likely Benign | -2.97 | Deleterious | 0.996 | Probably Damaging | 0.898 | Possibly Damaging | 2.21 | Pathogenic | 0.04 | Affected | 0.0661 | 0.2642 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3783C>G | S1261R 2D AIThe SynGAP1 missense variant S1261R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence indicates that S1261R is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.501700 | Disordered | 0.671500 | Binding | 0.889 | 0.574 | 0.250 | -4.363 | Likely Benign | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.190 | Likely Benign | -2.97 | Deleterious | 0.996 | Probably Damaging | 0.898 | Possibly Damaging | 2.21 | Pathogenic | 0.04 | Affected | 0.0661 | 0.2642 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.364C>A | P122T 2D AIThe SynGAP1 missense variant P122T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods indicates that P122T 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 | 0.618285 | Disordered | 0.672358 | Binding | 0.400 | 0.887 | 0.750 | -3.954 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.186 | Likely Benign | -1.43 | Neutral | 0.580 | Possibly Damaging | 0.185 | Benign | 4.19 | Benign | 0.13 | Tolerated | 0.2068 | 0.5270 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.364C>G | P122A 2D AIThe SynGAP1 missense variant P122A is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the substitution as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.672358 | Binding | 0.400 | 0.887 | 0.750 | -3.105 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.086 | Likely Benign | -1.66 | Neutral | 0.363 | Benign | 0.096 | Benign | 4.27 | Benign | 1.00 | Tolerated | 0.3991 | 0.4286 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.364C>T | P122S 2D AIThe SynGAP1 missense variant P122S is catalogued in gnomAD (ID 6‑33432229‑C‑T) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized returns a benign prediction, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status remains unavailable. Overall, the computational evidence overwhelmingly supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.672358 | Binding | 0.400 | 0.887 | 0.750 | 6-33432229-C-T | 1 | 6.20e-7 | -3.389 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -1.13 | Neutral | 0.036 | Benign | 0.025 | Benign | 4.22 | Benign | 0.31 | Tolerated | 3.61 | 5 | 0.4009 | 0.4759 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.365C>A | P122H 2D AIThe SynGAP1 missense variant P122H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence, including the high‑accuracy tools, points to a benign effect for P122H. 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 | 0.618285 | Disordered | 0.672358 | Binding | 0.400 | 0.887 | 0.750 | -4.993 | Likely Benign | 0.321 | Likely Benign | Likely Benign | 0.096 | Likely Benign | -1.82 | Neutral | 0.996 | Probably Damaging | 0.750 | Possibly Damaging | 4.14 | Benign | 0.03 | Affected | 0.2306 | 0.4213 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.365C>G | P122R 2D AIThe SynGAP1 missense variant P122R has no ClinVar record and is not listed in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) which reports “Likely Benign.” Pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the balance of evidence favors a benign effect for P122R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.672358 | Binding | 0.400 | 0.887 | 0.750 | -4.981 | Likely Benign | 0.572 | Likely Pathogenic | Likely Benign | 0.132 | Likely Benign | -1.74 | Neutral | 0.952 | Possibly Damaging | 0.521 | Possibly Damaging | 4.18 | Benign | 0.05 | Affected | 0.1796 | 0.2804 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.365C>T | P122L 2D AIThe SynGAP1 missense variant P122L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, while pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.672358 | Binding | 0.400 | 0.887 | 0.750 | -3.810 | Likely Benign | 0.181 | Likely Benign | Likely Benign | 0.167 | Likely Benign | -2.92 | Deleterious | 0.906 | Possibly Damaging | 0.420 | Benign | 4.16 | Benign | 0.05 | Affected | 0.2657 | 0.6362 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.349A>C | S117R 2D AIThe SynGAP1 missense variant S117R has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, whereas the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the majority of predictions lean toward a benign impact, and this does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.672422 | Binding | 0.357 | 0.877 | 0.625 | -4.187 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.276 | Likely Benign | -1.81 | Neutral | 0.845 | Possibly Damaging | 0.326 | Benign | 3.70 | Benign | 0.01 | Affected | 3.61 | 5 | 0.1040 | 0.3770 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.349A>G | S117G 2D AIThe SynGAP1 missense variant S117G is not reported in ClinVar (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 | 0.661982 | Disordered | 0.672422 | Binding | 0.357 | 0.877 | 0.625 | -3.280 | Likely Benign | 0.174 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -1.59 | Neutral | 0.390 | Benign | 0.066 | Benign | 3.73 | Benign | 0.01 | Affected | 0.2113 | 0.4627 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.349A>T | S117C 2D AIThe SynGAP1 missense variant S117C is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, 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 show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.672422 | Binding | 0.357 | 0.877 | 0.625 | -5.980 | Likely Benign | 0.201 | Likely Benign | Likely Benign | 0.246 | Likely Benign | -1.81 | Neutral | 0.992 | Probably Damaging | 0.667 | Possibly Damaging | 3.68 | Benign | 0.00 | Affected | 0.1222 | 0.5057 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.350G>A | S117N 2D AIThe SynGAP1 missense variant S117N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and consensus analyses indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.672422 | Binding | 0.357 | 0.877 | 0.625 | -5.704 | Likely Benign | 0.489 | Ambiguous | Likely Benign | 0.067 | Likely Benign | -1.06 | Neutral | 0.005 | Benign | 0.003 | Benign | 3.71 | Benign | 0.01 | Affected | 0.1491 | 0.4530 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| c.350G>C | S117T 2D AIThe SynGAP1 missense variant S117T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.672422 | Binding | 0.357 | 0.877 | 0.625 | -4.602 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -0.98 | Neutral | 0.608 | Possibly Damaging | 0.092 | Benign | 3.79 | Benign | 0.02 | Affected | 0.1527 | 0.5505 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.350G>T | S117I 2D AIThe SynGAP1 missense variant S117I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method, 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 | 0.661982 | Disordered | 0.672422 | Binding | 0.357 | 0.877 | 0.625 | -5.483 | Likely Benign | 0.559 | Ambiguous | Likely Benign | 0.137 | Likely Benign | -2.33 | Neutral | 0.971 | Probably Damaging | 0.598 | Possibly Damaging | 3.70 | Benign | 0.00 | Affected | 0.1060 | 0.5048 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.351C>A | S117R 2D AIThe SynGAP1 missense variant S117R has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification (3 benign vs. 1 pathogenic votes). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, whereas the SGM‑Consensus (majority vote) remains benign; Foldetta results are unavailable. Overall, the majority of tools (six benign vs. four pathogenic) and the consensus evidence lean toward a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.672422 | Binding | 0.357 | 0.877 | 0.625 | -4.187 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.144 | Likely Benign | -1.81 | Neutral | 0.845 | Possibly Damaging | 0.326 | Benign | 3.70 | Benign | 0.01 | Affected | 3.61 | 5 | 0.1040 | 0.3770 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.351C>G | S117R 2D AIThe SynGAP1 missense variant S117R is listed in ClinVar with no submitted interpretation and is present in gnomAD (ID 6‑33432216‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this is consistent with the absence of a pathogenic ClinVar annotation. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.672422 | Binding | 0.357 | 0.877 | 0.625 | 6-33432216-C-G | 1 | 6.20e-7 | -4.187 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.144 | Likely Benign | -1.81 | Neutral | 0.845 | Possibly Damaging | 0.326 | Benign | 3.70 | Benign | 0.01 | Affected | 3.61 | 5 | 0.1040 | 0.3770 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||
| c.2461T>A | C821S 2D  AIThe SynGAP1 missense variant C821S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, whereas the SGM‑Consensus (majority vote) supports a benign outcome. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for C821S, 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 | 0.745909 | Disordered | 0.672821 | Binding | 0.351 | 0.883 | 0.750 | -0.425 | Likely Benign | 0.898 | Likely Pathogenic | Ambiguous | 0.190 | Likely Benign | -0.47 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.91 | Benign | 1.00 | Tolerated | 0.5284 | 0.2012 | Weaken | 0 | -1 | -3.3 | -16.06 | ||||||||||||||||||||||||||||||||||||||
| c.2461T>C | C821R 2D  AIThe SynGAP1 missense variant C821R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, 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‑accuracy predictors (six out of nine) indicate a pathogenic impact, while three suggest 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. | 0.745909 | Disordered | 0.672821 | Binding | 0.351 | 0.883 | 0.750 | -3.997 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.183 | Likely Benign | -2.93 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.69 | Benign | 0.03 | Affected | 0.1944 | 0.1746 | -4 | -3 | -7.0 | 53.05 | ||||||||||||||||||||||||||||||||||||||||
| c.2461T>G | C821G 2D  AIThe SynGAP1 missense variant C821G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of available predictions (five pathogenic vs. three benign) lean toward pathogenicity. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar status because the variant has not yet been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.745909 | Disordered | 0.672821 | Binding | 0.351 | 0.883 | 0.750 | -4.613 | Likely Benign | 0.910 | Likely Pathogenic | Ambiguous | 0.187 | Likely Benign | -2.94 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.68 | Benign | 0.05 | Affected | 0.3287 | 0.2747 | -3 | -3 | -2.9 | -46.09 | ||||||||||||||||||||||||||||||||||||||||
| c.2462G>A | C821Y 2D  AIThe SynGAP1 missense variant C821Y is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, seven tools support pathogenicity while three support benignity, and no high‑accuracy consensus contradicts this trend. Therefore, the variant is most likely pathogenic based on the available predictions, and this assessment does not conflict with the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.745909 | Disordered | 0.672821 | Binding | 0.351 | 0.883 | 0.750 | -1.007 | Likely Benign | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.342 | Likely Benign | -3.11 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.66 | Benign | 0.01 | Affected | 0.1288 | 0.3187 | 0 | -2 | -3.8 | 60.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2462G>C | C821S 2D AIThe SynGAP1 missense variant C821S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, whereas the SGM‑Consensus (majority vote) supports a benign outcome. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for C821S, 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 | 0.745909 | Disordered | 0.672821 | Binding | 0.351 | 0.883 | 0.750 | -0.425 | Likely Benign | 0.898 | Likely Pathogenic | Ambiguous | 0.314 | Likely Benign | -0.47 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.91 | Benign | 1.00 | Tolerated | 0.5284 | 0.2012 | Weaken | 0 | -1 | -3.3 | -16.06 | ||||||||||||||||||||||||||||||||||||||
| c.2462G>T | C821F 2D  AIThe SynGAP1 missense variant C821F is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict any existing ClinVar status because the variant has not yet been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.745909 | Disordered | 0.672821 | Binding | 0.351 | 0.883 | 0.750 | 0.971 | Likely Benign | 0.924 | Likely Pathogenic | Ambiguous | 0.338 | Likely Benign | -3.33 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.66 | Benign | 0.01 | Affected | 0.1504 | 0.3505 | -4 | -2 | 0.3 | 44.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2463C>G | C821W 2D  AIThe SynGAP1 missense variant C821W is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs two benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evaluated predictors (six pathogenic vs three benign) indicate a pathogenic impact. This prediction is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.745909 | Disordered | 0.672821 | Binding | 0.351 | 0.883 | 0.750 | -4.843 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.201 | Likely Benign | -3.30 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.64 | Benign | 0.01 | Affected | 0.1742 | 0.3268 | -8 | -2 | -3.4 | 83.07 | ||||||||||||||||||||||||||||||||||||||||
| c.322A>C | K108Q 2D AIThe SynGAP1 missense variant K108Q is 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 from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.626927 | Disordered | 0.673331 | Binding | 0.338 | 0.858 | 0.875 | -3.676 | Likely Benign | 0.639 | Likely Pathogenic | Likely Benign | 0.168 | Likely Benign | -0.73 | Neutral | 0.998 | Probably Damaging | 0.981 | Probably Damaging | 4.09 | Benign | 0.06 | Tolerated | 0.4843 | 0.1322 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.322A>G | K108E 2D AIThe SynGAP1 K108E missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus indicates a likely benign outcome; Foldetta results are unavailable. Overall, the predictions are split evenly between benign and pathogenic, with no clear majority. Consequently, the variant’s impact remains uncertain, and there is no contradiction with ClinVar status, which currently lists no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.626927 | Disordered | 0.673331 | Binding | 0.338 | 0.858 | 0.875 | -3.679 | Likely Benign | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.166 | Likely Benign | -1.24 | Neutral | 0.993 | Probably Damaging | 0.956 | Probably Damaging | 4.12 | Benign | 0.04 | Affected | 0.4145 | 0.1166 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.323A>C | K108T 2D AIThe SynGAP1 missense variant K108T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is not available for this variant. Overall, the majority of evidence points toward a benign impact, and there is no ClinVar entry to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.626927 | Disordered | 0.673331 | Binding | 0.338 | 0.858 | 0.875 | -2.941 | Likely Benign | 0.855 | Likely Pathogenic | Ambiguous | 0.156 | Likely Benign | -1.48 | Neutral | 0.998 | Probably Damaging | 0.981 | Probably Damaging | 4.08 | Benign | 0.03 | Affected | 0.2179 | 0.3538 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||||||
| c.323A>G | K108R 2D AIThe SynGAP1 missense variant K108R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33432188‑A‑G). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized is benign, and the SGM‑Consensus itself is benign; Foldetta results are unavailable. 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 | 0.626927 | Disordered | 0.673331 | Binding | 0.338 | 0.858 | 0.875 | Uncertain | 1 | 6-33432188-A-G | 6 | 3.72e-6 | -2.892 | Likely Benign | 0.148 | Likely Benign | Likely Benign | 0.184 | Likely Benign | 0.37 | Neutral | 0.993 | Probably Damaging | 0.956 | Probably Damaging | 4.22 | Benign | 1.00 | Tolerated | 3.61 | 5 | 0.5286 | 0.1229 | Weaken | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||||
| c.323A>T | K108M 2D AIThe SynGAP1 K108M missense variant has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which collectively suggest a likely benign outcome. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and Foldetta stability analysis is unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.626927 | Disordered | 0.673331 | Binding | 0.338 | 0.858 | 0.875 | -3.863 | Likely Benign | 0.909 | Likely Pathogenic | Ambiguous | 0.216 | Likely Benign | -1.64 | Neutral | 0.999 | Probably Damaging | 0.990 | Probably Damaging | 4.03 | Benign | 0.01 | Affected | 0.1271 | 0.4144 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.324G>C | K108N 2D AISynGAP1 missense variant K108N is reported in gnomAD (6‑33432189‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign calls from REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign); pathogenic calls from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicting pathogenic, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign; Foldetta results are unavailable. Consequently, the evidence is evenly split, with no single prediction dominating. The variant is therefore not clearly benign or pathogenic based on current computational data, and this lack of consensus does not contradict any ClinVar classification, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.626927 | Disordered | 0.673331 | Binding | 0.338 | 0.858 | 0.875 | 6-33432189-G-C | 1 | 6.20e-7 | -3.015 | Likely Benign | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.068 | Likely Benign | -1.35 | Neutral | 0.998 | Probably Damaging | 0.981 | Probably Damaging | 4.07 | Benign | 0.03 | Affected | 3.61 | 5 | 0.3904 | 0.1820 | 0 | 1 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||
| c.324G>T | K108N 2D AIThe SynGAP1 missense variant K108N is not reported in ClinVar and has no gnomAD entry. Consensus predictions from multiple in‑silico tools are split: benign calls come from REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) which labels the variant as Likely Benign. Pathogenic calls arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized, the latter two high‑accuracy predictors both flagging the variant as Pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not return a result for this variant, so its stability impact is unavailable. Overall, the majority of high‑confidence tools (AlphaMissense‑Optimized and the SGM‑Consensus) disagree, with AlphaMissense‑Optimized indicating pathogenicity while the consensus suggests benign. Because ClinVar contains no classification, there is no contradiction; the variant is most likely pathogenic based on the most reliable predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.626927 | Disordered | 0.673331 | Binding | 0.338 | 0.858 | 0.875 | -3.015 | Likely Benign | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.068 | Likely Benign | -1.35 | Neutral | 0.998 | Probably Damaging | 0.981 | Probably Damaging | 4.07 | Benign | 0.03 | Affected | 3.61 | 5 | 0.3904 | 0.1820 | 0 | 1 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||
| c.3514C>A | H1172N 2D AIThe SynGAP1 missense variant H1172N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as tolerated or benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the available predictions points to a benign effect, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.626927 | Disordered | 0.673805 | Binding | 0.465 | 0.758 | 0.625 | -2.770 | Likely Benign | 0.282 | Likely Benign | Likely Benign | 0.255 | Likely Benign | -1.14 | Neutral | 0.625 | Possibly Damaging | 0.265 | Benign | 5.59 | Benign | 0.04 | Affected | 0.1512 | 0.2158 | 2 | 1 | -0.3 | -23.04 | ||||||||||||||||||||||||||||||||||||||
| c.3514C>G | H1172D 2D AIThe SynGAP1 missense variant H1172D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, 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; the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.626927 | Disordered | 0.673805 | Binding | 0.465 | 0.758 | 0.625 | -2.073 | Likely Benign | 0.710 | Likely Pathogenic | Likely Benign | 0.378 | Likely Benign | -1.29 | Neutral | 0.625 | Possibly Damaging | 0.333 | Benign | 5.46 | Benign | 0.04 | Affected | 0.2296 | 0.1417 | 1 | -1 | -0.3 | -22.05 | ||||||||||||||||||||||||||||||||||||||
| c.3514C>T | H1172Y 2D AIThe SynGAP1 H1172Y missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports the variant as Likely Benign, while AlphaMissense‑Default remains Uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and the Foldetta stability analysis is unavailable. Based on the preponderance of benign predictions and the lack of pathogenic evidence, the variant is most likely benign. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.626927 | Disordered | 0.673805 | Binding | 0.465 | 0.758 | 0.625 | -2.820 | Likely Benign | 0.373 | Ambiguous | Likely Benign | 0.356 | Likely Benign | -1.01 | Neutral | 0.925 | Possibly Damaging | 0.529 | Possibly Damaging | 5.42 | Benign | 0.01 | Affected | 0.0693 | 0.4335 | 0 | 2 | 1.9 | 26.03 | ||||||||||||||||||||||||||||||||||||||
| c.3515A>C | H1172P 2D AIThe SynGAP1 missense variant H1172P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, 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 | Coiled-coil | 0.626927 | Disordered | 0.673805 | Binding | 0.465 | 0.758 | 0.625 | -2.871 | Likely Benign | 0.653 | Likely Pathogenic | Likely Benign | 0.403 | Likely Benign | -2.09 | Neutral | 0.925 | Possibly Damaging | 0.529 | Possibly Damaging | 5.42 | Benign | 0.02 | Affected | 0.2033 | 0.4128 | 0 | -2 | 1.6 | -40.02 | ||||||||||||||||||||||||||||||||||||||
| c.3515A>G | H1172R 2D AIThe SynGAP1 missense variant H1172R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that H1172R is most likely benign, and this conclusion does not contradict any ClinVar status, as none is assigned to the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.626927 | Disordered | 0.673805 | Binding | 0.465 | 0.758 | 0.625 | -0.848 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -1.08 | Neutral | 0.001 | Benign | 0.004 | Benign | 5.46 | Benign | 0.05 | Affected | 0.1547 | 0.2219 | 2 | 0 | -1.3 | 19.05 | ||||||||||||||||||||||||||||||||||||||
| c.3515A>T | H1172L 2D AIThe SynGAP1 missense variant H1172L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for H1172L, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.626927 | Disordered | 0.673805 | Binding | 0.465 | 0.758 | 0.625 | -0.545 | Likely Benign | 0.446 | Ambiguous | Likely Benign | 0.426 | Likely Benign | -2.30 | Neutral | 0.451 | Benign | 0.265 | Benign | 5.47 | Benign | 0.01 | Affected | 0.0815 | 0.5285 | -2 | -3 | 7.0 | -23.98 | ||||||||||||||||||||||||||||||||||||||
| c.3516C>A | H1172Q 2D AIThe SynGAP1 missense variant H1172Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, 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 annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.626927 | Disordered | 0.673805 | Binding | 0.465 | 0.758 | 0.625 | -2.169 | Likely Benign | 0.414 | Ambiguous | Likely Benign | 0.227 | Likely Benign | -0.51 | Neutral | 0.451 | Benign | 0.265 | Benign | 5.47 | Benign | 0.39 | Tolerated | 0.1249 | 0.3557 | 3 | 0 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3516C>G | H1172Q 2D AIThe SynGAP1 missense variant H1172Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus confirms Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta) has no available result for this variant. Based on the collective predictions, H1172Q is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.626927 | Disordered | 0.673805 | Binding | 0.465 | 0.758 | 0.625 | -2.169 | Likely Benign | 0.414 | Ambiguous | Likely Benign | 0.227 | Likely Benign | -0.51 | Neutral | 0.451 | Benign | 0.265 | Benign | 5.47 | Benign | 0.39 | Tolerated | 0.1249 | 0.3557 | 3 | 0 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||||||
| c.298T>A | Y100N 2D AIThe SynGAP1 missense variant Y100N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. 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 | 0.699094 | Disordered | 0.675421 | Binding | 0.341 | 0.880 | 0.625 | -2.579 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.183 | Likely Benign | -0.66 | Neutral | 0.675 | Possibly Damaging | 0.099 | Benign | 4.23 | Benign | 0.00 | Affected | 0.2487 | 0.0373 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||||||||||||
| c.298T>C | Y100H 2D AIThe SynGAP1 missense variant Y100H is reported in gnomAD (variant ID 6-33432163‑T‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: the benign‑predicted set includes REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the pathogenic‑predicted set contains polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments reinforce the benign classification: 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 combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the consensus of available predictions indicates that Y100H is most likely benign, and this conclusion is not contradicted by any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.675421 | Binding | 0.341 | 0.880 | 0.625 | 6-33432163-T-C | 1 | 6.20e-7 | -2.094 | Likely Benign | 0.201 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -0.40 | Neutral | 0.978 | Probably Damaging | 0.500 | Possibly Damaging | 4.23 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2650 | 0.0313 | 2 | 0 | -1.9 | -26.03 | ||||||||||||||||||||||||||||||||||
| c.298T>G | Y100D 2D AIThe SynGAP1 missense variant Y100D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.675421 | Binding | 0.341 | 0.880 | 0.625 | -1.269 | Likely Benign | 0.215 | Likely Benign | Likely Benign | 0.233 | Likely Benign | -1.01 | Neutral | 0.003 | Benign | 0.003 | Benign | 4.22 | Benign | 0.00 | Affected | 0.4465 | 0.0373 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||||||||||||
| c.299A>C | Y100S 2D AIThe SynGAP1 missense variant Y100S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. 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 | 0.699094 | Disordered | 0.675421 | Binding | 0.341 | 0.880 | 0.625 | -1.217 | Likely Benign | 0.129 | Likely Benign | Likely Benign | 0.182 | Likely Benign | -0.14 | Neutral | 0.675 | Possibly Damaging | 0.175 | Benign | 4.31 | Benign | 0.00 | Affected | 0.5066 | 0.1600 | Weaken | -3 | -2 | 0.5 | -76.10 | ||||||||||||||||||||||||||||||||||||||
| c.299A>G | Y100C 2D AIThe SynGAP1 missense variant Y100C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.675421 | Binding | 0.341 | 0.880 | 0.625 | -3.789 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.172 | Likely Benign | -0.88 | Neutral | 0.994 | Probably Damaging | 0.816 | Possibly Damaging | 4.18 | Benign | 0.00 | Affected | 0.3073 | 0.2213 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||||||||||||
| c.299A>T | Y100F 2D AIThe SynGAP1 missense variant Y100F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.675421 | Binding | 0.341 | 0.880 | 0.625 | -3.056 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.139 | Likely Benign | -0.50 | Neutral | 0.928 | Possibly Damaging | 0.222 | Benign | 4.21 | Benign | 0.00 | Affected | 0.2784 | 0.3087 | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2602G>A | D868N 2D AIThe SynGAP1 D868N missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus likewise indicates Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.676362 | Binding | 0.262 | 0.815 | 0.250 | -3.052 | Likely Benign | 0.419 | Ambiguous | Likely Benign | 0.161 | Likely Benign | -2.01 | Neutral | 0.986 | Probably Damaging | 0.922 | Probably Damaging | 2.55 | Benign | 0.21 | Tolerated | 0.1977 | 0.7152 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2602G>C | D868H 2D AIThe SynGAP1 missense variant D868H is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (variant ID 6‑33443154‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs. 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of predictions lean toward a benign impact, and this is not contradicted by ClinVar status. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.525368 | Disordered | 0.676362 | Binding | 0.262 | 0.815 | 0.250 | 6-33443154-G-C | 1 | 6.20e-7 | -3.358 | Likely Benign | 0.763 | Likely Pathogenic | Likely Benign | 0.212 | Likely Benign | -2.34 | Neutral | 1.000 | Probably Damaging | 0.983 | Probably Damaging | 2.49 | Pathogenic | 0.08 | Tolerated | 3.82 | 4 | 0.2258 | 0.7837 | -1 | 1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||
| c.2602G>T | D868Y 2D AIThe SynGAP1 missense variant D868Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default all indicate deleteriousness. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Overall, the preponderance of evidence from multiple in silico predictors points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for D868Y. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.525368 | Disordered | 0.676362 | Binding | 0.262 | 0.815 | 0.250 | -6.031 | Likely Benign | 0.815 | Likely Pathogenic | Ambiguous | 0.256 | Likely Benign | -2.90 | Deleterious | 1.000 | Probably Damaging | 0.983 | Probably Damaging | 2.47 | Pathogenic | 0.05 | Affected | 0.1115 | 0.6847 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| c.2603A>C | D868A 2D AIThe SynGAP1 D868A 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, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta results are unavailable. Overall, the balance of evidence—including the benign prediction from the most accurate AlphaMissense‑Optimized model and the majority of benign calls—suggests that the variant is most likely benign. This conclusion does not contradict any ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.525368 | Disordered | 0.676362 | Binding | 0.262 | 0.815 | 0.250 | -2.764 | Likely Benign | 0.702 | Likely Pathogenic | Likely Benign | 0.139 | Likely Benign | -2.75 | Deleterious | 0.972 | Probably Damaging | 0.760 | Possibly Damaging | 2.54 | Benign | 0.21 | Tolerated | 0.4590 | 0.6990 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.2603A>G | D868G 2D AIThe SynGAP1 missense variant D868G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain. The high‑accuracy consensus (SGM Consensus) – derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN – is 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, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.525368 | Disordered | 0.676362 | Binding | 0.262 | 0.815 | 0.250 | -2.218 | Likely Benign | 0.552 | Ambiguous | Likely Benign | 0.113 | Likely Benign | -2.71 | Deleterious | 0.986 | Probably Damaging | 0.860 | Possibly Damaging | 2.51 | Benign | 0.21 | Tolerated | 0.4658 | 0.6414 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2603A>T | D868V 2D AIThe SynGAP1 missense variant D868V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, SIFT, and ESM1b, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.525368 | Disordered | 0.676362 | Binding | 0.262 | 0.815 | 0.250 | -5.200 | Likely Benign | 0.853 | Likely Pathogenic | Ambiguous | 0.182 | Likely Benign | -3.17 | Deleterious | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.49 | Pathogenic | 0.25 | Tolerated | 0.1485 | 0.6753 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.2604C>A | D868E 2D AIThe SynGAP1 missense variant D868E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic effect. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; no Foldetta stability data are available. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic claim. Thus, the variant is most likely benign, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.676362 | Binding | 0.262 | 0.815 | 0.250 | -3.792 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.064 | Likely Benign | -1.47 | Neutral | 0.966 | Probably Damaging | 0.848 | Possibly Damaging | 2.68 | Benign | 0.36 | Tolerated | 0.2092 | 0.6392 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2604C>G | D868E 2D AIThe SynGAP1 missense variant D868E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.676362 | Binding | 0.262 | 0.815 | 0.250 | -3.792 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -1.47 | Neutral | 0.966 | Probably Damaging | 0.848 | Possibly Damaging | 2.68 | Benign | 0.36 | Tolerated | 0.2092 | 0.6392 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.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 | -3.17 | Deleterious | 0.000 | Benign | 0.000 | Benign | 3.69 | Benign | 0.01 | Affected | 0.3559 | 0.3273 | -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 | -1.94 | Neutral | 0.327 | Benign | 0.100 | Benign | 3.76 | Benign | 0.02 | Affected | 3.61 | 5 | 0.3153 | 0.2741 | 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 | -3.19 | Deleterious | 0.609 | Possibly Damaging | 0.308 | Benign | 3.68 | Benign | 0.01 | Affected | 0.2052 | 0.4535 | 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 | -3.61 | Deleterious | 0.308 | Benign | 0.122 | Benign | 3.70 | Benign | 0.01 | Affected | 0.1962 | 0.4727 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.352A>C | M118L 2D AIThe SynGAP1 missense variant M118L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, 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, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) also benign; Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign effect for M118L, and this conclusion does not contradict any ClinVar status, as no ClinVar claim exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.694846 | Disordered | 0.676867 | Binding | 0.330 | 0.883 | 0.500 | -1.319 | Likely Benign | 0.206 | Likely Benign | Likely Benign | 0.218 | Likely Benign | -1.09 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.11 | Benign | 0.03 | Affected | 0.1835 | 0.4511 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.352A>G | M118V 2D AIThe SynGAP1 missense variant M118V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. The prediction is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.694846 | Disordered | 0.676867 | Binding | 0.330 | 0.883 | 0.500 | -2.322 | Likely Benign | 0.122 | Likely Benign | Likely Benign | 0.158 | Likely Benign | -1.23 | Neutral | 0.012 | Benign | 0.011 | Benign | 3.98 | Benign | 0.02 | Affected | 0.3326 | 0.3630 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||||||||||||
| c.352A>T | M118L 2D AIThe SynGAP1 missense variant M118L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only SIFT indicates a pathogenic effect, while the SGM‑Consensus (majority vote from 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 (derived from the four high‑accuracy tools) also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact for M118L, 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 | 0.694846 | Disordered | 0.676867 | Binding | 0.330 | 0.883 | 0.500 | -1.319 | Likely Benign | 0.206 | Likely Benign | Likely Benign | 0.218 | Likely Benign | -1.09 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.11 | Benign | 0.03 | Affected | 0.1835 | 0.4511 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.353T>A | M118K 2D AIThe SynGAP1 missense variant M118K is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (two pathogenic vs. two benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation, as none exists for M118K. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.694846 | Disordered | 0.676867 | Binding | 0.330 | 0.883 | 0.500 | -3.979 | Likely Benign | 0.767 | Likely Pathogenic | Likely Benign | 0.276 | Likely Benign | -2.98 | Deleterious | 0.396 | Benign | 0.099 | Benign | 3.84 | Benign | 0.01 | Affected | 0.2010 | 0.1131 | 0 | -1 | -5.8 | -3.02 | ||||||||||||||||||||||||||||||||||||||||
| c.353T>C | M118T 2D AIThe SynGAP1 missense variant M118T is not reported in ClinVar (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 evidence from multiple independent predictors and the high‑accuracy consensus strongly supports a benign impact. This conclusion is consistent with the lack of any ClinVar pathogenic 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 Benign | 0.694846 | Disordered | 0.676867 | Binding | 0.330 | 0.883 | 0.500 | -2.468 | Likely Benign | 0.454 | Ambiguous | Likely Benign | 0.217 | Likely Benign | -2.41 | Neutral | 0.396 | Benign | 0.067 | Benign | 3.86 | Benign | 0.08 | Tolerated | 0.2207 | 0.2237 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||||||||||||
| c.353T>G | M118R 2D AIThe SynGAP1 missense variant M118R is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign impact for M118R. This conclusion does not contradict any ClinVar annotation, as no ClinVar status is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.694846 | Disordered | 0.676867 | Binding | 0.330 | 0.883 | 0.500 | -3.318 | Likely Benign | 0.698 | Likely Pathogenic | Likely Benign | 0.286 | Likely Benign | -3.17 | Deleterious | 0.697 | Possibly Damaging | 0.202 | Benign | 3.83 | Benign | 0.00 | Affected | 0.2027 | 0.0913 | 0 | -1 | -6.4 | 24.99 | ||||||||||||||||||||||||||||||||||||||||
| c.354G>A | M118I 2D AIThe SynGAP1 missense variant M118I is not reported in ClinVar (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 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. 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 | 0.694846 | Disordered | 0.676867 | Binding | 0.330 | 0.883 | 0.500 | -3.396 | Likely Benign | 0.754 | Likely Pathogenic | Likely Benign | 0.139 | Likely Benign | -1.23 | Neutral | 0.005 | Benign | 0.004 | Benign | 3.99 | Benign | 0.02 | Affected | 0.1624 | 0.3570 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.354G>C | M118I 2D AIThe SynGAP1 missense variant M118I is not reported in ClinVar (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 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. 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 | 0.694846 | Disordered | 0.676867 | Binding | 0.330 | 0.883 | 0.500 | -3.396 | Likely Benign | 0.754 | Likely Pathogenic | Likely Benign | 0.140 | Likely Benign | -1.23 | Neutral | 0.005 | Benign | 0.004 | Benign | 3.99 | Benign | 0.02 | Affected | 0.1624 | 0.3570 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.354G>T | M118I 2D AIThe SynGAP1 missense variant M118I is not reported in ClinVar (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 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. 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 | 0.694846 | Disordered | 0.676867 | Binding | 0.330 | 0.883 | 0.500 | -3.396 | Likely Benign | 0.754 | Likely Pathogenic | Likely Benign | 0.139 | Likely Benign | -1.23 | Neutral | 0.005 | Benign | 0.004 | Benign | 3.99 | Benign | 0.02 | Affected | 0.1624 | 0.3570 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2722C>A | Q908K 2D AIThe SynGAP1 missense variant Q908K is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign interpretation: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign, while the majority of other predictors (polyPhen‑2 HumDiv and HumVar) indicate pathogenic. When predictions are grouped by agreement, the benign‑predicating tools outnumber the pathogenic ones, and the single uncertain call from AlphaMissense‑Default does not alter the overall trend. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Benign. No Foldetta stability analysis is available. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.678728 | Binding | 0.275 | 0.917 | 0.250 | -5.641 | Likely Benign | 0.549 | Ambiguous | Likely Benign | 0.139 | Likely Benign | -1.15 | Neutral | 0.963 | Probably Damaging | 0.973 | Probably Damaging | 2.67 | Benign | 0.22 | Tolerated | 0.1738 | 0.3711 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2722C>G | Q908E 2D AIThe SynGAP1 missense variant Q908E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign status: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for Q908E, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.678728 | Binding | 0.275 | 0.917 | 0.250 | -4.178 | Likely Benign | 0.271 | Likely Benign | Likely Benign | 0.139 | Likely Benign | -1.14 | Neutral | 0.963 | Probably Damaging | 0.973 | Probably Damaging | 2.58 | Benign | 1.00 | Tolerated | 0.1255 | 0.1886 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2723A>C | Q908P 2D AIThe SynGAP1 missense variant Q908P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for Q908P, 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 | 0.608892 | Disordered | 0.678728 | Binding | 0.275 | 0.917 | 0.250 | -4.446 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.196 | Likely Benign | -0.59 | Neutral | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.51 | Benign | 0.11 | Tolerated | 0.2379 | 0.5121 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2723A>G | Q908R 2D AIThe SynGAP1 missense variant Q908R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (both HumDiv and HumVar) predict a pathogenic outcome. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.678728 | Binding | 0.275 | 0.917 | 0.250 | -4.284 | Likely Benign | 0.485 | Ambiguous | Likely Benign | 0.170 | Likely Benign | -1.02 | Neutral | 0.985 | Probably Damaging | 0.982 | Probably Damaging | 2.75 | Benign | 0.10 | Tolerated | 0.1391 | 0.1743 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.2723A>T | Q908L 2D AIThe SynGAP1 missense variant Q908L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic impact. AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus is Likely Benign, and Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.678728 | Binding | 0.275 | 0.917 | 0.250 | -3.589 | Likely Benign | 0.420 | Ambiguous | Likely Benign | 0.193 | Likely Benign | -1.40 | Neutral | 0.985 | Probably Damaging | 0.982 | Probably Damaging | 2.53 | Benign | 0.05 | Affected | 0.0706 | 0.5655 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2724G>C | Q908H 2D AIThe SynGAP1 missense variant Q908H is listed in ClinVar (ID 436926.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443276‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This consensus does not contradict the ClinVar “Uncertain” classification, which remains inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.608892 | Disordered | 0.678728 | Binding | 0.275 | 0.917 | 0.250 | Conflicting | 4 | 6-33443276-G-C | 1 | 6.20e-7 | -4.658 | Likely Benign | 0.311 | Likely Benign | Likely Benign | 0.112 | Likely Benign | -0.74 | Neutral | 0.996 | Probably Damaging | 0.995 | Probably Damaging | 2.58 | Benign | 0.05 | Affected | 3.77 | 5 | 0.1293 | 0.3597 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||
| c.2724G>T | Q908H 2D AIThe SynGAP1 missense variant Q908H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all classify the change as benign or likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized reports benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. Foldetta results are not available. Overall, the majority of evidence points to a benign effect for Q908H, 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 | 0.608892 | Disordered | 0.678728 | Binding | 0.275 | 0.917 | 0.250 | -4.658 | Likely Benign | 0.311 | Likely Benign | Likely Benign | 0.110 | Likely Benign | -0.74 | Neutral | 0.996 | Probably Damaging | 0.995 | Probably Damaging | 2.58 | Benign | 0.05 | Affected | 3.77 | 5 | 0.1293 | 0.3597 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||
| c.310C>A | R104S 2D AIThe SynGAP1 missense variant R104S has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; no Foldetta stability result is available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.678998 | Binding | 0.339 | 0.869 | 0.625 | -2.790 | Likely Benign | 0.771 | Likely Pathogenic | Likely Benign | 0.143 | Likely Benign | -0.23 | Neutral | 0.625 | Possibly Damaging | 0.118 | Benign | 4.13 | Benign | 0.00 | Affected | 0.2490 | 0.3806 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.310C>G | R104G 2D AIThe SynGAP1 missense variant R104G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for R104G, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.678998 | Binding | 0.339 | 0.869 | 0.625 | -2.373 | Likely Benign | 0.452 | Ambiguous | Likely Benign | 0.109 | Likely Benign | -0.90 | Neutral | 0.835 | Possibly Damaging | 0.165 | Benign | 4.03 | Benign | 0.00 | Affected | 0.3111 | 0.3625 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.310C>T | R104C 2D  AIThe SynGAP1 missense variant R104C has no ClinVar entry and is present in gnomAD (ID 6‑33432175‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.678998 | Binding | 0.339 | 0.869 | 0.625 | 6-33432175-C-T | 2 | 1.24e-6 | -5.716 | Likely Benign | 0.475 | Ambiguous | Likely Benign | 0.109 | Likely Benign | -1.41 | Neutral | 0.993 | Probably Damaging | 0.446 | Benign | 3.99 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2954 | 0.3292 | -3 | -4 | 7.0 | -53.05 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||||
| c.311G>A | R104H 2D  AIThe SynGAP1 missense variant R104H is reported in gnomAD (variant ID 6‑33432176‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is also benign. Foldetta results are not available for this variant. Overall, the preponderance of evidence indicates that R104H 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 | 0.795062 | Disordered | 0.678998 | Binding | 0.339 | 0.869 | 0.625 | 6-33432176-G-A | 2 | 1.24e-6 | -4.126 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -1.42 | Neutral | 0.066 | Benign | 0.004 | Benign | 4.02 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2431 | 0.2102 | 0 | 2 | 1.3 | -19.05 | ||||||||||||||||||||||||||||||||||
| c.311G>C | R104P 2D AIThe SynGAP1 missense variant R104P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.678998 | Binding | 0.339 | 0.869 | 0.625 | -3.184 | Likely Benign | 0.510 | Ambiguous | Likely Benign | 0.200 | Likely Benign | -0.88 | Neutral | 0.947 | Possibly Damaging | 0.410 | Benign | 4.01 | Benign | 0.00 | Affected | 0.1759 | 0.4498 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.311G>T | R104L 2D AIThe SynGAP1 missense variant R104L is listed in ClinVar (ID 2746314.0) as Benign and is present in gnomAD (6‑33432176‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized result is benign, and the SGM‑Consensus (majority vote) is also benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the ClinVar benign classification and does not contradict the existing clinical annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.678998 | Binding | 0.339 | 0.869 | 0.625 | Benign | 1 | 6-33432176-G-T | 1 | 6.20e-7 | -3.563 | Likely Benign | 0.578 | Likely Pathogenic | Likely Benign | 0.170 | Likely Benign | -1.38 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.05 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1681 | 0.4894 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||
| c.2611C>A | H871N 2D AIThe SynGAP1 missense variant H871N is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification—there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.679301 | Binding | 0.279 | 0.858 | 0.250 | -3.303 | Likely Benign | 0.046 | Likely Benign | Likely Benign | 0.100 | Likely Benign | 0.69 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.69 | Benign | 0.40 | Tolerated | 0.1626 | 0.2507 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.2611C>G | H871D 2D AIThe SynGAP1 missense variant H871D is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.679301 | Binding | 0.279 | 0.858 | 0.250 | -3.263 | Likely Benign | 0.257 | Likely Benign | Likely Benign | 0.245 | Likely Benign | -0.51 | Neutral | 0.016 | Benign | 0.026 | Benign | 2.80 | Benign | 0.31 | Tolerated | 0.2271 | 0.1617 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2611C>T | H871Y 2D AIThe SynGAP1 missense variant H871Y 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, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. Foldetta, a protein‑folding stability method 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 | 0.480142 | Structured | 0.679301 | Binding | 0.279 | 0.858 | 0.250 | -4.070 | Likely Benign | 0.202 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -1.44 | Neutral | 0.510 | Possibly Damaging | 0.206 | Benign | 2.63 | Benign | 0.08 | Tolerated | 0.0872 | 0.3945 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.2612A>C | H871P 2D AIThe SynGAP1 missense variant H871P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus also reports likely benign; Foldetta results are unavailable. Overall, the consensus of the available predictions points to a benign impact, and this is consistent with the lack of ClinVar evidence; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.679301 | Binding | 0.279 | 0.858 | 0.250 | -3.420 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.207 | Likely Benign | -0.91 | Neutral | 0.510 | Possibly Damaging | 0.206 | Benign | 2.63 | Benign | 0.18 | Tolerated | 0.2163 | 0.3757 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2612A>G | H871R 2D AIThe SynGAP1 missense variant H871R is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.679301 | Binding | 0.279 | 0.858 | 0.250 | -3.894 | Likely Benign | 0.243 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -0.90 | Neutral | 0.144 | Benign | 0.085 | Benign | 2.67 | Benign | 0.23 | Tolerated | 0.1632 | 0.2099 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.2612A>T | H871L 2D AIThe SynGAP1 missense variant H871L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification—there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.679301 | Binding | 0.279 | 0.858 | 0.250 | -4.562 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.167 | Likely Benign | -2.16 | Neutral | 0.069 | Benign | 0.054 | Benign | 2.65 | Benign | 0.14 | Tolerated | 0.0953 | 0.4714 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||||||
| c.2613C>A | H871Q 2D AIThe SynGAP1 missense variant H871Q is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the collective evidence strongly supports a benign classification, and this conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.679301 | Binding | 0.279 | 0.858 | 0.250 | -4.049 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -0.67 | Neutral | 0.255 | Benign | 0.113 | Benign | 2.69 | Benign | 0.17 | Tolerated | 3.88 | 3 | 0.1384 | 0.3357 | 0 | 3 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||
| c.2613C>G | H871Q 2D AIThe SynGAP1 missense variant H871Q is reported in gnomAD (ID 6‑33443165‑C‑G) and has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability predictor, was not available for this variant. Overall, the evidence strongly supports a benign impact. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.679301 | Binding | 0.279 | 0.858 | 0.250 | 6-33443165-C-G | 1 | 6.20e-7 | -4.049 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -0.67 | Neutral | 0.255 | Benign | 0.113 | Benign | 2.69 | Benign | 0.17 | Tolerated | 3.88 | 3 | 0.1384 | 0.3357 | 0 | 3 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||
| c.2353C>A | R785S 2D AIThe SynGAP1 missense variant R785S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. The high‑accuracy consensus from SGM (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) favors pathogenicity, while the lack of a Foldetta result leaves that evidence inconclusive. Overall, the preponderance of pathogenic predictions indicates that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.859585 | Disordered | 0.681730 | Binding | 0.325 | 0.896 | 0.625 | -2.926 | Likely Benign | 0.886 | Likely Pathogenic | Ambiguous | 0.157 | Likely Benign | -2.93 | Deleterious | 0.980 | Probably Damaging | 0.765 | Possibly Damaging | 2.34 | Pathogenic | 0.01 | Affected | 0.3523 | 0.3800 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||
| c.2353C>G | R785G 2D AIThe SynGAP1 missense variant R785G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic outcome. High‑accuracy assessments further reveal that AlphaMissense‑Optimized predicts a benign effect, while the SGM‑Consensus again suggests pathogenicity; Foldetta stability analysis is not available for this variant. Overall, the majority of predictions lean toward pathogenicity, and this is consistent with the SGM‑Consensus result. Because the variant is not present in ClinVar, there is no existing clinical classification to contradict; thus, based on the available computational evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.859585 | Disordered | 0.681730 | Binding | 0.325 | 0.896 | 0.625 | -3.684 | Likely Benign | 0.697 | Likely Pathogenic | Likely Benign | 0.190 | Likely Benign | -3.44 | Deleterious | 0.980 | Probably Damaging | 0.818 | Possibly Damaging | 2.25 | Pathogenic | 0.00 | Affected | 0.3695 | 0.3686 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||
| c.2353C>T | R785C 2D AIThe SynGAP1 R785C missense variant is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33442905‑C‑T). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus—derived from a 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, has no available result for this variant. Overall, the majority of computational evidence points toward 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 | SH3-binding motif | 0.859585 | Disordered | 0.681730 | Binding | 0.325 | 0.896 | 0.625 | Uncertain | 1 | 6-33442905-C-T | 29 | 1.80e-5 | -5.887 | Likely Benign | 0.662 | Likely Pathogenic | Likely Benign | 0.126 | Likely Benign | -5.06 | Deleterious | 0.144 | Benign | 0.046 | Benign | 2.22 | Pathogenic | 0.00 | Affected | 3.64 | 6 | 0.3775 | 0.3530 | -4 | -3 | 7.0 | -53.05 | |||||||||||||||||||||||||||||||
| c.2354G>A | R785H 2D AIThe SynGAP1 R785H missense variant (ClinVar ID 2321588.0) is listed as “Uncertain” in ClinVar and is present in gnomAD (ID 6‑33442906‑G‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, whereas the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a pathogenic outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, does not provide a result for this variant. Overall, the majority of computational predictions (five pathogenic versus three benign) lean toward a pathogenic interpretation. Thus, the variant is most likely pathogenic based on current predictions, and this conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.859585 | Disordered | 0.681730 | Binding | 0.325 | 0.896 | 0.625 | Uncertain | 2 | 6-33442906-G-A | 4 | 2.50e-6 | -4.782 | Likely Benign | 0.388 | Ambiguous | Likely Benign | 0.129 | Likely Benign | -2.61 | Deleterious | 0.999 | Probably Damaging | 0.947 | Probably Damaging | 2.25 | Pathogenic | 0.01 | Affected | 3.64 | 6 | 0.3260 | 0.1589 | 2 | 0 | 1.3 | -19.05 | ||||||||||||||||||||||||||||||||
| c.2354G>C | R785P 2D AIThe SynGAP1 missense variant R785P is catalogued in gnomAD (6‑33442906‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further show AlphaMissense‑Optimized as Benign, while the SGM‑Consensus remains Likely Pathogenic; Foldetta results are unavailable. Overall, the balance of evidence, with seven pathogenic versus three benign predictions and a pathogenic consensus from SGM, indicates that R785P is most likely pathogenic. This conclusion does not contradict ClinVar, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.859585 | Disordered | 0.681730 | Binding | 0.325 | 0.896 | 0.625 | 6-33442906-G-C | -3.603 | Likely Benign | 0.721 | Likely Pathogenic | Likely Benign | 0.203 | Likely Benign | -4.12 | Deleterious | 0.998 | Probably Damaging | 0.958 | Probably Damaging | 2.24 | Pathogenic | 0.01 | Affected | 3.64 | 6 | 0.2370 | 0.4485 | -2 | 0 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||
| c.2354G>T | R785L 2D AIThe SynGAP1 missense variant R785L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; Foldetta results are unavailable. Overall, the balance of evidence leans toward a pathogenic effect, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.859585 | Disordered | 0.681730 | Binding | 0.325 | 0.896 | 0.625 | -4.457 | Likely Benign | 0.699 | Likely Pathogenic | Likely Benign | 0.158 | Likely Benign | -4.43 | Deleterious | 0.960 | Probably Damaging | 0.627 | Possibly Damaging | 2.26 | Pathogenic | 0.01 | Affected | 0.1993 | 0.4539 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||||||
| c.2404G>A | G802S 2D AIThe SynGAP1 missense variant G802S is catalogued in gnomAD (allele ID 6‑33442956‑G‑A) but has no entry in ClinVar. Functional prediction tools that assess evolutionary conservation and structural impact (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all uniformly predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments further support this view: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant, so it does not influence the assessment. **Overall, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.894241 | Disordered | 0.681966 | Binding | 0.294 | 0.898 | 0.625 | 6-33442956-G-A | 1 | 6.20e-7 | -2.663 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.098 | Likely Benign | 0.32 | Neutral | 0.001 | Benign | 0.006 | Benign | 2.83 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0.2682 | 0.5208 | 0 | 1 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||
| c.2404G>C | G802R 2D AIThe SynGAP1 missense variant G802R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Only SIFT predicts a pathogenic effect, and AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized reports benign, and the SGM‑Consensus (majority vote) likewise predicts likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence supports a benign classification for G802R, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.894241 | Disordered | 0.681966 | Binding | 0.294 | 0.898 | 0.625 | -4.756 | Likely Benign | 0.504 | Ambiguous | Likely Benign | 0.072 | Likely Benign | -1.05 | Neutral | 0.259 | Benign | 0.196 | Benign | 2.68 | Benign | 0.01 | Affected | 0.0995 | 0.4514 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.2404G>T | G802C 2D AIThe SynGAP1 missense variant G802C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; Foldetta results are not available. Overall, the majority of evidence—including the consensus of multiple independent predictors and the high‑accuracy tools—supports a benign classification for G802C. This conclusion is consistent with the lack of any ClinVar pathogenic 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 Benign | SH3-binding motif | 0.894241 | Disordered | 0.681966 | Binding | 0.294 | 0.898 | 0.625 | -6.332 | Likely Benign | 0.127 | Likely Benign | Likely Benign | 0.127 | Likely Benign | -1.60 | Neutral | 0.983 | Probably Damaging | 0.819 | Possibly Damaging | 2.65 | Benign | 0.00 | Affected | 0.1426 | 0.4126 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||||
| c.2405G>A | G802D 2D AIThe SynGAP1 missense variant G802D is listed in ClinVar with an “Uncertain” status and is present in gnomAD (6‑33442957‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—all classifying the change as benign. No tool predicts a pathogenic outcome. The high‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions points to a benign impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.894241 | Disordered | 0.681966 | Binding | 0.294 | 0.898 | 0.625 | Uncertain | 1 | 6-33442957-G-A | 1 | 6.20e-7 | -5.083 | Likely Benign | 0.476 | Ambiguous | Likely Benign | 0.153 | Likely Benign | -0.38 | Neutral | 0.126 | Benign | 0.138 | Benign | 2.72 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.1993 | 0.2742 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||
| c.2405G>C | G802A 2D AIThe SynGAP1 missense variant G802A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a “Likely Benign” status. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that G802A is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.894241 | Disordered | 0.681966 | Binding | 0.294 | 0.898 | 0.625 | -3.584 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -0.57 | Neutral | 0.059 | Benign | 0.089 | Benign | 2.74 | Benign | 0.02 | Affected | 0.3779 | 0.4554 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2405G>T | G802V 2D AIThe SynGAP1 missense variant G802V 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 only pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign. No Foldetta stability analysis is available for this variant. Overall, the consensus of the available predictions indicates that G802V is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.894241 | Disordered | 0.681966 | Binding | 0.294 | 0.898 | 0.625 | -3.871 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.49 | Neutral | 0.411 | Benign | 0.321 | Benign | 2.67 | Benign | 0.00 | Affected | 0.1345 | 0.3533 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||
| c.307G>A | G103S 2D AIThe SynGAP1 missense variant G103S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.687376 | Binding | 0.381 | 0.877 | 0.625 | -3.177 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -0.03 | Neutral | 0.565 | Possibly Damaging | 0.207 | Benign | 4.32 | Benign | 0.00 | Affected | 0.2816 | 0.4867 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.307G>C | G103R 2D AIThe SynGAP1 missense variant G103R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.687376 | Binding | 0.381 | 0.877 | 0.625 | -3.384 | Likely Benign | 0.710 | Likely Pathogenic | Likely Benign | 0.100 | Likely Benign | 0.00 | Neutral | 0.949 | Possibly Damaging | 0.708 | Possibly Damaging | 4.27 | Benign | 0.00 | Affected | 0.1198 | 0.4362 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.307G>T | G103C 2D AIThe SynGAP1 missense variant G103C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign effect for G103C, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.687376 | Binding | 0.381 | 0.877 | 0.625 | -5.681 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.128 | Likely Benign | -1.12 | Neutral | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 4.17 | Benign | 0.00 | Affected | 0.1494 | 0.3767 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.308G>A | G103D 2D AIThe SynGAP1 missense variant G103D is not reported in ClinVar and has no entry in gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT each predict a pathogenic impact. The AlphaMissense‑Default tool remains uncertain, and no Foldetta stability assessment is available. High‑accuracy tools specifically highlight benign predictions: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta data are missing. Overall, the balance of evidence points to a benign effect for G103D, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.687376 | Binding | 0.381 | 0.877 | 0.625 | -3.523 | Likely Benign | 0.477 | Ambiguous | Likely Benign | 0.110 | Likely Benign | -0.10 | Neutral | 0.949 | Possibly Damaging | 0.617 | Possibly Damaging | 4.26 | Benign | 0.00 | Affected | 0.2237 | 0.2896 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.308G>C | G103A 2D AIThe SynGAP1 missense variant G103A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta results are not available, so they do not influence the assessment. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.687376 | Binding | 0.381 | 0.877 | 0.625 | -3.549 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -0.08 | Neutral | 0.008 | Benign | 0.008 | Benign | 4.31 | Benign | 0.00 | Affected | 0.3941 | 0.3784 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.308G>T | G103V 2D AIThe SynGAP1 missense variant G103V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.687376 | Binding | 0.381 | 0.877 | 0.625 | -3.584 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.126 | Likely Benign | -0.96 | Neutral | 0.820 | Possibly Damaging | 0.376 | Benign | 4.22 | Benign | 0.00 | Affected | 0.1420 | 0.3404 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.2608C>A | L870M 2D AIThe SynGAP1 missense variant L870M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic effect. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.688079 | Binding | 0.274 | 0.850 | 0.125 | -4.809 | Likely Benign | 0.316 | Likely Benign | Likely Benign | 0.130 | Likely Benign | -1.01 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.60 | Benign | 0.10 | Tolerated | 0.0757 | 0.3956 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2608C>G | L870V 2D AIThe SynGAP1 missense variant L870V is listed in ClinVar (ID 946946.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, PolyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not conflict with the ClinVar designation of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.688079 | Binding | 0.274 | 0.850 | 0.125 | Uncertain | 1 | -4.123 | Likely Benign | 0.300 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -1.19 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.64 | Benign | 0.12 | Tolerated | 3.88 | 3 | 0.1549 | 0.3977 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.2609T>A | L870Q 2D AIThe SynGAP1 missense variant L870Q is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico 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 view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus itself is labeled likely benign. No output is available from the Foldetta stability analysis, so it does not influence the overall assessment. Based on the aggregate predictions, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.688079 | Binding | 0.274 | 0.850 | 0.125 | -4.029 | Likely Benign | 0.417 | Ambiguous | Likely Benign | 0.185 | Likely Benign | -1.90 | Neutral | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 2.63 | Benign | 0.02 | Affected | 0.1027 | 0.1003 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2609T>C | L870P 2D AIThe SynGAP1 missense variant L870P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.688079 | Binding | 0.274 | 0.850 | 0.125 | -4.462 | Likely Benign | 0.402 | Ambiguous | Likely Benign | 0.194 | Likely Benign | -1.92 | Neutral | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 2.59 | Benign | 0.13 | Tolerated | 0.3795 | 0.1864 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2609T>G | L870R 2D AIThe SynGAP1 missense variant L870R is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict the ClinVar status, which currently contains no classification for L870R. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.688079 | Binding | 0.274 | 0.850 | 0.125 | -4.578 | Likely Benign | 0.636 | Likely Pathogenic | Likely Benign | 0.175 | Likely Benign | -1.97 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.63 | Benign | 0.02 | Affected | 0.1147 | 0.0846 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.301C>A | H101N 2D AIThe SynGAP1 missense variant H101N 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 a majority vote of the benign‑predicted tools). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (derived from the same set of benign‑predicted tools) 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 does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.688356 | Binding | 0.370 | 0.884 | 0.625 | -3.598 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -0.49 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.20 | Benign | 0.00 | Affected | 0.1651 | 0.2994 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.301C>G | H101D 2D AIThe SynGAP1 missense variant H101D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion is not in conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.688356 | Binding | 0.370 | 0.884 | 0.625 | -2.788 | Likely Benign | 0.227 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -0.49 | Neutral | 0.824 | Possibly Damaging | 0.840 | Possibly Damaging | 4.20 | Benign | 0.00 | Affected | 0.2479 | 0.2272 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.301C>T | H101Y 2D AIThe SynGAP1 missense variant H101Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for H101Y, 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 | 0.791621 | Disordered | 0.688356 | Binding | 0.370 | 0.884 | 0.625 | -3.404 | Likely Benign | 0.123 | Likely Benign | Likely Benign | 0.099 | Likely Benign | -0.95 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.15 | Benign | 0.00 | Affected | 0.0862 | 0.4004 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.302A>C | H101P 2D AIThe SynGAP1 H101P missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.688356 | Binding | 0.370 | 0.884 | 0.625 | -2.042 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.170 | Likely Benign | 0.89 | Neutral | 0.943 | Possibly Damaging | 0.924 | Probably Damaging | 4.17 | Benign | 0.00 | Affected | 0.1777 | 0.3589 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.302A>G | H101R 2D AIThe SynGAP1 missense variant H101R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for H101R, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.688356 | Binding | 0.370 | 0.884 | 0.625 | -2.685 | Likely Benign | 0.211 | Likely Benign | Likely Benign | 0.141 | Likely Benign | -0.76 | Neutral | 0.824 | Possibly Damaging | 0.840 | Possibly Damaging | 4.21 | Benign | 0.00 | Affected | 0.1891 | 0.2225 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.302A>T | H101L 2D AIThe SynGAP1 missense variant H101L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for H101L, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.688356 | Binding | 0.370 | 0.884 | 0.625 | -1.376 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.129 | Likely Benign | -1.33 | Neutral | 0.824 | Possibly Damaging | 0.840 | Possibly Damaging | 4.19 | Benign | 0.00 | Affected | 0.0924 | 0.4960 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||||||
| c.303C>A | H101Q 2D AIThe SynGAP1 missense variant H101Q is listed in ClinVar with an uncertain significance (ClinVar ID 1307533.0) and is present in gnomAD (ID 6‑33432168‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) also benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to 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 | 0.791621 | Disordered | 0.688356 | Binding | 0.370 | 0.884 | 0.625 | Uncertain | 1 | 6-33432168-C-A | 1 | 6.20e-7 | -2.827 | Likely Benign | 0.124 | Likely Benign | Likely Benign | 0.147 | Likely Benign | -0.37 | Neutral | 0.824 | Possibly Damaging | 0.880 | Possibly Damaging | 4.24 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1487 | 0.3689 | 3 | 0 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||
| c.303C>G | H101Q 2D AIThe SynGAP1 missense variant H101Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for H101Q, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.688356 | Binding | 0.370 | 0.884 | 0.625 | -2.827 | Likely Benign | 0.124 | Likely Benign | Likely Benign | 0.149 | Likely Benign | -0.37 | Neutral | 0.824 | Possibly Damaging | 0.880 | Possibly Damaging | 4.24 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1487 | 0.3689 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||
| c.2605C>A | L869M 2D AIThe SynGAP1 missense variant L869M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is benign, and this conclusion does not contradict any ClinVar annotation (none present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.501700 | Disordered | 0.688653 | Binding | 0.272 | 0.839 | 0.250 | -4.294 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -0.09 | Neutral | 0.149 | Benign | 0.058 | Benign | 2.61 | Benign | 0.11 | Tolerated | 0.0710 | 0.3795 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2605C>G | L869V 2D AIThe SynGAP1 missense variant L869V 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 is benign and the SGM‑Consensus is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.501700 | Disordered | 0.688653 | Binding | 0.272 | 0.839 | 0.250 | -3.241 | Likely Benign | 0.161 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -0.33 | Neutral | 0.481 | Possibly Damaging | 0.300 | Benign | 2.86 | Benign | 0.11 | Tolerated | 0.1501 | 0.3616 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2606T>A | L869Q 2D AIThe SynGAP1 missense variant L869Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default remains uncertain, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.501700 | Disordered | 0.688653 | Binding | 0.272 | 0.839 | 0.250 | -2.925 | Likely Benign | 0.368 | Ambiguous | Likely Benign | 0.160 | Likely Benign | -0.57 | Neutral | 0.970 | Probably Damaging | 0.801 | Possibly Damaging | 2.60 | Benign | 0.06 | Tolerated | 0.0977 | 0.1203 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2606T>C | L869P 2D AIThe SynGAP1 missense variant L869P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification, and AlphaMissense‑Optimized independently predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence—including the high‑accuracy tools—supports a benign interpretation. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.501700 | Disordered | 0.688653 | Binding | 0.272 | 0.839 | 0.250 | -2.394 | Likely Benign | 0.523 | Ambiguous | Likely Benign | 0.174 | Likely Benign | -0.99 | Neutral | 0.990 | Probably Damaging | 0.900 | Possibly Damaging | 2.58 | Benign | 0.04 | Affected | 0.3687 | 0.1503 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2606T>G | L869R 2D AIThe SynGAP1 missense variant L869R is 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) as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this conclusion, so the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.501700 | Disordered | 0.688653 | Binding | 0.272 | 0.839 | 0.250 | -2.546 | Likely Benign | 0.567 | Likely Pathogenic | Likely Benign | 0.170 | Likely Benign | -0.79 | Neutral | 0.970 | Probably Damaging | 0.801 | Possibly Damaging | 2.60 | Benign | 0.29 | Tolerated | 0.1162 | 0.0846 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.367G>A | A123T 2D AIThe SynGAP1 missense variant A123T is reported as “Likely Benign” in ClinVar and is not present in gnomAD. Prediction tools that assess functional impact all converge on a benign outcome: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. Foldetta results are unavailable. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.689505 | Binding | 0.324 | 0.886 | 0.750 | -3.999 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.117 | Likely Benign | 0.59 | Neutral | 0.004 | Benign | 0.001 | Benign | 4.29 | Benign | 0.52 | Tolerated | 0.1912 | 0.7109 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.367G>C | A123P 2D AIThe SynGAP1 missense variant A123P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. 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 | 0.521092 | Disordered | 0.689505 | Binding | 0.324 | 0.886 | 0.750 | -2.930 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.166 | Likely Benign | -1.14 | Neutral | 0.838 | Possibly Damaging | 0.278 | Benign | 4.14 | Benign | 0.02 | Affected | 0.2301 | 0.5999 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.367G>T | A123S 2D AIThe SynGAP1 missense variant A123S 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 conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.689505 | Binding | 0.324 | 0.886 | 0.750 | -3.309 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -0.03 | Neutral | 0.131 | Benign | 0.039 | Benign | 4.21 | Benign | 0.28 | Tolerated | 0.2979 | 0.6011 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.368C>A | A123D 2D AIThe SynGAP1 missense variant A123D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.689505 | Binding | 0.324 | 0.886 | 0.750 | -3.515 | Likely Benign | 0.692 | Likely Pathogenic | Likely Benign | 0.168 | Likely Benign | -1.17 | Neutral | 0.718 | Possibly Damaging | 0.218 | Benign | 4.15 | Benign | 0.01 | Affected | 0.2325 | 0.2893 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.368C>G | A123G 2D AIThe SynGAP1 missense variant A123G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.689505 | Binding | 0.324 | 0.886 | 0.750 | -2.799 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -1.34 | Neutral | 0.421 | Benign | 0.074 | Benign | 4.13 | Benign | 0.03 | Affected | 0.2070 | 0.5039 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.368C>T | A123V 2D AIThe SynGAP1 missense variant A123V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.689505 | Binding | 0.324 | 0.886 | 0.750 | -4.119 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.040 | Likely Benign | -0.77 | Neutral | 0.010 | Benign | 0.003 | Benign | 4.15 | Benign | 0.02 | Affected | 0.1549 | 0.6874 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.2254T>A | S752T 2D AIThe SynGAP1 missense variant S752T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.604312 | Disordered | 0.690594 | Binding | 0.365 | 0.877 | 0.625 | -4.040 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.029 | Likely Benign | -1.33 | Neutral | 0.248 | Benign | 0.137 | Benign | 1.55 | Pathogenic | 0.07 | Tolerated | 0.1633 | 0.6342 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2254T>C | S752P 2D AIThe SynGAP1 missense variant S752P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for S752P, and this conclusion does not contradict the ClinVar status, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.604312 | Disordered | 0.690594 | Binding | 0.365 | 0.877 | 0.625 | -3.491 | Likely Benign | 0.158 | Likely Benign | Likely Benign | 0.183 | Likely Benign | -1.09 | Neutral | 0.998 | Probably Damaging | 0.912 | Probably Damaging | 1.51 | Pathogenic | 0.02 | Affected | 0.2288 | 0.5882 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2254T>G | S752A 2D AIThe SynGAP1 missense variant S752A has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this 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 | 0.604312 | Disordered | 0.690594 | Binding | 0.365 | 0.877 | 0.625 | -3.258 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -1.42 | Neutral | 0.910 | Possibly Damaging | 0.524 | Possibly Damaging | 1.59 | Pathogenic | 0.04 | Affected | 0.5092 | 0.5634 | Strenghten | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.2255C>G | S752W 2D AIThe SynGAP1 missense variant S752W is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas seven tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Pathogenic, and the Foldetta stability analysis is unavailable. Overall, the majority of predictions lean toward pathogenicity, and this conclusion is not contradicted by ClinVar status (which is absent). Thus, the variant is most likely pathogenic based on the collective evidence, despite the single benign prediction from AlphaMissense‑Optimized. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.604312 | Disordered | 0.690594 | Binding | 0.365 | 0.877 | 0.625 | -6.771 | Likely Benign | 0.565 | Likely Pathogenic | Likely Benign | 0.341 | Likely Benign | -3.54 | Deleterious | 1.000 | Probably Damaging | 0.992 | Probably Damaging | 1.49 | Pathogenic | 0.00 | Affected | 0.0837 | 0.6241 | -2 | -3 | -0.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2255C>T | S752L 2D AIThe SynGAP1 missense variant S752L is listed in ClinVar with an “Uncertain” status (ClinVar ID 2143952.0) and is present in gnomAD (ID 6‑33441720‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.604312 | Disordered | 0.690594 | Binding | 0.365 | 0.877 | 0.625 | Uncertain | 2 | 6-33441720-C-T | 6 | 3.72e-6 | -3.386 | Likely Benign | 0.182 | Likely Benign | Likely Benign | 0.195 | Likely Benign | -2.09 | Neutral | 0.993 | Probably Damaging | 0.641 | Possibly Damaging | 1.51 | Pathogenic | 0.01 | Affected | 3.99 | 5 | 0.1308 | 0.5909 | -3 | -2 | 4.6 | 26.08 | ||||||||||||||||||||||||||||||||
| c.2458T>A | Y820N 2D AIThe SynGAP1 Y820N variant is listed in ClinVar with an “Uncertain” significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, whereas polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default all predict a pathogenic outcome. AlphaMissense‑Optimized returns an “Uncertain” result. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs. two pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the predictions are evenly split between benign and pathogenic, with no high‑confidence pathogenic or benign signal. Thus, the variant is most likely of uncertain significance, which is consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.733139 | Disordered | 0.695550 | Binding | 0.293 | 0.883 | 0.625 | Uncertain | 1 | -9.032 | Likely Pathogenic | 0.842 | Likely Pathogenic | Ambiguous | 0.143 | Likely Benign | -1.53 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.74 | Benign | 0.20 | Tolerated | 0.2352 | 0.0704 | -2 | -2 | -2.2 | -49.07 | ||||||||||||||||||||||||||||||||||||||
| c.2458T>C | Y820H 2D AIThe SynGAP1 missense variant Y820H is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443010‑T‑C). Functional 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 assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leaning toward benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.733139 | Disordered | 0.695550 | Binding | 0.293 | 0.883 | 0.625 | 6-33443010-T-C | 5 | 3.10e-6 | -7.432 | In-Between | 0.928 | Likely Pathogenic | Ambiguous | 0.129 | Likely Benign | -0.13 | Neutral | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 2.70 | Benign | 0.24 | Tolerated | 3.77 | 5 | 0.2498 | 0.0704 | 2 | 0 | -1.9 | -26.03 | |||||||||||||||||||||||||||||||||||
| c.2458T>G | Y820D 2D AIThe SynGAP1 missense variant Y820D is not 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 this: 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, has no available result for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and high‑accuracy tools suggests that Y820D is most likely pathogenic, with no ClinVar status to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.733139 | Disordered | 0.695550 | Binding | 0.293 | 0.883 | 0.625 | -10.497 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.169 | Likely Benign | -2.77 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.73 | Benign | 0.08 | Tolerated | 0.4113 | 0.0704 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||||||||||||
| c.2459A>C | Y820S 2D AIThe SynGAP1 missense variant Y820S is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign (2 benign vs. 1 pathogenic). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for Y820S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.733139 | Disordered | 0.695550 | Binding | 0.293 | 0.883 | 0.625 | -7.094 | In-Between | 0.723 | Likely Pathogenic | Likely Benign | 0.101 | Likely Benign | -1.79 | Neutral | 0.999 | Probably Damaging | 0.951 | Probably Damaging | 2.80 | Benign | 0.22 | Tolerated | 0.5166 | 0.2291 | Weaken | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2459A>G | Y820C 2D AIThe SynGAP1 missense variant Y820C is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta results are unavailable. Overall, the balance of evidence—including the SGM‑Consensus—suggests the variant is most likely pathogenic, a conclusion that does not contradict the current ClinVar uncertain classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.733139 | Disordered | 0.695550 | Binding | 0.293 | 0.883 | 0.625 | Uncertain | 1 | -8.797 | Likely Pathogenic | 0.744 | Likely Pathogenic | Likely Benign | 0.113 | Likely Benign | -3.16 | Deleterious | 1.000 | Probably Damaging | 0.983 | Probably Damaging | 2.68 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0.3177 | 0.1915 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||||||||
| c.2459A>T | Y820F 2D AIThe SynGAP1 missense variant Y820F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for Y820F, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.695550 | Binding | 0.293 | 0.883 | 0.625 | -4.686 | Likely Benign | 0.301 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -1.67 | Neutral | 0.990 | Probably Damaging | 0.893 | Possibly Damaging | 2.69 | Benign | 0.21 | Tolerated | 0.2398 | 0.2636 | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.400A>C | S134R 2D AIThe SynGAP1 missense variant S134R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM‑Consensus as Likely Pathogenic; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.447574 | Structured | 0.695837 | Binding | 0.333 | 0.898 | 0.250 | -9.053 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.292 | Likely Benign | -2.54 | Deleterious | 0.380 | Benign | 0.147 | Benign | 3.84 | Benign | 0.00 | Affected | 0.0719 | 0.3528 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.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 | -2.19 | Neutral | 0.034 | Benign | 0.035 | Benign | 3.84 | Benign | 0.00 | Affected | 0.2268 | 0.4008 | 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 | -3.12 | Deleterious | 0.876 | Possibly Damaging | 0.417 | Benign | 3.79 | Benign | 0.00 | Affected | 0.0767 | 0.5151 | 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 | -1.62 | Neutral | 0.001 | Benign | 0.002 | Benign | 3.90 | Benign | 0.00 | Affected | 3.61 | 5 | 0.0964 | 0.4381 | 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 | -1.76 | Neutral | 0.034 | Benign | 0.047 | Benign | 3.85 | Benign | 0.00 | Affected | 3.61 | 5 | 0.1083 | 0.5326 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.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 | -3.27 | Deleterious | 0.041 | Benign | 0.031 | Benign | 3.81 | Benign | 0.00 | Affected | 0.0683 | 0.5191 | -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 | -2.54 | Deleterious | 0.380 | Benign | 0.147 | Benign | 3.84 | Benign | 0.00 | Affected | 0.0719 | 0.3528 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.402C>G | S134R 2D AIThe SynGAP1 missense variant S134R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict pathogenicity are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized also predicts Pathogenic, while the SGM‑Consensus remains Likely Pathogenic; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.447574 | Structured | 0.695837 | Binding | 0.333 | 0.898 | 0.250 | -9.053 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.146 | Likely Benign | -2.54 | Deleterious | 0.380 | Benign | 0.147 | Benign | 3.84 | Benign | 0.00 | Affected | 0.0719 | 0.3528 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.304T>A | L102M 2D AIThe SynGAP1 missense variant L102M is not reported 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 the variant, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.696014 | Binding | 0.357 | 0.885 | 0.625 | -5.033 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.129 | Likely Benign | 0.12 | Neutral | 0.984 | Probably Damaging | 0.969 | Probably Damaging | 4.14 | Benign | 0.00 | Affected | 0.1091 | 0.4176 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.304T>G | L102V 2D AIThe SynGAP1 missense variant L102V is listed in ClinVar (ID 1925749.0) with an “Uncertain” status and is present in gnomAD (6‑33432169‑T‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This consensus does not contradict the ClinVar “Uncertain” classification, which remains inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.696014 | Binding | 0.357 | 0.885 | 0.625 | Uncertain | 1 | 6-33432169-T-G | 1 | 6.20e-7 | -4.316 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.102 | Likely Benign | 0.32 | Neutral | 0.880 | Possibly Damaging | 0.899 | Possibly Damaging | 4.21 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1683 | 0.3671 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||
| c.305T>C | L102S 2D AIThe SynGAP1 missense variant L102S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus likewise indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for the L102S variant, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.696014 | Binding | 0.357 | 0.885 | 0.625 | -3.260 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.174 | Likely Benign | 0.54 | Neutral | 0.984 | Probably Damaging | 0.969 | Probably Damaging | 4.18 | Benign | 0.00 | Affected | 0.2785 | 0.1752 | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||||||||||||
| c.305T>G | L102W 2D AIThe SynGAP1 missense variant L102W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for L102W, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.696014 | Binding | 0.357 | 0.885 | 0.625 | -5.833 | Likely Benign | 0.202 | Likely Benign | Likely Benign | 0.125 | Likely Benign | -1.42 | Neutral | 0.996 | Probably Damaging | 0.984 | Probably Damaging | 4.09 | Benign | 0.00 | Affected | 0.0821 | 0.3078 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||||||||||||
| c.306G>C | L102F 2D AIThe SynGAP1 missense variant L102F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.696014 | Binding | 0.357 | 0.885 | 0.625 | -4.712 | Likely Benign | 0.094 | Likely Benign | Likely Benign | 0.144 | Likely Benign | -0.80 | Neutral | 0.984 | Probably Damaging | 0.969 | Probably Damaging | 4.13 | Benign | 0.00 | Affected | 0.0863 | 0.3205 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.306G>T | L102F 2D AIThe SynGAP1 missense variant L102F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.696014 | Binding | 0.357 | 0.885 | 0.625 | -4.712 | Likely Benign | 0.094 | Likely Benign | Likely Benign | 0.153 | Likely Benign | -0.80 | Neutral | 0.984 | Probably Damaging | 0.969 | Probably Damaging | 4.13 | Benign | 0.00 | Affected | 0.0863 | 0.3205 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2725A>C | M909L 2D AIThe SynGAP1 missense variant M909L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess pathogenicity uniformly predict a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the consensus of all available predictions points to a benign effect, and this is consistent with the lack of a ClinVar classification—there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.696196 | Binding | 0.314 | 0.914 | 0.250 | -1.417 | Likely Benign | 0.152 | Likely Benign | Likely Benign | 0.184 | Likely Benign | -0.85 | Neutral | 0.002 | Benign | 0.006 | Benign | 2.82 | Benign | 0.32 | Tolerated | 3.77 | 5 | 0.1591 | 0.4352 | 2 | 4 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.2725A>G | M909V 2D AIThe SynGAP1 missense variant M909V is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population evidence. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.696196 | Binding | 0.314 | 0.914 | 0.250 | -2.906 | Likely Benign | 0.230 | Likely Benign | Likely Benign | 0.164 | Likely Benign | -0.88 | Neutral | 0.288 | Benign | 0.147 | Benign | 2.97 | Benign | 0.45 | Tolerated | 0.3295 | 0.3600 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||||||||||||
| c.2725A>T | M909L 2D AIThe SynGAP1 missense variant M909L is catalogued in gnomAD (ID 6‑33443277‑A‑T) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the variant as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the consensus of all available predictions is benign, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.696196 | Binding | 0.314 | 0.914 | 0.250 | 6-33443277-A-T | 4 | 2.48e-6 | -1.417 | Likely Benign | 0.152 | Likely Benign | Likely Benign | 0.184 | Likely Benign | -0.85 | Neutral | 0.002 | Benign | 0.006 | Benign | 2.82 | Benign | 0.32 | Tolerated | 3.77 | 5 | 0.1591 | 0.4352 | 2 | 4 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||
| c.2726T>A | M909K 2D AIThe SynGAP1 missense variant M909K is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster into two groups: benign (SGM‑Consensus, REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized) and pathogenic (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default). High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign. Foldetta, a protein‑folding stability method, was not available for this variant. Overall, the preponderance of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.696196 | Binding | 0.314 | 0.914 | 0.250 | -5.024 | Likely Benign | 0.748 | Likely Pathogenic | Likely Benign | 0.126 | Likely Benign | -1.17 | Neutral | 0.965 | Probably Damaging | 0.629 | Possibly Damaging | 2.71 | Benign | 0.18 | Tolerated | 0.1585 | 0.0628 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||||||
| c.2726T>C | M909T 2D AIThe SynGAP1 missense variant M909T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates likely benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the majority of evidence points to a benign impact for M909T, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.696196 | Binding | 0.314 | 0.914 | 0.250 | -3.053 | Likely Benign | 0.647 | Likely Pathogenic | Likely Benign | 0.109 | Likely Benign | -0.74 | Neutral | 0.901 | Possibly Damaging | 0.430 | Benign | 2.86 | Benign | 1.00 | Tolerated | 0.2157 | 0.2085 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||||||||||||
| c.2726T>G | M909R 2D AIThe SynGAP1 missense variant M909R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this conclusion, so the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.696196 | Binding | 0.314 | 0.914 | 0.250 | -3.064 | Likely Benign | 0.699 | Likely Pathogenic | Likely Benign | 0.127 | Likely Benign | -1.23 | Neutral | 0.965 | Probably Damaging | 0.703 | Possibly Damaging | 2.70 | Benign | 0.12 | Tolerated | 0.1745 | 0.0809 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||||||
| c.2727G>A | M909I 2D AIThe SynGAP1 missense variant M909I is not reported in ClinVar (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, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.696196 | Binding | 0.314 | 0.914 | 0.250 | -3.636 | Likely Benign | 0.703 | Likely Pathogenic | Likely Benign | 0.097 | Likely Benign | -1.15 | Neutral | 0.481 | Possibly Damaging | 0.220 | Benign | 2.82 | Benign | 0.25 | Tolerated | 0.1392 | 0.3298 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2727G>C | M909I 2D AIThe SynGAP1 missense variant M909I is not reported in ClinVar (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, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.696196 | Binding | 0.314 | 0.914 | 0.250 | -3.636 | Likely Benign | 0.703 | Likely Pathogenic | Likely Benign | 0.097 | Likely Benign | -1.15 | Neutral | 0.481 | Possibly Damaging | 0.220 | Benign | 2.82 | Benign | 0.25 | Tolerated | 0.1392 | 0.3298 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2727G>T | M909I 2D AIThe SynGAP1 missense variant M909I is not reported in ClinVar (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, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.696196 | Binding | 0.314 | 0.914 | 0.250 | -3.636 | Likely Benign | 0.703 | Likely Pathogenic | Likely Benign | 0.097 | Likely Benign | -1.15 | Neutral | 0.481 | Possibly Damaging | 0.220 | Benign | 2.82 | Benign | 0.25 | Tolerated | 0.1392 | 0.3298 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.370G>A | A124T 2D AIThe SynGAP1 missense variant A124T is reported in gnomAD (6-33432235‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags it as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are unavailable. Taken together, the preponderance of evidence points to a benign impact. 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 | 0.509769 | Disordered | 0.699139 | Binding | 0.340 | 0.883 | 0.750 | 6-33432235-G-A | 1 | 6.20e-7 | -3.551 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.046 | Likely Benign | -0.26 | Neutral | 0.734 | Possibly Damaging | 0.187 | Benign | 4.17 | Benign | 0.78 | Tolerated | 3.61 | 5 | 0.1828 | 0.7680 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.370G>C | A124P 2D AIThe SynGAP1 missense variant A124P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for A124P, 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 | 0.699139 | Binding | 0.340 | 0.883 | 0.750 | -3.030 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.134 | Likely Benign | -1.19 | Neutral | 0.984 | Probably Damaging | 0.690 | Possibly Damaging | 4.05 | Benign | 0.03 | Affected | 0.2293 | 0.6141 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.370G>T | A124S 2D AIThe SynGAP1 missense variant A124 S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.699139 | Binding | 0.340 | 0.883 | 0.750 | -1.933 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.053 | Likely Benign | 0.35 | Neutral | 0.849 | Possibly Damaging | 0.303 | Benign | 4.22 | Benign | 0.65 | Tolerated | 0.3018 | 0.6192 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.371C>A | A124E 2D AIThe SynGAP1 missense variant A124E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for A124E, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.699139 | Binding | 0.340 | 0.883 | 0.750 | -3.444 | Likely Benign | 0.667 | Likely Pathogenic | Likely Benign | 0.208 | Likely Benign | -1.21 | Neutral | 0.993 | Probably Damaging | 0.733 | Possibly Damaging | 4.11 | Benign | 0.01 | Affected | 0.1498 | 0.2233 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.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 | -0.75 | Neutral | 0.934 | Possibly Damaging | 0.447 | Possibly Damaging | 4.06 | Benign | 0.04 | Affected | 0.2433 | 0.5388 | 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 | -1.52 | Neutral | 0.173 | Benign | 0.009 | Benign | 4.07 | Benign | 0.03 | Affected | 3.61 | 5 | 0.1415 | 0.7433 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||
| c.3511G>A | A1171T 2D AIThe SynGAP1 missense variant A1171T is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All available in‑silico predictors classify the change as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a “Likely Benign” outcome. No tool predicts pathogenicity. High‑accuracy assessments confirm the benign prediction: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.702689 | Binding | 0.472 | 0.775 | 0.500 | Uncertain | 1 | -3.658 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.201 | Likely Benign | -0.48 | Neutral | 0.245 | Benign | 0.138 | Benign | 5.45 | Benign | 0.07 | Tolerated | 4.32 | 4 | 0.1421 | 0.5465 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.3511G>C | A1171P 2D AIThe SynGAP1 A1171P missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. AlphaMissense‑Optimized is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy tools therefore provide a benign consensus (SGM‑Consensus) with no definitive pathogenic signal, and no evidence from Foldetta. Based on the aggregate predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.702689 | Binding | 0.472 | 0.775 | 0.500 | -3.625 | Likely Benign | 0.897 | Likely Pathogenic | Ambiguous | 0.355 | Likely Benign | -1.00 | Neutral | 0.918 | Possibly Damaging | 0.601 | Possibly Damaging | 5.31 | Benign | 0.05 | Affected | 0.1910 | 0.3810 | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||||||||||
| c.3511G>T | A1171S 2D AIThe SynGAP1 missense variant A1171S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly classify the change 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 methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the lack of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.702689 | Binding | 0.472 | 0.775 | 0.500 | -2.875 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.156 | Likely Benign | -0.24 | Neutral | 0.009 | Benign | 0.012 | Benign | 5.54 | Benign | 0.08 | Tolerated | 0.2536 | 0.4676 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||||
| c.3511_3512delinsTG | A1171C 2D  AIThe SynGAP1 missense variant A1171C (ClinVar ID 1723483.0) is listed as “Uncertain” in ClinVar and is not present in gnomAD. Prediction tools that converge on a benign outcome include PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, all of which report a benign or neutral effect. In contrast, PolyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign,” reinforcing the benign signal. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote) as benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.702689 | Binding | 0.472 | 0.775 | 0.500 | Uncertain | 1 | -5.363 | Likely Benign | 0.496 | Ambiguous | Likely Benign | -1.16 | Neutral | 0.978 | Probably Damaging | 0.825 | Possibly Damaging | 5.32 | Benign | 0.02 | Affected | 4.32 | 4 | 0.1102 | 0.4921 | -2 | 0 | 0.7 | 32.06 | ||||||||||||||||||||||||||||||||||||
| c.3512C>A | A1171D 2D AIThe SynGAP1 missense variant A1171D is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” and Foldetta results are unavailable. Overall, the balance of evidence from multiple independent predictors and the SGM‑Consensus points to a benign impact for A1171D. This conclusion is consistent with the absence of a ClinVar classification, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.702689 | Binding | 0.472 | 0.775 | 0.500 | -3.897 | Likely Benign | 0.814 | Likely Pathogenic | Ambiguous | 0.312 | Likely Benign | -0.80 | Neutral | 0.611 | Possibly Damaging | 0.326 | Benign | 5.34 | Benign | 0.02 | Affected | 0.1952 | 0.2494 | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||||
| c.3512C>G | A1171G 2D AIThe SynGAP1 missense variant A1171G (Ala→Gly at residue 1171) is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign effect, and no tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome, while Foldetta results are unavailable. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.702689 | Binding | 0.472 | 0.775 | 0.500 | -3.487 | Likely Benign | 0.286 | Likely Benign | Likely Benign | 0.141 | Likely Benign | -0.60 | Neutral | 0.245 | Benign | 0.138 | Benign | 5.38 | Benign | 0.08 | Tolerated | 0.1957 | 0.3201 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3512C>T | A1171V 2D AIThe SynGAP1 missense variant A1171V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign effect, and no tool predicts pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is likely benign; Foldetta results are not available. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.702689 | Binding | 0.472 | 0.775 | 0.500 | -3.516 | Likely Benign | 0.325 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -0.72 | Neutral | 0.245 | Benign | 0.138 | Benign | 5.34 | Benign | 0.11 | Tolerated | 0.1019 | 0.4611 | 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 | -3.78 | Deleterious | 0.036 | Benign | 0.014 | Benign | 2.85 | Benign | 0.01 | Affected | 0.1502 | 0.4995 | 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 | -3.55 | Deleterious | 0.580 | Possibly Damaging | 0.140 | Benign | 2.88 | Benign | 0.02 | Affected | 0.3341 | 0.4245 | 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 | -3.57 | Deleterious | 0.580 | Possibly Damaging | 0.140 | Benign | 2.86 | Benign | 0.02 | Affected | 3.61 | 5 | 0.3408 | 0.4594 | 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 | -4.18 | Deleterious | 0.996 | Probably Damaging | 0.750 | Possibly Damaging | 2.82 | Benign | 0.01 | Affected | 0.1598 | 0.4263 | 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 | -4.33 | Deleterious | 0.952 | Possibly Damaging | 0.521 | Possibly Damaging | 2.83 | Benign | 0.09 | Tolerated | 0.1461 | 0.2913 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.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 | -4.82 | Deleterious | 0.906 | Possibly Damaging | 0.272 | Benign | 2.83 | Benign | 0.01 | Affected | 0.2189 | 0.6478 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2728G>A | G910S 2D AIThe SynGAP1 missense variant G910S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.707319 | Binding | 0.264 | 0.917 | 0.250 | -3.195 | Likely Benign | 0.331 | Likely Benign | Likely Benign | 0.234 | Likely Benign | -1.54 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.79 | Benign | 0.06 | Tolerated | 0.2671 | 0.4492 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2728G>C | G910R 2D AIThe SynGAP1 missense variant G910R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, with no conflict with ClinVar status because no ClinVar assertion exists. Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.707319 | Binding | 0.264 | 0.917 | 0.250 | -4.566 | Likely Benign | 0.945 | Likely Pathogenic | Ambiguous | 0.235 | Likely Benign | -1.78 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.86 | Benign | 0.02 | Affected | 0.0875 | 0.4198 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2728G>T | G910C 2D AIThe SynGAP1 missense variant G910C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic) and Foldetta data are unavailable. Overall, the majority of tools (five pathogenic vs four benign) lean toward a pathogenic interpretation, and the high‑accuracy benign prediction from AlphaMissense‑Optimized does not override this trend. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.762850 | Disordered | 0.707319 | Binding | 0.264 | 0.917 | 0.250 | -6.359 | Likely Benign | 0.723 | Likely Pathogenic | Likely Benign | 0.252 | Likely Benign | -3.11 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.69 | Benign | 0.01 | Affected | 0.1179 | 0.4194 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||||||
| c.2729G>A | G910D 2D AIThe SynGAP1 missense variant G910D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are unavailable. Overall, the majority of evidence points toward a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign based on current predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.707319 | Binding | 0.264 | 0.917 | 0.250 | -4.190 | Likely Benign | 0.856 | Likely Pathogenic | Ambiguous | 0.214 | Likely Benign | -1.87 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.84 | Benign | 0.05 | Affected | 0.1642 | 0.1477 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2729G>C | G910A 2D AIThe SynGAP1 missense variant G910A is listed in ClinVar with an “Uncertain” status (ClinVar ID 2091237.0) and is present in gnomAD (6‑33443281‑G‑C). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. The remaining predictions are uncertain: AlphaMissense‑Default is inconclusive, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.707319 | Binding | 0.264 | 0.917 | 0.250 | Uncertain | 1 | 6-33443281-G-C | 1 | 6.20e-7 | -3.587 | Likely Benign | 0.361 | Ambiguous | Likely Benign | 0.209 | Likely Benign | -1.43 | Neutral | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 2.78 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.3753 | 0.4544 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||
| c.2729G>T | G910V 2D AIThe SynGAP1 missense variant G910V is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443281‑G‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of tools (five pathogenic vs. four benign) predict a pathogenic impact. This prediction does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.762850 | Disordered | 0.707319 | Binding | 0.264 | 0.917 | 0.250 | 6-33443281-G-T | 1 | 6.20e-7 | -4.362 | Likely Benign | 0.724 | Likely Pathogenic | Likely Benign | 0.237 | Likely Benign | -2.69 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.73 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1179 | 0.3662 | -3 | -1 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||
| c.2455G>A | A819T 2D AIThe SynGAP1 missense variant A819T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs 2 benign) and Foldetta data are unavailable. Overall, the majority of conventional predictors lean toward pathogenicity, but the single high‑accuracy tool predicts benign and the consensus is unresolved. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.694846 | Disordered | 0.707644 | Binding | 0.317 | 0.892 | 0.625 | -3.421 | Likely Benign | 0.675 | Likely Pathogenic | Likely Benign | 0.287 | Likely Benign | -2.23 | Neutral | 0.998 | Probably Damaging | 0.963 | Probably Damaging | 2.29 | Pathogenic | 0.01 | Affected | 0.1443 | 0.7583 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2455G>C | A819P 2D AIThe SynGAP1 missense variant A819P is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as likely pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the preponderance of evidence points to a pathogenic impact for A819P, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.694846 | Disordered | 0.707644 | Binding | 0.317 | 0.892 | 0.625 | -5.542 | Likely Benign | 0.789 | Likely Pathogenic | Ambiguous | 0.342 | Likely Benign | -3.18 | Deleterious | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.17 | Pathogenic | 0.01 | Affected | 0.1920 | 0.5753 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2455G>T | A819S 2D AIThe SynGAP1 missense variant A819S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for A819S, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.694846 | Disordered | 0.707644 | Binding | 0.317 | 0.892 | 0.625 | -3.420 | Likely Benign | 0.331 | Likely Benign | Likely Benign | 0.199 | Likely Benign | -1.49 | Neutral | 0.994 | Probably Damaging | 0.900 | Possibly Damaging | 2.33 | Pathogenic | 0.27 | Tolerated | 0.2729 | 0.6404 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2456C>A | A819E 2D AIThe SynGAP1 missense variant A819E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. In contrast, the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. ESM1b is uncertain, and no Foldetta stability assessment is available. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic, and Foldetta data are unavailable. Based on the preponderance of pathogenic predictions and the lack of any benign consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.694846 | Disordered | 0.707644 | Binding | 0.317 | 0.892 | 0.625 | -7.333 | In-Between | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.292 | Likely Benign | -2.85 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.19 | Pathogenic | 0.00 | Affected | 0.1189 | 0.2037 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2456C>G | A819G 2D AIThe SynGAP1 missense variant A819G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta results are unavailable. Overall, the majority of predictions (six benign vs three pathogenic) support a benign classification. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.694846 | Disordered | 0.707644 | Binding | 0.317 | 0.892 | 0.625 | -5.730 | Likely Benign | 0.714 | Likely Pathogenic | Likely Benign | 0.116 | Likely Benign | -2.17 | Neutral | 0.104 | Benign | 0.121 | Benign | 2.29 | Pathogenic | 0.03 | Affected | 0.2363 | 0.5396 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2456C>T | A819V 2D AIThe SynGAP1 missense variant A819V is catalogued in gnomAD (ID 6‑33443008‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas a majority of tools predict a pathogenic outcome: polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two benign vs. two pathogenic), and Foldetta stability analysis is unavailable. Overall, the balance of evidence favors a pathogenic classification for A819V, and this assessment does not contradict any ClinVar status because the variant is not yet reported in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.694846 | Disordered | 0.707644 | Binding | 0.317 | 0.892 | 0.625 | 6-33443008-C-T | 1 | 6.19e-7 | -4.944 | Likely Benign | 0.797 | Likely Pathogenic | Ambiguous | 0.246 | Likely Benign | -2.40 | Neutral | 0.998 | Probably Damaging | 0.963 | Probably Damaging | 2.19 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.1098 | 0.6664 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||
| c.3784A>C | I1262L 2D AIThe SynGAP1 missense variant I1262L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and PROVEAN, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; ESM1b remains uncertain. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (pathogenic), and PROVEAN (benign)—also indicates pathogenic. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic impact for I1262L, 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. | Coiled-coil | 0.497853 | Structured | 0.707863 | Binding | 0.886 | 0.576 | 0.125 | -7.334 | In-Between | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.269 | Likely Benign | -1.66 | Neutral | 0.981 | Probably Damaging | 0.970 | Probably Damaging | 1.94 | Pathogenic | 0.00 | Affected | 0.0735 | 0.3246 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3784A>G | I1262V 2D AIThe SynGAP1 I1262V 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, PROVEAN, and ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments are less decisive: AlphaMissense‑Optimized rates the variant as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta folding‑stability data are unavailable. Overall, the majority of standard predictors lean toward pathogenicity, but the most reliable tools provide no clear verdict. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.497853 | Structured | 0.707863 | Binding | 0.886 | 0.576 | 0.125 | -6.773 | Likely Benign | 0.814 | Likely Pathogenic | Ambiguous | 0.237 | Likely Benign | -0.82 | Neutral | 0.958 | Probably Damaging | 0.970 | Probably Damaging | 1.99 | Pathogenic | 0.00 | Affected | 0.1049 | 0.3270 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3784A>T | I1262F 2D AIThe SynGAP1 missense variant I1262F is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool in the dataset predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports that the variant is most likely pathogenic, and this conclusion is consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.497853 | Structured | 0.707863 | Binding | 0.886 | 0.576 | 0.125 | -11.343 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.515 | Likely Pathogenic | -3.32 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.81 | Pathogenic | 0.00 | Affected | 0.0532 | 0.2731 | 1 | 0 | -1.7 | 34.02 | ||||||||||||||||||||||||||||||||||||||
| c.3785T>A | I1262N 2D AIThe SynGAP1 missense variant I1262N is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools largely agree on a deleterious effect: REVEL predicts a benign outcome, whereas all other evaluated algorithms—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely pathogenic status. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus confirms a likely pathogenic classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the preponderance of computational evidence indicates that I1262N is most likely pathogenic, and this conclusion is consistent with the absence of any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.497853 | Structured | 0.707863 | Binding | 0.886 | 0.576 | 0.125 | -14.512 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.463 | Likely Benign | -5.81 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.79 | Pathogenic | 0.00 | Affected | 0.0940 | 0.0340 | -2 | -3 | -8.0 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3785T>C | I1262T 2D AIThe SynGAP1 missense variant I1262T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool in the dataset predicts a benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic status. The Foldetta stability analysis is not available for this variant. Overall, the consensus of all available predictions points to a pathogenic effect, and this conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.497853 | Structured | 0.707863 | Binding | 0.886 | 0.576 | 0.125 | -11.985 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.514 | Likely Pathogenic | -4.14 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.81 | Pathogenic | 0.00 | Affected | 0.1109 | 0.1419 | 0 | -1 | -5.2 | -12.05 | ||||||||||||||||||||||||||||||||||||||
| c.3785T>G | I1262S 2D AIThe SynGAP1 missense variant I1262S is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: 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, has no available result for this variant. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently has no entry for I1262S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.497853 | Structured | 0.707863 | Binding | 0.886 | 0.576 | 0.125 | -15.167 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.483 | Likely Benign | -4.98 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.80 | Pathogenic | 0.00 | Affected | 0.2943 | 0.1110 | -1 | -2 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||||||||||
| c.3786C>G | I1262M 2D AIThe SynGAP1 missense variant I1262M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and PROVEAN, while pathogenic predictions are made by polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus also leans 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 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 | Coiled-coil | 0.497853 | Structured | 0.707863 | Binding | 0.886 | 0.576 | 0.125 | -9.081 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.248 | Likely Benign | -2.49 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.81 | Pathogenic | 0.00 | Affected | 0.0671 | 0.2726 | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3418A>C | T1140P 2D AIThe SynGAP1 missense variant T1140P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for T1140P, and this conclusion is consistent with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.926919 | Disordered | 0.708094 | Binding | 0.293 | 0.854 | 1.000 | -1.921 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -1.49 | Neutral | 0.761 | Possibly Damaging | 0.478 | Possibly Damaging | 2.61 | Benign | 0.32 | Tolerated | 0.2044 | 0.3837 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3418A>G | T1140A 2D AIThe SynGAP1 missense variant T1140A 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 | 0.926919 | Disordered | 0.708094 | Binding | 0.293 | 0.854 | 1.000 | -3.838 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -0.36 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.71 | Benign | 1.00 | Tolerated | 0.3949 | 0.3463 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3418A>T | T1140S 2D AIThe SynGAP1 missense variant T1140S is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population evidence. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.926919 | Disordered | 0.708094 | Binding | 0.293 | 0.854 | 1.000 | -2.805 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.052 | Likely Benign | -0.27 | Neutral | 0.025 | Benign | 0.010 | Benign | 3.25 | Benign | 0.91 | Tolerated | 0.3401 | 0.3504 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3419C>A | T1140K 2D AIThe SynGAP1 missense variant T1140K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The 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—including the high‑accuracy consensus—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 | 0.926919 | Disordered | 0.708094 | Binding | 0.293 | 0.854 | 1.000 | -4.053 | Likely Benign | 0.657 | Likely Pathogenic | Likely Benign | 0.068 | Likely Benign | -1.65 | Neutral | 0.611 | Possibly Damaging | 0.257 | Benign | 2.63 | Benign | 0.22 | Tolerated | 0.1196 | 0.2950 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||||
| c.3419C>G | T1140R 2D AIThe SynGAP1 missense variant T1140R is listed in gnomAD (ID 6‑33444454‑C‑G) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.926919 | Disordered | 0.708094 | Binding | 0.293 | 0.854 | 1.000 | 6-33444454-C-G | 1 | 6.20e-7 | -4.245 | Likely Benign | 0.682 | Likely Pathogenic | Likely Benign | 0.073 | Likely Benign | -1.69 | Neutral | 0.761 | Possibly Damaging | 0.398 | Benign | 2.61 | Benign | 0.15 | Tolerated | 4.32 | 4 | 0.0997 | 0.2442 | -1 | -1 | -3.8 | 55.08 | ||||||||||||||||||||||||||||||||||
| c.3419C>T | T1140I 2D AIThe SynGAP1 missense variant T1140I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports it as likely benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, and AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods indicates that the variant is most likely benign, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.926919 | Disordered | 0.708094 | Binding | 0.293 | 0.854 | 1.000 | -5.205 | Likely Benign | 0.368 | Ambiguous | Likely Benign | 0.058 | Likely Benign | -1.85 | Neutral | 0.611 | Possibly Damaging | 0.398 | Benign | 2.61 | Benign | 0.08 | Tolerated | 0.0948 | 0.4648 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.2350G>A | A784T 2D AIThe SynGAP1 missense variant A784T is listed in ClinVar (ID 962668.0) as Benign and is not reported in gnomAD. Across the available in‑silico predictors, every tool examined—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classifies the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized reports a benign effect, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. A Foldetta stability analysis is unavailable, so it does not influence the overall interpretation. Based on the unanimous benign predictions and the ClinVar designation, the variant is most likely benign, with no contradiction to the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.801317 | Disordered | 0.708872 | Binding | 0.314 | 0.896 | 0.625 | Benign | 1 | -3.579 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.046 | Likely Benign | 1.23 | Neutral | 0.001 | Benign | 0.006 | Benign | 2.92 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1493 | 0.6659 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.2350G>C | A784P 2D AIThe SynGAP1 missense variant A784P is reported in gnomAD (variant ID 6-33442902‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods points to a benign impact for A784P. This conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.801317 | Disordered | 0.708872 | Binding | 0.314 | 0.896 | 0.625 | 6-33442902-G-C | 4 | 2.48e-6 | -3.777 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.189 | Likely Benign | -0.73 | Neutral | 0.586 | Possibly Damaging | 0.396 | Benign | 2.66 | Benign | 0.19 | Tolerated | 3.64 | 6 | 0.1846 | 0.4771 | -1 | 1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||||||
| c.2350G>T | A784S 2D AIThe SynGAP1 missense variant A784S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess sequence conservation and structural impact uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the collective evidence strongly supports a benign classification, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.801317 | Disordered | 0.708872 | Binding | 0.314 | 0.896 | 0.625 | -2.233 | Likely Benign | 0.094 | Likely Benign | Likely Benign | 0.027 | Likely Benign | 0.41 | Neutral | 0.004 | Benign | 0.010 | Benign | 2.72 | Benign | 0.67 | Tolerated | 0.2624 | 0.5171 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2351C>A | A784D 2D AIThe SynGAP1 missense variant A784D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.801317 | Disordered | 0.708872 | Binding | 0.314 | 0.896 | 0.625 | -3.784 | Likely Benign | 0.766 | Likely Pathogenic | Likely Benign | 0.206 | Likely Benign | -1.21 | Neutral | 0.411 | Benign | 0.237 | Benign | 2.68 | Benign | 0.16 | Tolerated | 0.1824 | 0.2193 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2351C>G | A784G 2D AIThe SynGAP1 missense variant A784G is reported in gnomAD (ID 6‑33442903‑C‑G) and has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are unavailable. Overall, the evidence strongly suggests 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 | 0.801317 | Disordered | 0.708872 | Binding | 0.314 | 0.896 | 0.625 | 6-33442903-C-G | 1 | 6.20e-7 | -3.370 | Likely Benign | 0.158 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -1.24 | Neutral | 0.224 | Benign | 0.138 | Benign | 2.67 | Benign | 0.26 | Tolerated | 3.64 | 6 | 0.2303 | 0.4418 | 0 | 1 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.2351C>T | A784V 2D AIThe SynGAP1 missense variant A784V is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess sequence conservation and structural impact uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the collective evidence strongly supports a benign classification, and this conclusion is consistent with the lack of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.801317 | Disordered | 0.708872 | Binding | 0.314 | 0.896 | 0.625 | -3.901 | Likely Benign | 0.205 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -0.97 | Neutral | 0.126 | Benign | 0.138 | Benign | 2.72 | Benign | 0.26 | Tolerated | 0.1150 | 0.5803 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| 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 | -2.17 | Neutral | 0.287 | Benign | 0.038 | Benign | 3.91 | Benign | 0.01 | Affected | 0.3561 | 0.3037 | -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 | -2.98 | Deleterious | 0.989 | Probably Damaging | 0.420 | Benign | 3.88 | Benign | 0.00 | Affected | 0.1583 | 0.3005 | 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 | -1.04 | Neutral | 0.006 | Benign | 0.001 | Benign | 4.04 | Benign | 0.02 | Affected | 3.74 | 4 | 0.3018 | 0.2852 | 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 | -2.25 | Neutral | 0.748 | Possibly Damaging | 0.110 | Benign | 3.92 | Benign | 0.01 | Affected | 0.2295 | 0.3741 | 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 | -2.02 | Neutral | 0.080 | Benign | 0.012 | Benign | 3.92 | Benign | 0.01 | Affected | 0.1965 | 0.3834 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| 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 | -2.20 | Neutral | 0.160 | Benign | 0.045 | Benign | 3.95 | Benign | 0.00 | Affected | 0.2569 | 0.2418 | 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 | -2.27 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.01 | Benign | 0.00 | Affected | 0.2780 | 0.3399 | 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 | -2.47 | Neutral | 0.160 | Benign | 0.045 | Benign | 3.98 | Benign | 0.00 | Affected | 0.2496 | 0.2646 | -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 | -1.29 | Neutral | 0.851 | Possibly Damaging | 0.221 | Benign | 3.90 | Benign | 0.00 | Affected | 0.1631 | 0.1907 | 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 | -2.46 | Neutral | 0.160 | Benign | 0.045 | Benign | 3.96 | Benign | 0.00 | Affected | 0.4833 | 0.0000 | -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 | -3.19 | Deleterious | 0.952 | Possibly Damaging | 0.570 | Possibly Damaging | 3.88 | Benign | 0.00 | Affected | 0.2682 | 0.1270 | -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 | -2.27 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.01 | Benign | 0.00 | Affected | 0.2780 | 0.3399 | 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 | -2.27 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.01 | Benign | 0.00 | Affected | 0.2780 | 0.3399 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| 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 | -0.96 | Neutral | 0.952 | Possibly Damaging | 0.500 | Possibly Damaging | 4.19 | Benign | 0.35 | Tolerated | 3.74 | 4 | 0.2023 | 0.4053 | -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 | -0.64 | Neutral | 0.580 | Possibly Damaging | 0.140 | Benign | 4.21 | Benign | 0.75 | Tolerated | 0.3890 | 0.3353 | 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 | -1.35 | Neutral | 0.734 | Possibly Damaging | 0.243 | Benign | 4.20 | Benign | 0.24 | Tolerated | 3.74 | 4 | 0.3893 | 0.3697 | -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 | -1.90 | Neutral | 0.996 | Probably Damaging | 0.750 | Possibly Damaging | 4.14 | Benign | 0.03 | Affected | 0.2207 | 0.3414 | 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 | -1.76 | Neutral | 0.984 | Probably Damaging | 0.601 | Possibly Damaging | 4.19 | Benign | 0.08 | Tolerated | 0.1810 | 0.2401 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.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 | -0.47 | Neutral | 0.952 | Possibly Damaging | 0.500 | Possibly Damaging | 4.20 | Benign | 0.38 | Tolerated | 3.74 | 4 | 0.2548 | 0.5137 | -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 | 0.12 | Neutral | 0.016 | Benign | 0.021 | Benign | 4.14 | Benign | 0.85 | Tolerated | 0.1251 | 0.5794 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.385T>C | S129P 2D AIThe SynGAP1 missense variant S129P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of tools, including the high‑accuracy predictors, indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.713635 | Binding | 0.311 | 0.880 | 0.625 | -2.469 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.220 | Likely Benign | -0.09 | Neutral | 0.454 | Possibly Damaging | 0.133 | Benign | 4.11 | Benign | 0.32 | Tolerated | 0.1998 | 0.4989 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.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 | -0.08 | Neutral | 0.007 | Benign | 0.007 | Benign | 4.21 | Benign | 0.15 | Tolerated | 0.5031 | 0.4619 | Weaken | 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 | -1.49 | Neutral | 0.888 | Possibly Damaging | 0.367 | Benign | 4.06 | Benign | 0.01 | Affected | 0.0523 | 0.5471 | -2 | -3 | -0.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.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 | -0.18 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.14 | Benign | 0.05 | Affected | 3.74 | 4 | 0.0885 | 0.5249 | -2 | -3 | 4.6 | 26.08 | ||||||||||||||||||||||||||||||||||
| c.2452C>A | P818T 2D AIThe SynGAP1 missense variant P818T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default all classify the variant as damaging. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Based on the preponderance of pathogenic predictions and the SGM‑Consensus outcome, the variant is most likely pathogenic; this conclusion is not contradicted by any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.599170 | Disordered | 0.715889 | Binding | 0.371 | 0.893 | 0.625 | -6.864 | Likely Benign | 0.936 | Likely Pathogenic | Ambiguous | 0.265 | Likely Benign | -4.58 | Deleterious | 0.994 | Probably Damaging | 0.927 | Probably Damaging | 2.01 | Pathogenic | 0.02 | Affected | 0.1797 | 0.6453 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2452C>G | P818A 2D AIThe SynGAP1 missense variant P818A 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 HumVar, SIFT, and ESM1b, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, FATHMM, 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 preponderance of evidence from both consensus and high‑accuracy tools indicates that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.599170 | Disordered | 0.715889 | Binding | 0.371 | 0.893 | 0.625 | -6.084 | Likely Benign | 0.820 | Likely Pathogenic | Ambiguous | 0.157 | Likely Benign | -4.37 | Deleterious | 0.543 | Possibly Damaging | 0.306 | Benign | 2.15 | Pathogenic | 0.06 | Tolerated | 0.3574 | 0.5724 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2452C>T | P818S 2D AIThe SynGAP1 missense variant P818S is catalogued in gnomAD (ID 6‑33443004‑C‑T) but has no ClinVar entry. Functional prediction tools split in two groups: benign calls come from REVEL and ESM1b, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The consensus predictor SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments are limited: AlphaMissense‑Optimized yields an uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available prediction for this residue. Taken together, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar status because none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.599170 | Disordered | 0.715889 | Binding | 0.371 | 0.893 | 0.625 | 6-33443004-C-T | 1 | 6.20e-7 | -5.740 | Likely Benign | 0.932 | Likely Pathogenic | Ambiguous | 0.203 | Likely Benign | -4.38 | Deleterious | 0.989 | Probably Damaging | 0.824 | Possibly Damaging | 2.04 | Pathogenic | 0.04 | Affected | 3.77 | 5 | 0.3581 | 0.6199 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.2453C>A | P818Q 2D AIThe SynGAP1 missense variant P818Q is not listed in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools that agree on a benign effect include REVEL, SIFT, and ESM1b, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that P818Q 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 | 0.599170 | Disordered | 0.715889 | Binding | 0.371 | 0.893 | 0.625 | -6.855 | Likely Benign | 0.969 | Likely Pathogenic | Likely Pathogenic | 0.303 | Likely Benign | -4.07 | Deleterious | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 1.97 | Pathogenic | 0.27 | Tolerated | 0.1569 | 0.5456 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2453C>G | P818R 2D AIThe SynGAP1 missense variant P818R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated predictors—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. ESM1b is uncertain and does not contribute to a consensus. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Pathogenic” designation. AlphaMissense‑Optimized independently predicts pathogenicity, while Foldetta results are unavailable. Based on the preponderance of pathogenic predictions and the SGM consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.599170 | Disordered | 0.715889 | Binding | 0.371 | 0.893 | 0.625 | -7.267 | In-Between | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.374 | Likely Benign | -5.12 | Deleterious | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 1.97 | Pathogenic | 0.03 | Affected | 0.1499 | 0.4547 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2453C>T | P818L 2D AIThe SynGAP1 missense variant P818L is catalogued in gnomAD (ID 6‑33443005‑C‑T) but has no ClinVar entry. Functional prediction tools fall into two consensus groups: benign predictions come from REVEL and ESM1b, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). AlphaMissense‑Optimized returns an uncertain result. High‑accuracy assessments are limited: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus indicates “Likely Pathogenic,” and Foldetta data are unavailable. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Thus, the variant is most likely pathogenic based on current predictive tools. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.599170 | Disordered | 0.715889 | Binding | 0.371 | 0.893 | 0.625 | 6-33443005-C-T | 1 | 6.20e-7 | -6.064 | Likely Benign | 0.938 | Likely Pathogenic | Ambiguous | 0.285 | Likely Benign | -5.81 | Deleterious | 0.997 | Probably Damaging | 0.954 | Probably Damaging | 1.98 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.2351 | 0.6951 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| c.3421C>A | P1141T 2D AIThe SynGAP1 missense variant P1141T is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD: not present). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs. two pathogenic). High‑accuracy methods give AlphaMissense‑Optimized a benign prediction; the SGM Consensus remains inconclusive, and Foldetta (combining FoldX‑MD and Rosetta) has no available result. Overall, the balance of evidence, particularly the benign call from the high‑accuracy AlphaMissense‑Optimized model, suggests that the variant is most likely benign, and this assessment does not contradict the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.930790 | Disordered | 0.716087 | Binding | 0.364 | 0.852 | 1.000 | -4.090 | Likely Benign | 0.176 | Likely Benign | Likely Benign | 0.106 | Likely Benign | -3.85 | Deleterious | 0.856 | Possibly Damaging | 0.723 | Possibly Damaging | 0.98 | Pathogenic | 0.00 | Affected | 0.1594 | 0.6145 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||||||
| c.3421C>G | P1141A 2D AIThe SynGAP1 missense variant P1141A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it yields a 2‑to‑2 split. Foldetta, a protein‑folding‑stability method that combines FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools therefore provide mixed evidence: AlphaMissense‑Optimized indicates benign, while the consensus and stability analyses are unavailable. Overall, the majority of individual predictors (five versus four) favor a pathogenic interpretation, and this does not contradict any ClinVar annotation because 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. | 0.930790 | Disordered | 0.716087 | Binding | 0.364 | 0.852 | 1.000 | -3.885 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -3.67 | Deleterious | 0.856 | Possibly Damaging | 0.492 | Possibly Damaging | 1.00 | Pathogenic | 0.00 | Affected | 0.3525 | 0.5135 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3421C>T | P1141S 2D AIThe SynGAP1 missense variant P1141S is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic). Foldetta results are unavailable. Overall, five of the nine evaluated tools predict pathogenicity while four predict benignity, giving a slight majority toward a deleterious effect. Thus, the variant is most likely pathogenic based on current computational predictions, and this assessment does not contradict any ClinVar status because the variant has not yet been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.930790 | Disordered | 0.716087 | Binding | 0.364 | 0.852 | 1.000 | -2.574 | Likely Benign | 0.187 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -3.58 | Deleterious | 0.856 | Possibly Damaging | 0.492 | Possibly Damaging | 0.99 | Pathogenic | 0.00 | Affected | 0.3379 | 0.5566 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3422C>A | P1141Q 2D AIThe SynGAP1 missense variant P1141Q is not 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.930790 | Disordered | 0.716087 | Binding | 0.364 | 0.852 | 1.000 | -4.331 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -2.72 | Deleterious | 0.074 | Benign | 0.047 | Benign | 0.97 | Pathogenic | 0.00 | Affected | 0.1449 | 0.5186 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||||||
| c.3422C>G | P1141R 2D AIThe SynGAP1 missense variant P1141R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus indicates a likely pathogenic outcome; a Foldetta stability analysis is unavailable. Overall, the majority of computational predictions (seven pathogenic vs. three benign) support a pathogenic classification. This consensus does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.930790 | Disordered | 0.716087 | Binding | 0.364 | 0.852 | 1.000 | -4.768 | Likely Benign | 0.626 | Likely Pathogenic | Likely Benign | 0.120 | Likely Benign | -3.90 | Deleterious | 0.913 | Possibly Damaging | 0.690 | Possibly Damaging | 0.97 | Pathogenic | 0.00 | Affected | 0.1329 | 0.3614 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3422C>T | P1141L 2D AIThe SynGAP1 missense variant P1141L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans pathogenic (two pathogenic versus one benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy tools indicates that P1141L 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. | 0.930790 | Disordered | 0.716087 | Binding | 0.364 | 0.852 | 1.000 | -3.817 | Likely Benign | 0.352 | Ambiguous | Likely Benign | 0.110 | Likely Benign | -4.64 | Deleterious | 0.954 | Possibly Damaging | 0.759 | Possibly Damaging | 0.98 | Pathogenic | 0.00 | Affected | 0.2147 | 0.6099 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||||||
| 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 | -0.77 | Neutral | 0.877 | Possibly Damaging | 0.580 | Possibly Damaging | 3.57 | Benign | 0.03 | Affected | 0.0856 | 0.2229 | 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 | -1.27 | Neutral | 0.247 | Benign | 0.163 | Benign | 3.61 | Benign | 0.03 | Affected | 0.1561 | 0.1883 | 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 | -2.65 | Deleterious | 0.535 | Possibly Damaging | 0.259 | Benign | 3.53 | Benign | 0.01 | Affected | 0.1316 | 0.0879 | -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 | -3.16 | Deleterious | 0.700 | Possibly Damaging | 0.483 | Possibly Damaging | 3.52 | Benign | 0.00 | Affected | 0.3270 | 0.1048 | -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 | -2.57 | Deleterious | 0.002 | Benign | 0.005 | Benign | 3.55 | Benign | 0.00 | Affected | 0.1522 | 0.0479 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| 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 | -0.41 | Neutral | 0.924 | Possibly Damaging | 0.857 | Possibly Damaging | 4.20 | Benign | 0.07 | Tolerated | 0.2017 | 0.4473 | 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 | -0.72 | Neutral | 0.924 | Possibly Damaging | 0.857 | Possibly Damaging | 4.19 | Benign | 0.08 | Tolerated | 4.32 | 2 | 0.1620 | 0.2587 | 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 | -0.10 | Neutral | 0.990 | Probably Damaging | 0.954 | Probably Damaging | 4.15 | Benign | 0.03 | Affected | 0.2414 | 0.4466 | 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 | -0.32 | Neutral | 0.967 | Probably Damaging | 0.901 | Possibly Damaging | 4.21 | Benign | 0.05 | Affected | 0.1697 | 0.2343 | 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 | -1.63 | Neutral | 0.967 | Probably Damaging | 0.901 | Possibly Damaging | 4.11 | Benign | 0.02 | Affected | 0.0975 | 0.5286 | -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 | -1.09 | Neutral | 0.990 | Probably Damaging | 0.969 | Probably Damaging | 4.10 | Benign | 0.01 | Affected | 0.1727 | 0.3970 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.390A>T | Q130H 2D AIThe SynGAP1 missense variant Q130H is not reported in ClinVar and has no entry in gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT each predict a pathogenic impact. The AlphaMissense‑Default tool remains uncertain, and no Foldetta stability assessment is available. High‑accuracy tools specifically highlight benign predictions: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta data are missing. Overall, the balance of evidence points to a benign effect for the variant, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.718853 | Binding | 0.306 | 0.885 | 0.375 | -3.828 | Likely Benign | 0.387 | Ambiguous | Likely Benign | 0.074 | Likely Benign | -1.09 | Neutral | 0.990 | Probably Damaging | 0.969 | Probably Damaging | 4.10 | Benign | 0.01 | Affected | 0.1727 | 0.3970 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3508A>C | S1170R 2D AIThe SynGAP1 missense variant S1170R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the majority of conventional predictors lean toward pathogenicity, but the high‑accuracy consensus is split. Thus, the variant is most likely pathogenic based on the preponderance of predictions, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.622677 | Disordered | 0.719138 | Binding | 0.417 | 0.767 | 0.500 | -1.451 | Likely Benign | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.475 | Likely Benign | -1.89 | Neutral | 0.998 | Probably Damaging | 0.966 | Probably Damaging | 5.39 | Benign | 0.04 | Affected | 0.0770 | 0.3444 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3508A>G | S1170G 2D AIThe SynGAP1 missense variant S1170G is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on benign impact include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.622677 | Disordered | 0.719138 | Binding | 0.417 | 0.767 | 0.500 | Uncertain | 1 | -4.288 | Likely Benign | 0.221 | Likely Benign | Likely Benign | 0.349 | Likely Benign | -0.81 | Neutral | 0.241 | Benign | 0.229 | Benign | 5.31 | Benign | 0.54 | Tolerated | 4.32 | 4 | 0.2705 | 0.4558 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||
| c.3508A>T | S1170C 2D AIThe S1170C missense change occurs in a coiled‑coil region of SynGAP1. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect include PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized; those that predict a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” status. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign, while Foldetta results are unavailable. Overall, the balance of evidence, particularly from the high‑accuracy tools, points to a benign impact for S1170C. This conclusion is not contradicted by ClinVar, which currently contains no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.622677 | Disordered | 0.719138 | Binding | 0.417 | 0.767 | 0.500 | -6.393 | Likely Benign | 0.416 | Ambiguous | Likely Benign | 0.566 | Likely Pathogenic | -2.07 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 5.30 | Benign | 0.02 | Affected | 0.0872 | 0.5850 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||
| c.3509G>A | S1170N 2D AIThe SynGAP1 missense variant S1170N is reported in gnomAD (6‑33444544‑G‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. AlphaMissense‑Default is uncertain, and no Foldetta stability assessment is available. High‑accuracy predictions from AlphaMissense‑Optimized and the SGM‑Consensus both indicate a benign outcome, while the absence of a Foldetta result leaves that aspect unresolved. Overall, the majority of evidence points to a benign effect for S1170N, and this conclusion is not contradicted by any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.622677 | Disordered | 0.719138 | Binding | 0.417 | 0.767 | 0.500 | 6-33444544-G-A | 1 | 6.20e-7 | -3.705 | Likely Benign | 0.413 | Ambiguous | Likely Benign | 0.342 | Likely Benign | -0.18 | Neutral | 0.992 | Probably Damaging | 0.925 | Probably Damaging | 5.39 | Benign | 0.86 | Tolerated | 4.32 | 4 | 0.1132 | 0.4238 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||
| c.3509G>C | S1170T 2D AIThe SynGAP1 missense variant S1170T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates “Likely Benign.” In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for S1170T, and this conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.622677 | Disordered | 0.719138 | Binding | 0.417 | 0.767 | 0.500 | -3.771 | Likely Benign | 0.163 | Likely Benign | Likely Benign | 0.338 | Likely Benign | -1.13 | Neutral | 0.992 | Probably Damaging | 0.925 | Probably Damaging | 5.37 | Benign | 0.08 | Tolerated | 0.1258 | 0.5897 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3509G>T | S1170I 2D AIThe SynGAP1 missense variant S1170I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote) also predicts benign, and the Foldetta protein‑folding stability analysis is unavailable. Taken together, the preponderance of high‑confidence predictions indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.622677 | Disordered | 0.719138 | Binding | 0.417 | 0.767 | 0.500 | -3.813 | Likely Benign | 0.635 | Likely Pathogenic | Likely Benign | 0.600 | Likely Pathogenic | -2.16 | Neutral | 0.998 | Probably Damaging | 0.990 | Probably Damaging | 5.29 | Benign | 0.01 | Affected | 0.0754 | 0.5329 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||
| c.3510T>A | S1170R 2D AIThe SynGAP1 missense variant S1170R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, whereas tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of individual predictors lean toward pathogenicity, with the SGM‑Consensus providing a counter‑signal; the evidence is therefore inconclusive. The variant is most likely pathogenic according to the prevailing predictions, and this does not contradict ClinVar status, which has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.622677 | Disordered | 0.719138 | Binding | 0.417 | 0.767 | 0.500 | -1.451 | Likely Benign | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.452 | Likely Benign | -1.89 | Neutral | 0.998 | Probably Damaging | 0.966 | Probably Damaging | 5.39 | Benign | 0.04 | Affected | 0.0770 | 0.3444 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3510T>G | S1170R 2D AIThe SynGAP1 missense variant S1170R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized model classifies the variant as pathogenic, whereas the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of conventional predictors lean toward pathogenicity, and the most accurate tools also favor a pathogenic classification, with no conflict from ClinVar or gnomAD data. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.622677 | Disordered | 0.719138 | Binding | 0.417 | 0.767 | 0.500 | -1.451 | Likely Benign | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.452 | Likely Benign | -1.89 | Neutral | 0.998 | Probably Damaging | 0.966 | Probably Damaging | 5.39 | Benign | 0.04 | Affected | 0.0770 | 0.3444 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3424T>A | S1142T 2D AIThe SynGAP1 missense variant S1142T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.719935 | Binding | 0.276 | 0.844 | 1.000 | -3.712 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.106 | Likely Benign | -1.63 | Neutral | 0.611 | Possibly Damaging | 0.324 | Benign | 2.69 | Benign | 0.00 | Affected | 0.1548 | 0.6427 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3424T>C | S1142P 2D AIThe SynGAP1 missense variant S1142P is listed in ClinVar (ID 2747352.0) as Benign and is present in gnomAD (variant ID 6‑33444459‑T‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar classification and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.719935 | Binding | 0.276 | 0.844 | 1.000 | Likely Benign | 1 | 6-33444459-T-C | 1 | 6.20e-7 | -2.713 | Likely Benign | 0.222 | Likely Benign | Likely Benign | 0.107 | Likely Benign | -2.19 | Neutral | 0.918 | Possibly Damaging | 0.761 | Possibly Damaging | 2.64 | Benign | 0.00 | Affected | 4.32 | 4 | 0.2080 | 0.5618 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||
| c.3424T>G | S1142A 2D AIThe SynGAP1 missense variant S1142A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it to be pathogenic. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) confirms a 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 indicates that S1142A is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.719935 | Binding | 0.276 | 0.844 | 1.000 | -3.694 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -1.31 | Neutral | 0.002 | Benign | 0.015 | Benign | 2.73 | Benign | 0.00 | Affected | 0.4689 | 0.5319 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3425C>A | S1142Y 2D  AIThe SynGAP1 missense variant S1142Y is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta results are unavailable. Overall, the majority of conventional predictors lean toward pathogenicity, but the single high‑accuracy benign prediction and the inconclusive consensus temper this view. Thus, the variant is most likely pathogenic based on the current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.919029 | Disordered | 0.719935 | Binding | 0.276 | 0.844 | 1.000 | -6.146 | Likely Benign | 0.569 | Likely Pathogenic | Likely Benign | 0.200 | Likely Benign | -3.39 | Deleterious | 0.971 | Probably Damaging | 0.876 | Possibly Damaging | 2.64 | Benign | 0.00 | Affected | 0.0849 | 0.5429 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||||||
| c.3425C>G | S1142C 2D AIThe SynGAP1 missense variant S1142C is not 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, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields benign, and Foldetta data are unavailable. Consequently, the variant is most likely benign based on the collective evidence, and this conclusion does not conflict with any ClinVar annotation because no ClinVar entry exists for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.919029 | Disordered | 0.719935 | Binding | 0.276 | 0.844 | 1.000 | -7.355 | In-Between | 0.182 | Likely Benign | Likely Benign | 0.146 | Likely Benign | -2.89 | Deleterious | 0.992 | Probably Damaging | 0.866 | Possibly Damaging | 2.70 | Benign | 0.00 | Affected | 0.1170 | 0.6016 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3425C>T | S1142F 2D  AIThe SynGAP1 missense variant S1142F has no ClinVar record and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority, and Foldetta data are unavailable. Overall, the balance of evidence—especially from the high‑accuracy tools—suggests that the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.919029 | Disordered | 0.719935 | Binding | 0.276 | 0.844 | 1.000 | -5.074 | Likely Benign | 0.508 | Ambiguous | Likely Benign | 0.206 | Likely Benign | -3.70 | Deleterious | 0.918 | Possibly Damaging | 0.827 | Possibly Damaging | 2.65 | Benign | 0.00 | Affected | 0.0861 | 0.5603 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||||
| c.3415C>A | Q1139K 2D AIThe SynGAP1 missense variant Q1139K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.721191 | Binding | 0.313 | 0.866 | 1.000 | -4.768 | Likely Benign | 0.222 | Likely Benign | Likely Benign | 0.253 | Likely Benign | -1.70 | Neutral | 0.004 | Benign | 0.006 | Benign | 5.44 | Benign | 0.00 | Affected | 0.1667 | 0.4139 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3415C>G | Q1139E 2D AIThe SynGAP1 missense variant Q1139E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign or likely benign outcome, whereas only SIFT classifies it as pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign. Foldetta, a protein‑folding stability method, 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 lack of ClinVar evidence for pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.721191 | Binding | 0.313 | 0.866 | 1.000 | -3.065 | Likely Benign | 0.204 | Likely Benign | Likely Benign | 0.285 | Likely Benign | -1.34 | Neutral | 0.112 | Benign | 0.089 | Benign | 5.36 | Benign | 0.00 | Affected | 0.1360 | 0.2269 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3416A>C | Q1139P 2D AIThe SynGAP1 missense variant Q1139P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 HumDiv and SIFT predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.721191 | Binding | 0.313 | 0.866 | 1.000 | -3.753 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.437 | Likely Benign | -1.74 | Neutral | 0.812 | Possibly Damaging | 0.396 | Benign | 5.28 | Benign | 0.00 | Affected | 0.2199 | 0.5349 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3416A>G | Q1139R 2D AIThe SynGAP1 missense variant Q1139R is not reported in ClinVar (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), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar annotation—there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.721191 | Binding | 0.313 | 0.866 | 1.000 | -4.249 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.315 | Likely Benign | -1.91 | Neutral | 0.126 | Benign | 0.138 | Benign | 5.47 | Benign | 0.00 | Affected | 0.1342 | 0.2405 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.3416A>T | Q1139L 2D AIThe SynGAP1 missense variant Q1139L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, PROVEAN and SIFT predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.721191 | Binding | 0.313 | 0.866 | 1.000 | -1.689 | Likely Benign | 0.153 | Likely Benign | Likely Benign | 0.472 | Likely Benign | -3.75 | Deleterious | 0.224 | Benign | 0.237 | Benign | 5.30 | Benign | 0.00 | Affected | 0.0745 | 0.5599 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3417G>C | Q1139H 2D AIThe SynGAP1 missense variant Q1139H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.721191 | Binding | 0.313 | 0.866 | 1.000 | -3.962 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.265 | Likely Benign | -2.40 | Neutral | 0.002 | Benign | 0.007 | Benign | 5.41 | Benign | 0.00 | Affected | 0.1313 | 0.3801 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3417G>T | Q1139H 2D AIThe SynGAP1 missense variant Q1139H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the preponderance of benign predictions and the lack of contradictory evidence, the variant is most likely benign. This assessment does not conflict with ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.721191 | Binding | 0.313 | 0.866 | 1.000 | -3.962 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.265 | Likely Benign | -2.40 | Neutral | 0.002 | Benign | 0.007 | Benign | 5.41 | Benign | 0.00 | Affected | 0.1313 | 0.3801 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3433A>C | N1145H 2D  AIThe SynGAP1 missense variant N1145H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while polyPhen‑2 (HumDiv and HumVar) and SIFT predict pathogenic. Grouping by consensus, the benign‑predicting tools outnumber the pathogenic ones. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized scores benign, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a likely benign outcome. Foldetta results are unavailable. Overall, the computational evidence supports a benign classification for the variant, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.722723 | Binding | 0.284 | 0.850 | 1.000 | -2.974 | Likely Benign | 0.187 | Likely Benign | Likely Benign | 0.391 | Likely Benign | -2.42 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 5.41 | Benign | 0.02 | Affected | 0.1520 | 0.7233 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3433A>G | N1145D 2D  AIThe SynGAP1 missense variant N1145D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.722723 | Binding | 0.284 | 0.850 | 1.000 | -3.053 | Likely Benign | 0.682 | Likely Pathogenic | Likely Benign | 0.332 | Likely Benign | -2.04 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 5.57 | Benign | 0.08 | Tolerated | 0.2082 | 0.3956 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3433A>T | N1145Y 2D  AIThe SynGAP1 missense variant N1145Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include ESM1b, FATHMM, and AlphaMissense‑Optimized, whereas REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT uniformly predict a pathogenic impact. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields benign, while Foldetta results are unavailable. Overall, the majority of conventional tools predict pathogenicity, but the high‑accuracy consensus leans benign. 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. | 0.922952 | Disordered | 0.722723 | Binding | 0.284 | 0.850 | 1.000 | -2.945 | Likely Benign | 0.451 | Ambiguous | Likely Benign | 0.543 | Likely Pathogenic | -4.07 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 5.40 | Benign | 0.01 | Affected | 0.0622 | 0.6337 | -2 | -2 | 2.2 | 49.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3434A>C | N1145T 2D  AIThe SynGAP1 missense variant N1145T is reported in gnomAD (ID 6‑33444469‑A‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) predict the variant to be pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta’s protein‑folding stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact for N1145T, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.722723 | Binding | 0.284 | 0.850 | 1.000 | 6-33444469-A-C | 1 | 6.20e-7 | -1.915 | Likely Benign | 0.217 | Likely Benign | Likely Benign | 0.403 | Likely Benign | -2.17 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 5.45 | Benign | 0.07 | Tolerated | 4.32 | 4 | 0.1418 | 0.7209 | 0 | 0 | 2.8 | -13.00 | ||||||||||||||||||||||||||||||||||
| c.3434A>G | N1145S 2D  AIThe SynGAP1 missense variant N1145S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33444469‑A‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, PolyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.722723 | Binding | 0.284 | 0.850 | 1.000 | Uncertain | 1 | 6-33444469-A-G | 2 | 1.24e-6 | -0.989 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.308 | Likely Benign | -1.15 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 5.55 | Benign | 0.89 | Tolerated | 4.32 | 4 | 0.4078 | 0.6708 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||||||||
| c.3434A>T | N1145I 2D  AIThe SynGAP1 missense variant N1145I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools cluster into two groups: pathogenic predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; benign predictions come from ESM1b, FATHMM, and AlphaMissense‑Optimized. AlphaMissense‑Default is uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, while Foldetta results are unavailable. Overall, the majority of conventional predictors indicate pathogenicity, whereas the high‑accuracy subset leans benign. Based on the aggregate evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.922952 | Disordered | 0.722723 | Binding | 0.284 | 0.850 | 1.000 | -3.172 | Likely Benign | 0.378 | Ambiguous | Likely Benign | 0.504 | Likely Pathogenic | -4.19 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 5.41 | Benign | 0.00 | Affected | 0.0720 | 0.6145 | -2 | -3 | 8.0 | -0.94 | ||||||||||||||||||||||||||||||||||||||||
| c.3435C>A | N1145K 2D  AIThe SynGAP1 missense variant N1145K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.722723 | Binding | 0.284 | 0.850 | 1.000 | -2.545 | Likely Benign | 0.814 | Likely Pathogenic | Ambiguous | 0.440 | Likely Benign | -2.40 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.50 | Benign | 0.03 | Affected | 0.1959 | 0.6018 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3435C>G | N1145K 2D AIThe SynGAP1 missense variant N1145K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which collectively suggest a likely benign impact. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and Foldetta stability analysis is unavailable. Overall, the balance of evidence leans toward a benign interpretation, with no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.722723 | Binding | 0.284 | 0.850 | 1.000 | -2.545 | Likely Benign | 0.814 | Likely Pathogenic | Ambiguous | 0.440 | Likely Benign | -2.40 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.50 | Benign | 0.03 | Affected | 0.1959 | 0.6018 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2257G>A | A753T 2D AIThe SynGAP1 missense variant A753T is catalogued in gnomAD (ID 6‑33441722‑G‑A) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool listed—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classifies the change as benign. No pathogenic predictions are reported. Grouping by agreement, all available tools fall into the benign category, with no tools indicating pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status remains unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.722781 | Binding | 0.381 | 0.873 | 0.625 | 6-33441722-G-A | 2 | 1.24e-6 | -4.298 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -0.42 | Neutral | 0.022 | Benign | 0.018 | Benign | 2.70 | Benign | 0.28 | Tolerated | 3.99 | 5 | 0.1672 | 0.6997 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.2257G>C | A753P 2D AIThe SynGAP1 missense variant A753P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation—there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.722781 | Binding | 0.381 | 0.873 | 0.625 | -2.486 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -0.05 | Neutral | 0.966 | Probably Damaging | 0.575 | Possibly Damaging | 2.59 | Benign | 0.30 | Tolerated | 0.2143 | 0.5442 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2257G>T | A753S 2D AIThe SynGAP1 missense variant A753S is reported as “Likely Benign” in ClinVar and is not present in gnomAD. Prediction tools that assess functional impact all converge on a benign outcome: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. Foldetta results are unavailable. Overall, 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 | 0.521092 | Disordered | 0.722781 | Binding | 0.381 | 0.873 | 0.625 | -3.656 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.105 | Likely Benign | 0.25 | Neutral | 0.062 | Benign | 0.015 | Benign | 3.03 | Benign | 0.59 | Tolerated | 0.2905 | 0.5899 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2258C>A | A753D 2D AISynGAP1 missense variant A753D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all score benign, while only polyPhen‑2 HumDiv predicts pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy tools corroborate this view: AlphaMissense‑Optimized reports a benign outcome, SGM‑Consensus likewise indicates Likely Benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign classification, and this conclusion does not contradict the ClinVar status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.722781 | Binding | 0.381 | 0.873 | 0.625 | -5.836 | Likely Benign | 0.408 | Ambiguous | Likely Benign | 0.113 | Likely Benign | -1.66 | Neutral | 0.669 | Possibly Damaging | 0.265 | Benign | 2.60 | Benign | 0.60 | Tolerated | 0.2151 | 0.2200 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2258C>G | A753G 2D AIThe SynGAP1 missense variant A753G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. Foldetta results are not available, so they do not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.722781 | Binding | 0.381 | 0.873 | 0.625 | -4.257 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -1.10 | Neutral | 0.625 | Possibly Damaging | 0.192 | Benign | 2.62 | Benign | 0.65 | Tolerated | 0.2447 | 0.5089 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2258C>T | A753V 2D AIThe SynGAP1 missense variant A753V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. Foldetta results are not available, so they do not influence the assessment. Overall, the majority of computational evidence indicates that A753V is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.722781 | Binding | 0.381 | 0.873 | 0.625 | -3.759 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -1.55 | Neutral | 0.669 | Possibly Damaging | 0.192 | Benign | 2.71 | Benign | 0.18 | Tolerated | 0.1344 | 0.5953 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.3427A>C | T1143P 2D AIThe SynGAP1 missense variant T1143P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.722918 | Binding | 0.275 | 0.837 | 1.000 | -2.307 | Likely Benign | 0.155 | Likely Benign | Likely Benign | 0.183 | Likely Benign | 0.80 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.69 | Benign | 0.24 | Tolerated | 0.1818 | 0.4108 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3427A>G | T1143A 2D AIThe SynGAP1 missense variant T1143A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of benign predictions and the consensus from high‑accuracy methods, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.722918 | Binding | 0.275 | 0.837 | 1.000 | -3.340 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -1.19 | Neutral | 0.877 | Possibly Damaging | 0.675 | Possibly Damaging | 2.80 | Benign | 0.43 | Tolerated | 0.3252 | 0.3546 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3427A>T | T1143S 2D AIThe SynGAP1 missense variant T1143S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods indicates that T1143S is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.722918 | Binding | 0.275 | 0.837 | 1.000 | -2.427 | Likely Benign | 0.150 | Likely Benign | Likely Benign | 0.086 | Likely Benign | -1.34 | Neutral | 0.573 | Possibly Damaging | 0.230 | Benign | 2.76 | Benign | 0.74 | Tolerated | 0.2810 | 0.3640 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3428C>A | T1143K 2D AIThe SynGAP1 missense variant T1143K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, whereas the SGM‑Consensus (majority vote) supports a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact for T1143K, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.722918 | Binding | 0.275 | 0.837 | 1.000 | -3.498 | Likely Benign | 0.811 | Likely Pathogenic | Ambiguous | 0.163 | Likely Benign | -2.03 | Neutral | 0.986 | Probably Damaging | 0.895 | Possibly Damaging | 2.78 | Benign | 0.14 | Tolerated | 0.1266 | 0.2936 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||||
| c.3428C>G | T1143R 2D AIThe SynGAP1 missense variant T1143R is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools cluster into two groups: benign predictions include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from AlphaMissense‑Default, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. 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 favors benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.722918 | Binding | 0.275 | 0.837 | 1.000 | -2.882 | Likely Benign | 0.782 | Likely Pathogenic | Likely Benign | 0.175 | Likely Benign | -2.31 | Neutral | 0.996 | Probably Damaging | 0.951 | Probably Damaging | 2.73 | Benign | 0.09 | Tolerated | 0.1087 | 0.3060 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||||||||||||
| c.3428C>T | T1143I 2D AIThe SynGAP1 missense variant T1143I is not reported in ClinVar and has no entries in gnomAD, indicating it has not been catalogued in these databases. Functional prediction tools largely agree that the substitution is benign: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify it as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic effect. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy predictions from AlphaMissense‑Optimized and the SGM‑Consensus both support a benign outcome, while the absence of a Foldetta result leaves the structural impact unresolved. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.722918 | Binding | 0.275 | 0.837 | 1.000 | -3.554 | Likely Benign | 0.560 | Ambiguous | Likely Benign | 0.163 | Likely Benign | -1.87 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.68 | Benign | 0.10 | Tolerated | 0.1013 | 0.4274 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.2731G>A | V911I 2D AIThe SynGAP1 missense variant V911I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” while Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.685117 | Disordered | 0.724137 | Binding | 0.327 | 0.914 | 0.375 | -3.983 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.024 | Likely Benign | -0.32 | Neutral | 0.451 | Benign | 0.209 | Benign | 2.70 | Benign | 0.22 | Tolerated | 0.0881 | 0.4331 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2731G>C | V911L 2D AIThe SynGAP1 missense variant V911L is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a benign outcome: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. No tool in the dataset indicates a pathogenic effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign effect, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is classified as Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence strongly supports a benign classification, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.685117 | Disordered | 0.724137 | Binding | 0.327 | 0.914 | 0.375 | -2.722 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.100 | Likely Benign | -0.39 | Neutral | 0.451 | Benign | 0.157 | Benign | 2.73 | Benign | 0.16 | Tolerated | 0.1067 | 0.5310 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2731G>T | V911F 2D AIThe SynGAP1 missense variant V911F is not reported 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 V911F, 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 | 0.685117 | Disordered | 0.724137 | Binding | 0.327 | 0.914 | 0.375 | -4.454 | Likely Benign | 0.169 | Likely Benign | Likely Benign | 0.079 | Likely Benign | -1.08 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 2.68 | Benign | 0.04 | Affected | 0.0749 | 0.4380 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||||||||||||
| c.2732T>A | V911D 2D AIThe SynGAP1 missense variant V911D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of high‑confidence predictors indicate a benign impact, and this is consistent with the lack of ClinVar evidence. Therefore, 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 | 0.685117 | Disordered | 0.724137 | Binding | 0.327 | 0.914 | 0.375 | -4.422 | Likely Benign | 0.624 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | -0.41 | Neutral | 0.500 | Possibly Damaging | 0.157 | Benign | 2.71 | Benign | 0.05 | Affected | 0.1416 | 0.1289 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||||||||||||
| c.2732T>C | V911A 2D AIThe SynGAP1 missense variant V911A is not reported in ClinVar and is absent from gnomAD. All evaluated in silico predictors classify the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta results are unavailable. Based on the consensus of all 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 | 0.685117 | Disordered | 0.724137 | Binding | 0.327 | 0.914 | 0.375 | -3.030 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.118 | Likely Benign | 0.08 | Neutral | 0.264 | Benign | 0.102 | Benign | 2.77 | Benign | 0.41 | Tolerated | 0.3069 | 0.3336 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| c.2732T>G | V911G 2D AIThe SynGAP1 missense variant V911G is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). All available in silico predictors classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity, so the benign group includes every listed predictor, while the pathogenic group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a benign verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.685117 | Disordered | 0.724137 | Binding | 0.327 | 0.914 | 0.375 | -2.754 | Likely Benign | 0.222 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -0.04 | Neutral | 0.004 | Benign | 0.003 | Benign | 2.74 | Benign | 0.16 | Tolerated | 0.2307 | 0.3360 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||||||||||||
| 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 | -2.75 | Deleterious | 0.115 | Benign | 0.026 | Benign | 4.10 | Benign | 0.02 | Affected | 0.2823 | 0.5338 | 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 | -3.82 | Deleterious | 0.983 | Probably Damaging | 0.656 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 3.61 | 5 | 0.1070 | 0.4667 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||
| c.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 | -4.42 | Deleterious | 0.998 | Probably Damaging | 0.840 | Possibly Damaging | 3.88 | Benign | 0.00 | Affected | 0.1339 | 0.4356 | -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 | -3.29 | Deleterious | 0.888 | Possibly Damaging | 0.435 | Benign | 3.92 | Benign | 0.02 | Affected | 0.2093 | 0.2550 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.392G>C | G131A 2D AIThe SynGAP1 missense variant G131A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign. Foldetta results are unavailable. Overall, the majority of evidence (5 benign vs 3 pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.724779 | Binding | 0.302 | 0.891 | 0.250 | -4.891 | Likely Benign | 0.512 | Ambiguous | Likely Benign | 0.138 | Likely Benign | -2.96 | Deleterious | 0.620 | Possibly Damaging | 0.157 | Benign | 3.99 | Benign | 0.01 | Affected | 0.3981 | 0.4814 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.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 | -4.25 | Deleterious | 0.983 | Probably Damaging | 0.559 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 0.1168 | 0.4175 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3430T>A | L1144M 2D AIThe SynGAP1 missense variant L1144M is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: **benign** – REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized; **pathogenic** – polyPhen‑2 (HumDiv and HumVar) and SIFT. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Benign. Foldetta predictions are unavailable. Overall, the majority of evidence points to a benign effect for L1144M, and this conclusion does not conflict with 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 | 0.950334 | Disordered | 0.726803 | Binding | 0.277 | 0.840 | 1.000 | -4.787 | Likely Benign | 0.199 | Likely Benign | Likely Benign | 0.277 | Likely Benign | -0.25 | Neutral | 0.999 | Probably Damaging | 0.979 | Probably Damaging | 5.38 | Benign | 0.05 | Affected | 0.0846 | 0.3863 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3430T>G | L1144V 2D AIThe SynGAP1 missense variant L1144V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.950334 | Disordered | 0.726803 | Binding | 0.277 | 0.840 | 1.000 | -4.025 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.227 | Likely Benign | -0.04 | Neutral | 0.952 | Possibly Damaging | 0.770 | Possibly Damaging | 5.43 | Benign | 0.70 | Tolerated | 0.1553 | 0.3297 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3431T>C | L1144S 2D AIThe SynGAP1 missense variant L1144S has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls come from REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. Grouping by consensus, the majority of tools (four benign vs. five pathogenic) lean slightly toward pathogenicity, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels 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 predictor, did not return a result for this variant. Overall, the computational evidence most strongly suggests the variant is benign, and this conclusion does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.950334 | Disordered | 0.726803 | Binding | 0.277 | 0.840 | 1.000 | -2.248 | Likely Benign | 0.683 | Likely Pathogenic | Likely Benign | 0.580 | Likely Pathogenic | -1.69 | Neutral | 1.000 | Probably Damaging | 0.979 | Probably Damaging | 5.41 | Benign | 0.01 | Affected | 0.3045 | 0.0863 | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||||||||||||
| c.3431T>G | L1144W 2D AIThe SynGAP1 missense variant L1144W is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33444466‑T‑G). Prediction tools that agree on a benign effect include ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split; Foldetta results are unavailable. Overall, the majority of predictions (six pathogenic vs. three benign) indicate a pathogenic impact. This conclusion is not contradicted by ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.950334 | Disordered | 0.726803 | Binding | 0.277 | 0.840 | 1.000 | 6-33444466-T-G | 1 | 6.20e-7 | -5.745 | Likely Benign | 0.707 | Likely Pathogenic | Likely Benign | 0.575 | Likely Pathogenic | -2.87 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 5.36 | Benign | 0.01 | Affected | 4.32 | 4 | 0.0703 | 0.3166 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||||||||
| c.3432G>C | L1144F 2D AIThe SynGAP1 missense variant L1144F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.950334 | Disordered | 0.726803 | Binding | 0.277 | 0.840 | 1.000 | -4.375 | Likely Benign | 0.406 | Ambiguous | Likely Benign | 0.415 | Likely Benign | -1.71 | Neutral | 0.999 | Probably Damaging | 0.969 | Probably Damaging | 5.69 | Benign | 0.04 | Affected | 0.0685 | 0.3283 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3432G>T | L1144F 2D AIThe SynGAP1 missense variant L1144F 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 high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the aggregate evidence, the variant is most likely benign. This assessment does not contradict ClinVar status, as no ClinVar claim exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.950334 | Disordered | 0.726803 | Binding | 0.277 | 0.840 | 1.000 | -4.375 | Likely Benign | 0.406 | Ambiguous | Likely Benign | 0.415 | Likely Benign | -1.71 | Neutral | 0.999 | Probably Damaging | 0.969 | Probably Damaging | 5.69 | Benign | 0.04 | Affected | 0.0685 | 0.3283 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2449T>A | S817T 2D AIThe SynGAP1 missense variant S817T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also leans benign, and Foldetta results are unavailable. Overall, the balance of evidence from both general and high‑accuracy predictors points to a benign impact for S817T. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.490133 | Structured | 0.727082 | Binding | 0.314 | 0.901 | 0.625 | -6.544 | Likely Benign | 0.492 | Ambiguous | Likely Benign | 0.157 | Likely Benign | -1.95 | Neutral | 0.990 | Probably Damaging | 0.846 | Possibly Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.1622 | 0.6482 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2449T>C | S817P 2D AIThe SynGAP1 missense variant S817P is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Overall, the majority of tools and the consensus score indicate a pathogenic effect, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.490133 | Structured | 0.727082 | Binding | 0.314 | 0.901 | 0.625 | -4.633 | Likely Benign | 0.724 | Likely Pathogenic | Likely Benign | 0.201 | Likely Benign | -3.26 | Deleterious | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.39 | Pathogenic | 0.00 | Affected | 0.2272 | 0.6023 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2449T>G | S817A 2D AIThe SynGAP1 missense variant S817A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also resolves to benign, while Foldetta results are unavailable. Overall, the majority of high‑confidence predictions indicate a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.490133 | Structured | 0.727082 | Binding | 0.314 | 0.901 | 0.625 | -6.321 | Likely Benign | 0.429 | Ambiguous | Likely Benign | 0.116 | Likely Benign | -1.86 | Neutral | 0.977 | Probably Damaging | 0.846 | Possibly Damaging | 2.45 | Pathogenic | 0.00 | Affected | 0.5207 | 0.5866 | Strenghten | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2450C>T | S817L 2D AIThe SynGAP1 missense variant S817L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports 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 points to a pathogenic effect. This conclusion does not contradict 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 | 0.490133 | Structured | 0.727082 | Binding | 0.314 | 0.901 | 0.625 | -7.612 | In-Between | 0.659 | Likely Pathogenic | Likely Benign | 0.226 | Likely Benign | -3.90 | Deleterious | 0.997 | Probably Damaging | 0.945 | Probably Damaging | 2.41 | Pathogenic | 0.00 | Affected | 0.1226 | 0.5662 | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| 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 | -3.23 | Deleterious | 0.084 | Benign | 0.020 | Benign | 3.36 | Benign | 0.00 | Affected | 0.2306 | 0.1698 | 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 | -2.99 | Deleterious | 0.000 | Benign | 0.002 | Benign | 3.46 | Benign | 0.00 | Affected | 3.61 | 5 | 0.2564 | 0.2669 | 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 | -3.86 | Deleterious | 0.084 | Benign | 0.034 | Benign | 3.38 | Benign | 0.00 | Affected | 0.2349 | 0.1725 | -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 | -1.98 | Neutral | 0.272 | Benign | 0.126 | Benign | 3.39 | Benign | 0.00 | Affected | 0.1635 | 0.1526 | 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 | -4.54 | Deleterious | 0.567 | Possibly Damaging | 0.249 | Benign | 3.31 | Benign | 0.00 | Affected | 0.4869 | 0.0000 | -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 | -4.55 | Deleterious | 0.938 | Possibly Damaging | 0.498 | Possibly Damaging | 3.29 | Benign | 0.00 | Affected | 0.2677 | 0.0925 | -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 | -2.99 | Deleterious | 0.000 | Benign | 0.002 | Benign | 3.46 | Benign | 0.00 | Affected | 3.61 | 5 | 0.2564 | 0.2669 | 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 | -2.99 | Deleterious | 0.000 | Benign | 0.002 | Benign | 3.46 | Benign | 0.00 | Affected | 3.61 | 5 | 0.2564 | 0.2669 | 0 | 2 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||||
| c.3436C>A | P1146T 2D AIThe SynGAP1 missense variant P1146T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, as well as the SGM‑Consensus call of “Likely Benign.” In contrast, PROVEAN, polyPhen‑2 HumDiv, and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Foldetta results are not available. Overall, the majority of evidence points to a benign effect for P1146T, 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 | 0.919029 | Disordered | 0.732173 | Binding | 0.415 | 0.837 | 1.000 | -3.494 | Likely Benign | 0.272 | Likely Benign | Likely Benign | 0.454 | Likely Benign | -4.11 | Deleterious | 0.573 | Possibly Damaging | 0.334 | Benign | 5.51 | Benign | 0.00 | Affected | 0.1478 | 0.5789 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3436C>G | P1146A 2D AIThe SynGAP1 missense variant P1146A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus 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 P1146A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.732173 | Binding | 0.415 | 0.837 | 1.000 | -3.896 | Likely Benign | 0.203 | Likely Benign | Likely Benign | 0.300 | Likely Benign | -3.56 | Deleterious | 0.972 | Probably Damaging | 0.760 | Possibly Damaging | 5.53 | Benign | 0.00 | Affected | 0.3516 | 0.4791 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3436C>T | P1146S 2D AIThe SynGAP1 missense variant P1146S is reported in ClinVar as “Not submitted” and is present in gnomAD (variant ID 6-33444471-C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of a ClinVar pathogenic classification. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.732173 | Binding | 0.415 | 0.837 | 1.000 | 6-33444471-C-T | 2 | 1.24e-6 | -3.045 | Likely Benign | 0.318 | Likely Benign | Likely Benign | 0.470 | Likely Benign | -3.66 | Deleterious | 0.945 | Possibly Damaging | 0.760 | Possibly Damaging | 5.52 | Benign | 0.00 | Affected | 4.32 | 4 | 0.3408 | 0.5186 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3437C>A | P1146H 2D AIThe SynGAP1 missense variant P1146H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include ESM1b, FATHMM, and AlphaMissense‑Optimized, whereas a majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT) predict a pathogenic impact; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign outcome (2 benign vs. 1 pathogenic, 1 uncertain). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic 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. | 0.919029 | Disordered | 0.732173 | Binding | 0.415 | 0.837 | 1.000 | -4.428 | Likely Benign | 0.518 | Ambiguous | Likely Benign | 0.529 | Likely Pathogenic | -4.93 | Deleterious | 1.000 | Probably Damaging | 0.983 | Probably Damaging | 5.46 | Benign | 0.00 | Affected | 0.1625 | 0.4512 | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||||||
| c.3437C>G | P1146R 2D AIThe SynGAP1 missense variant P1146R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. Tools that agree on a benign effect are ESM1b, FATHMM, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of available predictions (seven pathogenic versus three benign) indicate that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, as the variant has no existing ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.919029 | Disordered | 0.732173 | Binding | 0.415 | 0.837 | 1.000 | -3.826 | Likely Benign | 0.729 | Likely Pathogenic | Likely Benign | 0.603 | Likely Pathogenic | -4.81 | Deleterious | 0.996 | Probably Damaging | 0.967 | Probably Damaging | 5.50 | Benign | 0.00 | Affected | 0.1315 | 0.3193 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3437C>T | P1146L 2D AISynGAP1 missense variant P1146L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include ESM1b, FATHMM, and AlphaMissense‑Optimized, whereas a separate group predicts pathogenicity: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. AlphaMissense‑Default remains 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 favors a benign outcome, while Foldetta results are unavailable. Overall, the majority of conventional predictors indicate pathogenicity, but the most accurate tools lean benign. Thus, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.919029 | Disordered | 0.732173 | Binding | 0.415 | 0.837 | 1.000 | -2.182 | Likely Benign | 0.483 | Ambiguous | Likely Benign | 0.564 | Likely Pathogenic | -5.25 | Deleterious | 0.992 | Probably Damaging | 0.912 | Probably Damaging | 5.51 | Benign | 0.00 | Affected | 0.2151 | 0.6446 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3505G>A | E1169K 2D AISynGAP1 missense variant E1169K is listed in gnomAD (ID 6‑33444540‑G‑A) but has no ClinVar record. Functional prediction tools fall into two groups: benign predictions come from SGM‑Consensus, REVEL, PROVEAN, ESM1b, and FATHMM; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign. Foldetta stability analysis is unavailable. Overall, the evidence is split evenly, with one high‑accuracy tool supporting pathogenicity and the consensus tool supporting benignity. Therefore, the variant’s impact remains uncertain; it is not contradicted by ClinVar status, which has no entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.732455 | Binding | 0.400 | 0.781 | 0.625 | 6-33444540-G-A | 1 | 6.20e-7 | -3.335 | Likely Benign | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.185 | Likely Benign | -1.81 | Neutral | 0.997 | Probably Damaging | 0.898 | Possibly Damaging | 2.51 | Benign | 0.00 | Affected | 3.88 | 3 | 0.1969 | 0.6422 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||
| c.3505G>C | E1169Q 2D AIThe SynGAP1 missense variant E1169Q is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33444540‑G‑C). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and ESM1b, while pathogenic predictions are made by polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, more tools (five) predict pathogenicity than benign (three), and no evidence from ClinVar contradicts this assessment. Thus, the variant is most likely pathogenic based on the current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.699094 | Disordered | 0.732455 | Binding | 0.400 | 0.781 | 0.625 | 6-33444540-G-C | 1 | 6.20e-7 | -3.096 | Likely Benign | 0.852 | Likely Pathogenic | Ambiguous | 0.119 | Likely Benign | -1.27 | Neutral | 0.872 | Possibly Damaging | 0.701 | Possibly Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.88 | 3 | 0.0940 | 0.6392 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||
| c.3506A>C | E1169A 2D AIThe SynGAP1 missense variant E1169A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign impact include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, a majority‑vote method from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and Foldetta results are unavailable. Considering the consensus of benign‑predicting tools and the SGM‑Consensus outcome, the variant is most likely benign. This assessment does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.732455 | Binding | 0.400 | 0.781 | 0.625 | -2.132 | Likely Benign | 0.901 | Likely Pathogenic | Ambiguous | 0.217 | Likely Benign | -2.46 | Neutral | 0.995 | Probably Damaging | 0.949 | Probably Damaging | 2.50 | Benign | 0.00 | Affected | 0.3714 | 0.6293 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3506A>G | E1169G 2D AIThe SynGAP1 missense variant E1169G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evaluated predictors (five pathogenic vs. three benign) lean toward a pathogenic classification. This prediction is not contradicted by ClinVar status, as the variant is not yet catalogued there. Thus, based on current computational evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.699094 | Disordered | 0.732455 | Binding | 0.400 | 0.781 | 0.625 | -3.172 | Likely Benign | 0.940 | Likely Pathogenic | Ambiguous | 0.203 | Likely Benign | -2.33 | Neutral | 0.995 | Probably Damaging | 0.963 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 0.3005 | 0.6019 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3506A>T | E1169V 2D AIThe SynGAP1 E1169V missense variant is not reported in ClinVar and is absent from gnomAD. Consensus from standard prediction algorithms shows a split: benign predictions come from REVEL, ESM1b, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a pathogenic signal: AlphaMissense‑Optimized is pathogenic, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—remains inconclusive (2 pathogenic vs 2 benign), and Foldetta stability analysis is unavailable. Overall, the preponderance of evidence (seven pathogenic vs three benign predictions) indicates that E1169V is most likely pathogenic. 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. | 0.699094 | Disordered | 0.732455 | Binding | 0.400 | 0.781 | 0.625 | -2.482 | Likely Benign | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.227 | Likely Benign | -2.94 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.51 | Benign | 0.00 | Affected | 0.0581 | 0.7028 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||||
| c.3507G>C | E1169D 2D AIThe SynGAP1 missense variant E1169D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of consensus tools predict a pathogenic impact, and no ClinVar entry contradicts 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. | 0.699094 | Disordered | 0.732455 | Binding | 0.400 | 0.781 | 0.625 | -3.457 | Likely Benign | 0.913 | Likely Pathogenic | Ambiguous | 0.104 | Likely Benign | -1.12 | Neutral | 0.989 | Probably Damaging | 0.924 | Probably Damaging | 2.49 | Pathogenic | 0.00 | Affected | 0.1597 | 0.3968 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3507G>T | E1169D 2D AIThe SynGAP1 missense variant E1169D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of consensus tools predict a pathogenic impact, and no ClinVar entry contradicts 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. | 0.699094 | Disordered | 0.732455 | Binding | 0.400 | 0.781 | 0.625 | -3.457 | Likely Benign | 0.913 | Likely Pathogenic | Ambiguous | 0.103 | Likely Benign | -1.12 | Neutral | 0.989 | Probably Damaging | 0.924 | Probably Damaging | 2.49 | Pathogenic | 0.00 | Affected | 0.1597 | 0.3968 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2407A>C | K803Q 2D AIThe SynGAP1 missense variant K803Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of high‑confidence predictions lean toward a benign impact, and there is no ClinVar entry to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.827927 | Disordered | 0.733908 | Binding | 0.349 | 0.900 | 0.625 | -2.792 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.108 | Likely Benign | -2.01 | Neutral | 0.984 | Probably Damaging | 0.773 | Possibly Damaging | 2.36 | Pathogenic | 0.00 | Affected | 0.4810 | 0.1398 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||||||||||
| c.2407A>G | K803E 2D AIThe SynGAP1 missense variant K803E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while 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 tools (five pathogenic vs. four benign) predict a pathogenic impact. Thus, the variant is most likely pathogenic, and this prediction does not contradict any ClinVar status because the variant has not yet been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.827927 | Disordered | 0.733908 | Binding | 0.349 | 0.900 | 0.625 | -3.889 | Likely Benign | 0.650 | Likely Pathogenic | Likely Benign | 0.172 | Likely Benign | -2.06 | Neutral | 0.896 | Possibly Damaging | 0.596 | Possibly Damaging | 2.38 | Pathogenic | 0.00 | Affected | 0.4043 | 0.1357 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.2408A>C | K803T 2D AIThe SynGAP1 missense variant K803T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. In contrast, the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicate it is likely pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as benign, whereas the SGM‑Consensus indicates it is likely pathogenic; a Foldetta stability analysis is not available. Overall, the balance of evidence points to a pathogenic effect for K803T, 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 | SH3-binding motif | 0.827927 | Disordered | 0.733908 | Binding | 0.349 | 0.900 | 0.625 | -3.571 | Likely Benign | 0.584 | Likely Pathogenic | Likely Benign | 0.121 | Likely Benign | -2.90 | Deleterious | 0.946 | Possibly Damaging | 0.741 | Possibly Damaging | 2.40 | Pathogenic | 0.00 | Affected | 0.2417 | 0.4395 | 0 | -1 | 3.2 | -27.07 | ||||||||||||||||||||||||||||||||||||||
| c.2408A>G | K803R 2D AIThe SynGAP1 missense variant K803R is listed in ClinVar (ID 834618.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—SIFT and FATHMM—predict pathogenicity. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates the variant is most likely benign, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.827927 | Disordered | 0.733908 | Binding | 0.349 | 0.900 | 0.625 | Uncertain | 1 | -2.281 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.018 | Likely Benign | -1.52 | Neutral | 0.103 | Benign | 0.038 | Benign | 2.38 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.4857 | 0.1715 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||||||
| c.2408A>T | K803I 2D  AIThe SynGAP1 K803I 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 and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. The high‑accuracy AlphaMissense‑Optimized assessment is uncertain, and the SGM‑Consensus (derived from a 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, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion does not contradict the ClinVar status, which currently contains no classification for K803I. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.827927 | Disordered | 0.733908 | Binding | 0.349 | 0.900 | 0.625 | -5.207 | Likely Benign | 0.894 | Likely Pathogenic | Ambiguous | 0.196 | Likely Benign | -4.06 | Deleterious | 0.995 | Probably Damaging | 0.913 | Probably Damaging | 2.31 | Pathogenic | 0.00 | Affected | 0.1425 | 0.3889 | -2 | -3 | 8.4 | -15.01 | ||||||||||||||||||||||||||||||||||||||
| c.2409A>C | K803N 2D AIThe SynGAP1 K803N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, 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, PROVEAN) is inconclusive because it yields a 2‑to‑2 split. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, more tools predict pathogenicity (five) than benignity (three), and the high‑accuracy assessments do not overturn this trend. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.827927 | Disordered | 0.733908 | Binding | 0.349 | 0.900 | 0.625 | -5.039 | Likely Benign | 0.807 | Likely Pathogenic | Ambiguous | 0.045 | Likely Benign | -2.13 | Neutral | 0.896 | Possibly Damaging | 0.673 | Possibly Damaging | 2.34 | Pathogenic | 0.00 | Affected | 0.3805 | 0.2035 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2409A>T | K803N 2D AIThe SynGAP1 K803N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑to‑2 split. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, more tools (five) predict pathogenicity than benign (three), and the high‑accuracy assessments do not overturn this trend. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.827927 | Disordered | 0.733908 | Binding | 0.349 | 0.900 | 0.625 | -5.039 | Likely Benign | 0.807 | Likely Pathogenic | Ambiguous | 0.045 | Likely Benign | -2.13 | Neutral | 0.896 | Possibly Damaging | 0.673 | Possibly Damaging | 2.34 | Pathogenic | 0.00 | Affected | 0.3805 | 0.2035 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2347A>C | M783L 2D AIThe SynGAP1 missense variant M783L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess sequence conservation and structural impact uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the collective evidence strongly supports a benign classification, and this conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | -1.915 | Likely Benign | 0.138 | Likely Benign | Likely Benign | 0.108 | Likely Benign | -0.48 | Neutral | 0.004 | Benign | 0.006 | Benign | 2.99 | Benign | 1.00 | Tolerated | 0.1727 | 0.4461 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2347A>G | M783V 2D AIThe SynGAP1 missense variant M783V is catalogued in gnomAD (ID 6‑33442899‑A‑G) and has no ClinVar entry. All evaluated in‑silico predictors classify it as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta results are unavailable. Consequently, the variant is most likely benign, and this prediction 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 | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | 6-33442899-A-G | 1 | 6.21e-7 | -3.453 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -0.96 | Neutral | 0.072 | Benign | 0.026 | Benign | 2.85 | Benign | 0.12 | Tolerated | 3.64 | 6 | 0.3444 | 0.3710 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||||||||||||||
| c.2347A>T | M783L 2D AIThe SynGAP1 missense variant M783L 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. High‑accuracy consensus methods reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability approach, has no available result for this variant. Overall, the collective evidence strongly supports a benign interpretation, and this conclusion is consistent with the lack of a ClinVar classification—there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | -1.915 | Likely Benign | 0.138 | Likely Benign | Likely Benign | 0.110 | Likely Benign | -0.48 | Neutral | 0.004 | Benign | 0.006 | Benign | 2.99 | Benign | 1.00 | Tolerated | 0.1727 | 0.4461 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2348T>A | M783K 2D AIThe SynGAP1 missense variant M783K is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence points toward a benign impact. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | -4.923 | Likely Benign | 0.693 | Likely Pathogenic | Likely Benign | 0.206 | Likely Benign | -2.70 | Deleterious | 0.925 | Possibly Damaging | 0.424 | Benign | 2.66 | Benign | 0.01 | Affected | 0.1730 | 0.0912 | 0 | -1 | -5.8 | -3.02 | ||||||||||||||||||||||||||||||||||||||||
| c.2348T>C | M783T 2D AIThe SynGAP1 missense variant M783T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as tolerated or benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a damaging or pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign status. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign. Foldetta results are not available for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and the high‑accuracy consensus points to a benign effect, with no conflict with ClinVar reporting. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | -4.064 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -2.08 | Neutral | 0.625 | Possibly Damaging | 0.265 | Benign | 2.69 | Benign | 0.03 | Affected | 0.2217 | 0.2308 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||||||||||||
| c.2348T>G | M783R 2D AIThe SynGAP1 missense variant M783R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs four benign) lean toward a pathogenic impact. 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. | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | -3.849 | Likely Benign | 0.655 | Likely Pathogenic | Likely Benign | 0.208 | Likely Benign | -2.69 | Deleterious | 0.925 | Possibly Damaging | 0.529 | Possibly Damaging | 2.66 | Benign | 0.01 | Affected | 0.1815 | 0.0893 | 0 | -1 | -6.4 | 24.99 | ||||||||||||||||||||||||||||||||||||||||
| c.2349G>A | M783I 2D AIThe SynGAP1 missense variant M783I is listed in ClinVar as a benign alteration (ClinVar ID 3618151.0) and is present in the gnomAD database (gnomAD ID 6‑33442901‑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, and PROVEAN). No tool in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a likely benign effect. The Foldetta protein‑folding stability analysis is not available for this variant. Overall, the computational evidence strongly suggests that the variant is most likely benign, in agreement with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | Benign | 1 | 6-33442901-G-A | 6 | 3.72e-6 | -3.560 | Likely Benign | 0.418 | Ambiguous | Likely Benign | 0.042 | Likely Benign | -0.54 | Neutral | 0.004 | Benign | 0.006 | Benign | 2.87 | Benign | 0.22 | Tolerated | 3.64 | 6 | 0.1540 | 0.3710 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||
| c.2349G>C | M783I 2D AIThe SynGAP1 missense variant M783I is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Consensus from multiple in‑silico predictors classifies the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all return benign scores, and AlphaMissense‑Optimized also predicts a benign effect. No tool in the set indicates pathogenicity. The high‑accuracy assessments corroborate this view: AlphaMissense‑Optimized reports a benign outcome, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Benign classification, and Foldetta data are unavailable. Consequently, the aggregate evidence strongly supports a benign interpretation for M783I, and this conclusion does not conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | -3.560 | Likely Benign | 0.418 | Ambiguous | Likely Benign | 0.042 | Likely Benign | -0.54 | Neutral | 0.004 | Benign | 0.006 | Benign | 2.87 | Benign | 0.22 | Tolerated | 3.64 | 6 | 0.1540 | 0.3710 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.2349G>T | M783I 2D AIThe SynGAP1 missense variant M783I is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools uniformly indicate a benign effect. Benign calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts pathogenicity; AlphaMissense‑Default remains uncertain. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely benign outcome. Foldetta stability analysis is unavailable, so it does not influence the assessment. Overall, the computational evidence strongly supports a benign classification for M783I, 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 | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | -3.560 | Likely Benign | 0.418 | Ambiguous | Likely Benign | 0.042 | Likely Benign | -0.54 | Neutral | 0.004 | Benign | 0.006 | Benign | 2.87 | Benign | 0.22 | Tolerated | 3.64 | 6 | 0.1540 | 0.3710 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.3412T>A | S1138T 2D AIThe SynGAP1 missense variant S1138T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for S1138T, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.738250 | Binding | 0.346 | 0.869 | 1.000 | -5.243 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.370 | Likely Benign | -1.21 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 5.45 | Benign | 0.23 | Tolerated | 0.1844 | 0.6653 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3412T>C | S1138P 2D AIThe SynGAP1 missense variant S1138P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.738250 | Binding | 0.346 | 0.869 | 1.000 | -5.023 | Likely Benign | 0.187 | Likely Benign | Likely Benign | 0.456 | Likely Benign | -1.21 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.41 | Benign | 0.10 | Tolerated | 0.2297 | 0.5856 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3412T>G | S1138A 2D AIThe SynGAP1 missense variant S1138A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. 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 | 0.891961 | Disordered | 0.738250 | Binding | 0.346 | 0.869 | 1.000 | -5.821 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.354 | Likely Benign | -0.99 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 5.47 | Benign | 0.24 | Tolerated | 0.4387 | 0.5748 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3413C>A | S1138Y 2D AIThe SynGAP1 missense variant S1138Y is listed in ClinVar with an “Uncertain” significance and is present in gnomAD (ID 6‑33444448‑C‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy predictions from AlphaMissense‑Optimized and the SGM Consensus both indicate a benign outcome, while Foldetta data are missing. Overall, the balance of evidence—especially from the high‑accuracy tools—suggests that the variant is most likely benign. This benign prediction does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.891961 | Disordered | 0.738250 | Binding | 0.346 | 0.869 | 1.000 | Uncertain | 1 | 6-33444448-C-A | 3 | 1.86e-6 | -6.610 | Likely Benign | 0.449 | Ambiguous | Likely Benign | 0.391 | Likely Benign | -2.51 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 5.41 | Benign | 0.05 | Affected | 4.32 | 4 | 0.1034 | 0.5449 | -2 | -3 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||
| c.3413C>G | S1138C 2D AIThe SynGAP1 missense variant S1138C is catalogued in gnomAD (ID 6‑33444448‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the preponderance of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, as no ClinVar classification exists for S1138C. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.738250 | Binding | 0.346 | 0.869 | 1.000 | 6-33444448-C-G | 1 | 6.20e-7 | -7.850 | In-Between | 0.117 | Likely Benign | Likely Benign | 0.425 | Likely Benign | -2.48 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 5.40 | Benign | 0.04 | Affected | 4.32 | 4 | 0.1472 | 0.6396 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||
| c.3413C>T | S1138F 2D AIThe SynGAP1 missense variant S1138F is not reported in ClinVar and is present in gnomAD (ID 6‑33444448‑C‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. The high‑accuracy AlphaMissense‑Optimized score is benign. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b (benign), FATHMM (benign), and PROVEAN (pathogenic), resolves to benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions indicates a benign effect. This conclusion is consistent with the absence of a ClinVar classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.891961 | Disordered | 0.738250 | Binding | 0.346 | 0.869 | 1.000 | 6-33444448-C-T | 1 | 6.20e-7 | -6.298 | Likely Benign | 0.379 | Ambiguous | Likely Benign | 0.407 | Likely Benign | -2.88 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 5.42 | Benign | 0.03 | Affected | 4.32 | 4 | 0.0991 | 0.5623 | -2 | -3 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||
| c.2734A>C | T912P 2D AIThe SynGAP1 missense variant T912P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.740671 | Binding | 0.285 | 0.909 | 0.250 | -2.955 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.087 | Likely Benign | -0.78 | Neutral | 0.217 | Benign | 0.121 | Benign | 4.00 | Benign | 0.00 | Affected | 0.1832 | 0.4608 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2734A>G | T912A 2D AIThe SynGAP1 missense variant T912A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion is 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 | 0.724957 | Disordered | 0.740671 | Binding | 0.285 | 0.909 | 0.250 | -3.084 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -1.50 | Neutral | 0.973 | Probably Damaging | 0.856 | Possibly Damaging | 4.03 | Benign | 0.00 | Affected | 0.3754 | 0.3841 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2734A>T | T912S 2D AIThe SynGAP1 missense variant T912S 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. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for T912S, 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 | 0.724957 | Disordered | 0.740671 | Binding | 0.285 | 0.909 | 0.250 | -2.647 | Likely Benign | 0.127 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -1.05 | Neutral | 0.994 | Probably Damaging | 0.856 | Possibly Damaging | 4.18 | Benign | 0.00 | Affected | 0.3078 | 0.3893 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2735C>A | T912N 2D  AIThe SynGAP1 missense variant T912N is listed in ClinVar with an uncertain significance (ClinVar ID 2337624.0) and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign. No Foldetta (FoldX‑MD/Rosetta) stability result is available, so it does not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.740671 | Binding | 0.285 | 0.909 | 0.250 | Uncertain | 1 | -4.260 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -1.15 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 3.96 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1095 | 0.3750 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||||||||
| c.2735C>G | T912S 2D AIThe SynGAP1 missense variant T912S 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. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for T912S, 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 | 0.724957 | Disordered | 0.740671 | Binding | 0.285 | 0.909 | 0.250 | -2.647 | Likely Benign | 0.127 | Likely Benign | Likely Benign | 0.128 | Likely Benign | -1.05 | Neutral | 0.994 | Probably Damaging | 0.856 | Possibly Damaging | 4.18 | Benign | 0.00 | Affected | 0.3078 | 0.3893 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2735C>T | T912I 2D AIThe SynGAP1 missense variant T912I is listed in gnomAD (ID 6‑33443287‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (FoldX‑MD/Rosetta stability assessment) has no available result for this variant. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta data is missing. Overall, the majority of reliable predictors indicate a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.740671 | Binding | 0.285 | 0.909 | 0.250 | 6-33443287-C-T | 2 | 1.24e-6 | -4.461 | Likely Benign | 0.522 | Ambiguous | Likely Benign | 0.117 | Likely Benign | -1.27 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 3.95 | Benign | 0.00 | Affected | 3.77 | 5 | 0.0945 | 0.5615 | -1 | 0 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||||||
| c.3787A>C | I1263L 2D AIThe SynGAP1 missense variant I1263L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two benign, two pathogenic). Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.425610 | Structured | 0.740957 | Binding | 0.867 | 0.574 | 0.000 | -1.210 | Likely Benign | 0.699 | Likely Pathogenic | Likely Benign | 0.194 | Likely Benign | -1.66 | Neutral | 0.011 | Benign | 0.022 | Benign | 1.94 | Pathogenic | 0.00 | Affected | 0.0717 | 0.2890 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3787A>G | I1263V 2D AIThe SynGAP1 missense variant I1263V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (two benign vs. two pathogenic votes), and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.425610 | Structured | 0.740957 | Binding | 0.867 | 0.574 | 0.000 | -4.230 | Likely Benign | 0.729 | Likely Pathogenic | Likely Benign | 0.221 | Likely Benign | -0.83 | Neutral | 0.437 | Benign | 0.170 | Benign | 1.99 | Pathogenic | 0.00 | Affected | 0.1136 | 0.3102 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3787A>T | I1263F 2D AIThe SynGAP1 missense variant I1263F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta results are unavailable. Because the majority of evidence points to a deleterious effect and there is no ClinVar annotation to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.425610 | Structured | 0.740957 | Binding | 0.867 | 0.574 | 0.000 | -5.887 | Likely Benign | 0.952 | Likely Pathogenic | Ambiguous | 0.335 | Likely Benign | -3.32 | Deleterious | 0.968 | Probably Damaging | 0.637 | Possibly Damaging | 1.81 | Pathogenic | 0.00 | Affected | 0.0494 | 0.2375 | 1 | 0 | -1.7 | 34.02 | ||||||||||||||||||||||||||||||||||||||
| c.3788T>A | I1263N 2D AIThe SynGAP1 missense variant I1263N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.425610 | Structured | 0.740957 | Binding | 0.867 | 0.574 | 0.000 | -9.158 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.379 | Likely Benign | -5.80 | Deleterious | 0.995 | Probably Damaging | 0.913 | Probably Damaging | 1.79 | Pathogenic | 0.00 | Affected | 0.1041 | 0.0340 | -2 | -3 | -8.0 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3788T>C | I1263T 2D AIThe SynGAP1 missense variant I1263T is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33446780‑T‑C). Functional prediction tools largely agree on a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report pathogenicity, while only ESM1b predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods points to a pathogenic effect, which aligns with the ClinVar designation of uncertainty but does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.425610 | Structured | 0.740957 | Binding | 0.867 | 0.574 | 0.000 | Uncertain | 1 | 6-33446780-T-C | 2 | 1.24e-6 | -6.564 | Likely Benign | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.529 | Likely Pathogenic | -4.15 | Deleterious | 0.946 | Possibly Damaging | 0.673 | Possibly Damaging | 1.81 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1221 | 0.1051 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||||
| c.3788T>G | I1263S 2D AIThe SynGAP1 missense variant I1263S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious outcome: 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 preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.425610 | Structured | 0.740957 | Binding | 0.867 | 0.574 | 0.000 | -8.074 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.493 | Likely Benign | -4.97 | Deleterious | 0.984 | Probably Damaging | 0.825 | Possibly Damaging | 1.80 | Pathogenic | 0.00 | Affected | 0.3242 | 0.0910 | -1 | -2 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||||||||||
| c.3789T>G | I1263M 2D AIThe SynGAP1 missense variant I1263M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs 2 benign). High‑accuracy methods are not available: AlphaMissense‑Optimized is benign, but AlphaMissense‑Default is pathogenic; Foldetta results are missing. Overall, the majority of predictions (five pathogenic vs four benign) lean toward a pathogenic impact. This conclusion does not contradict ClinVar status, as the variant has no existing ClinVar classification. 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. | Coiled-coil | 0.425610 | Structured | 0.740957 | Binding | 0.867 | 0.574 | 0.000 | -2.839 | Likely Benign | 0.701 | Likely Pathogenic | Likely Benign | 0.291 | Likely Benign | -2.49 | Neutral | 0.968 | Probably Damaging | 0.789 | Possibly Damaging | 1.81 | Pathogenic | 0.00 | Affected | 0.0654 | 0.2170 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3439A>C | T1147P 2D AIThe SynGAP1 missense variant T1147P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.746520 | Binding | 0.345 | 0.839 | 0.875 | -2.849 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.425 | Likely Benign | -2.17 | Neutral | 0.000 | Benign | 0.002 | Benign | 5.41 | Benign | 0.02 | Affected | 0.1925 | 0.4490 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3439A>G | T1147A 2D AIThe SynGAP1 missense variant T1147A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign effect, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.746520 | Binding | 0.345 | 0.839 | 0.875 | -3.115 | Likely Benign | 0.061 | Likely Benign | Likely Benign | 0.188 | Likely Benign | -1.60 | Neutral | 0.001 | Benign | 0.004 | Benign | 5.54 | Benign | 0.03 | Affected | 0.3816 | 0.3705 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3439A>T | T1147S 2D AIThe SynGAP1 missense variant T1147S is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population evidence. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.746520 | Binding | 0.345 | 0.839 | 0.875 | -2.593 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -0.51 | Neutral | 0.126 | Benign | 0.096 | Benign | 5.48 | Benign | 0.08 | Tolerated | 0.3129 | 0.3757 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3440C>A | T1147K 2D AIThe SynGAP1 missense variant T1147K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the preponderance of benign predictions and the lack of pathogenic evidence, T1147K 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 | 0.831250 | Disordered | 0.746520 | Binding | 0.345 | 0.839 | 0.875 | -3.921 | Likely Benign | 0.564 | Ambiguous | Likely Benign | 0.386 | Likely Benign | -2.29 | Neutral | 0.126 | Benign | 0.096 | Benign | 5.50 | Benign | 0.02 | Affected | 0.1148 | 0.3200 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||||
| c.3440C>G | T1147R 2D AIThe SynGAP1 missense variant T1147R 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 T1147R, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.746520 | Binding | 0.345 | 0.839 | 0.875 | -3.234 | Likely Benign | 0.534 | Ambiguous | Likely Benign | 0.442 | Likely Benign | -2.44 | Neutral | 0.411 | Benign | 0.139 | Benign | 5.46 | Benign | 0.01 | Affected | 0.1014 | 0.2742 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||||||||||||
| c.3440C>T | T1147I 2D AIThe SynGAP1 missense variant T1147I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.746520 | Binding | 0.345 | 0.839 | 0.875 | -3.552 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.423 | Likely Benign | -2.03 | Neutral | 0.259 | Benign | 0.059 | Benign | 5.42 | Benign | 0.01 | Affected | 0.1029 | 0.4968 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.2446T>A | S816T 2D AIThe SynGAP1 missense variant S816T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -3.957 | Likely Benign | 0.408 | Ambiguous | Likely Benign | 0.064 | Likely Benign | -1.05 | Neutral | 0.990 | Probably Damaging | 0.846 | Possibly Damaging | 2.65 | Benign | 0.32 | Tolerated | 0.1573 | 0.5529 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2446T>C | S816P 2D AIThe SynGAP1 missense variant S816P is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of other predictors (polyPhen‑2 HumDiv and HumVar) suggest pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus likewise indicates Likely Benign; Foldetta data are unavailable. Overall, the preponderance of evidence points to a benign effect for S816P, and this conclusion is not in conflict with ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -3.662 | Likely Benign | 0.510 | Ambiguous | Likely Benign | 0.160 | Likely Benign | -0.26 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.66 | Benign | 0.45 | Tolerated | 0.2298 | 0.5102 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2446T>G | S816A 2D AIThe SynGAP1 missense variant S816A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports 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. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -4.543 | Likely Benign | 0.310 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.07 | Neutral | 0.953 | Possibly Damaging | 0.799 | Possibly Damaging | 2.67 | Benign | 0.59 | Tolerated | 0.5307 | 0.4532 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.2447C>A | S816Y 2D AIThe SynGAP1 missense variant S816Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default, all of which classify the substitution as deleterious. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized yields an uncertain result, while Foldetta data are unavailable. Based on the preponderance of pathogenic predictions and the SGM‑Consensus, the variant is most likely pathogenic; this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -8.369 | Likely Pathogenic | 0.880 | Likely Pathogenic | Ambiguous | 0.222 | Likely Benign | -2.83 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.60 | Benign | 0.03 | Affected | 0.0668 | 0.4741 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2447C>G | S816C 2D AIThe SynGAP1 missense variant S816C has no ClinVar record and is not present in gnomAD. Functional prediction tools fall into two groups: benign predictions come from REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the evidence is mixed, with an equal split between benign and pathogenic calls among general predictors and conflicting outcomes from the two high‑accuracy tools. The variant is most likely pathogenic based on the predominance of pathogenic predictions, and this assessment does not contradict ClinVar status, which currently has no entry for S816C. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -7.998 | In-Between | 0.605 | Likely Pathogenic | Likely Benign | 0.246 | Likely Benign | -2.75 | Deleterious | 1.000 | Probably Damaging | 0.992 | Probably Damaging | 2.59 | Benign | 0.06 | Tolerated | 0.1167 | 0.5472 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.2447C>T | S816F 2D AIThe SynGAP1 missense variant S816F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls from REVEL and FATHMM, while pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. When predictions are grouped, two tools predict benign and six predict pathogenic. High‑accuracy assessment further supports a pathogenic interpretation: AlphaMissense‑Optimized is uncertain, but the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both conventional and high‑accuracy predictors indicates that S816F is most likely pathogenic, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -8.804 | Likely Pathogenic | 0.903 | Likely Pathogenic | Ambiguous | 0.232 | Likely Benign | -3.21 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.59 | Benign | 0.03 | Affected | 0.0605 | 0.5014 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.2260G>A | E754K 2D AIThe SynGAP1 missense variant E754K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Consensus among in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized all predict a benign effect, whereas polyPhen‑2 HumDiv and AlphaMissense‑Default predict pathogenicity; ESM1b remains uncertain. High‑accuracy assessment further supports a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta data are unavailable. Consequently, the variant is most likely benign according to the aggregate predictions, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.750531 | Binding | 0.357 | 0.872 | 0.500 | -7.620 | In-Between | 0.610 | Likely Pathogenic | Likely Benign | 0.138 | Likely Benign | -1.33 | Neutral | 0.801 | Possibly Damaging | 0.412 | Benign | 2.50 | Benign | 0.26 | Tolerated | 0.2159 | 0.7136 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||||
| c.2260G>C | E754Q 2D AIThe SynGAP1 missense variant E754Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral impact. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign classification, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.750531 | Binding | 0.357 | 0.872 | 0.500 | -5.324 | Likely Benign | 0.314 | Likely Benign | Likely Benign | 0.106 | Likely Benign | -0.76 | Neutral | 0.891 | Possibly Damaging | 0.596 | Possibly Damaging | 2.48 | Pathogenic | 0.27 | Tolerated | 0.1112 | 0.6714 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2261A>C | E754A 2D AIThe SynGAP1 missense variant E754A is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD: not present). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction (2 benign vs. 1 pathogenic votes). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict 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. | 0.505461 | Disordered | 0.750531 | Binding | 0.357 | 0.872 | 0.500 | -4.688 | Likely Benign | 0.381 | Ambiguous | Likely Benign | 0.049 | Likely Benign | -1.56 | Neutral | 0.801 | Possibly Damaging | 0.412 | Benign | 2.49 | Pathogenic | 0.31 | Tolerated | 0.3549 | 0.6283 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2261A>G | E754G 2D AIThe SynGAP1 missense variant E754G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are 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 | 0.505461 | Disordered | 0.750531 | Binding | 0.357 | 0.872 | 0.500 | -5.029 | Likely Benign | 0.313 | Likely Benign | Likely Benign | 0.080 | Likely Benign | -0.52 | Neutral | 0.801 | Possibly Damaging | 0.339 | Benign | 2.94 | Benign | 0.13 | Tolerated | 0.2631 | 0.5820 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.2261A>T | E754V 2D AIThe SynGAP1 missense variant E754V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence (five benign versus four pathogenic predictions) and the high‑accuracy benign call suggest 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. | 0.505461 | Disordered | 0.750531 | Binding | 0.357 | 0.872 | 0.500 | -6.147 | Likely Benign | 0.601 | Likely Pathogenic | Likely Benign | 0.157 | Likely Benign | -1.86 | Neutral | 0.966 | Probably Damaging | 0.773 | Possibly Damaging | 2.45 | Pathogenic | 0.28 | Tolerated | 0.0730 | 0.7417 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||||
| c.2262G>C | E754D 2D AIThe SynGAP1 missense variant E754D is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.750531 | Binding | 0.357 | 0.872 | 0.500 | -2.360 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.27 | Neutral | 0.002 | Benign | 0.007 | Benign | 2.53 | Benign | 0.45 | Tolerated | 0.1725 | 0.3983 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2262G>T | E754D 2D AIThe SynGAP1 missense variant E754D is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this trend: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.750531 | Binding | 0.357 | 0.872 | 0.500 | -2.360 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.27 | Neutral | 0.002 | Benign | 0.007 | Benign | 2.53 | Benign | 0.45 | Tolerated | 0.1725 | 0.3983 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3409C>A | H1137N 2D AIThe SynGAP1 missense variant H1137N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 HumDiv and SIFT predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.756488 | Binding | 0.314 | 0.879 | 0.875 | -3.105 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.208 | Likely Benign | -1.53 | Neutral | 0.625 | Possibly Damaging | 0.353 | Benign | 5.34 | Benign | 0.00 | Affected | 0.1983 | 0.3638 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3409C>G | H1137D 2D AIThe SynGAP1 missense variant H1137D is not reported in ClinVar and has no allele in gnomAD. Consensus predictions from multiple in‑silico tools cluster around a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign. Pathogenicity is suggested only by polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for H1137D, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.756488 | Binding | 0.314 | 0.879 | 0.875 | -4.934 | Likely Benign | 0.343 | Ambiguous | Likely Benign | 0.418 | Likely Benign | -2.26 | Neutral | 0.802 | Possibly Damaging | 0.430 | Benign | 5.56 | Benign | 0.00 | Affected | 0.2519 | 0.2916 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.3409C>T | H1137Y 2D AIThe SynGAP1 missense variant H1137Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for H1137Y, 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 | 0.903857 | Disordered | 0.756488 | Binding | 0.314 | 0.879 | 0.875 | -4.506 | Likely Benign | 0.124 | Likely Benign | Likely Benign | 0.310 | Likely Benign | -1.93 | Neutral | 0.925 | Possibly Damaging | 0.629 | Possibly Damaging | 5.28 | Benign | 0.00 | Affected | 0.1073 | 0.5123 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.3410A>C | H1137P 2D AIThe SynGAP1 missense variant H1137P is listed in ClinVar as a benign alteration (ClinVar ID 3685596.0) and is present in the gnomAD database (gnomAD ID 6‑33444445‑A‑C). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (derived from the same four high‑accuracy predictors) also indicates benign. No Foldetta (FoldX‑MD/Rosetta stability) result is available for this variant. Overall, the majority of predictions, including the most reliable tools, support a benign classification, which is consistent with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.756488 | Binding | 0.314 | 0.879 | 0.875 | Benign | 1 | 6-33444445-A-C | 12 | 7.44e-6 | -2.098 | Likely Benign | 0.054 | Likely Benign | Likely Benign | 0.419 | Likely Benign | -1.93 | Neutral | 0.925 | Possibly Damaging | 0.703 | Possibly Damaging | 5.29 | Benign | 0.00 | Affected | 4.32 | 4 | 0.2045 | 0.4501 | -2 | 0 | 1.6 | -40.02 | ||||||||||||||||||||||||||||||||
| c.3410A>G | H1137R 2D AIThe SynGAP1 missense variant H1137R is reported in gnomAD (ID 6‑33444445‑A‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, 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 (majority vote) also indicates Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.756488 | Binding | 0.314 | 0.879 | 0.875 | 6-33444445-A-G | 1 | 6.20e-7 | -3.468 | Likely Benign | 0.228 | Likely Benign | Likely Benign | 0.296 | Likely Benign | -1.19 | Neutral | 0.925 | Possibly Damaging | 0.629 | Possibly Damaging | 5.32 | Benign | 0.00 | Affected | 4.32 | 4 | 0.2131 | 0.3449 | 0 | 2 | -1.3 | 19.05 | ||||||||||||||||||||||||||||||||||
| c.3410A>T | H1137L 2D AIThe SynGAP1 missense variant H1137L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of benign predictions and the consensus from high‑accuracy methods, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.756488 | Binding | 0.314 | 0.879 | 0.875 | -2.215 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.359 | Likely Benign | -2.77 | Deleterious | 0.802 | Possibly Damaging | 0.534 | Possibly Damaging | 5.30 | Benign | 0.00 | Affected | 0.1199 | 0.6082 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||||||
| c.3411T>A | H1137Q 2D AIThe SynGAP1 missense variant H1137Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while polyPhen‑2 (HumDiv and HumVar) and SIFT predict pathogenic. Grouping by consensus, the benign‑predicting tools outnumber the pathogenic ones. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized scores benign, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.756488 | Binding | 0.314 | 0.879 | 0.875 | -2.958 | Likely Benign | 0.110 | Likely Benign | Likely Benign | 0.239 | Likely Benign | -1.19 | Neutral | 0.925 | Possibly Damaging | 0.703 | Possibly Damaging | 5.34 | Benign | 0.00 | Affected | 0.1873 | 0.4090 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3411T>G | H1137Q 2D AIThe SynGAP1 missense variant H1137Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for H1137Q, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.756488 | Binding | 0.314 | 0.879 | 0.875 | -2.958 | Likely Benign | 0.110 | Likely Benign | Likely Benign | 0.239 | Likely Benign | -1.19 | Neutral | 0.925 | Possibly Damaging | 0.703 | Possibly Damaging | 5.34 | Benign | 0.00 | Affected | 0.1873 | 0.4090 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3790G>A | G1264S 2D AIThe SynGAP1 missense variant G1264S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: benign predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized classifies the variant as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. Foldetta results are unavailable. Overall, the evidence strongly supports a benign classification, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -0.797 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.147 | Likely Benign | 0.82 | Neutral | 0.062 | Benign | 0.033 | Benign | 2.94 | Benign | 1.00 | Tolerated | 0.2376 | 0.4256 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||||||||
| c.3790G>C | G1264R 2D AIThe SynGAP1 missense variant G1264R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those predicting a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to the variant being most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -4.482 | Likely Benign | 0.759 | Likely Pathogenic | Likely Benign | 0.094 | Likely Benign | -1.82 | Neutral | 0.934 | Possibly Damaging | 0.541 | Possibly Damaging | 2.73 | Benign | 0.09 | Tolerated | 0.0861 | 0.3860 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3790G>T | G1264C 2D AIThe SynGAP1 missense variant G1264C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence supports a benign classification for G1264C, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -5.666 | Likely Benign | 0.280 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -1.03 | Neutral | 0.997 | Probably Damaging | 0.870 | Possibly Damaging | 2.74 | Benign | 0.09 | Tolerated | 0.1087 | 0.3691 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||||
| c.3791G>A | G1264D 2D AIThe SynGAP1 missense variant G1264D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while only AlphaMissense‑Default predicts it as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is also benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -4.725 | Likely Benign | 0.648 | Likely Pathogenic | Likely Benign | 0.097 | Likely Benign | -1.29 | Neutral | 0.012 | Benign | 0.011 | Benign | 2.72 | Benign | 0.23 | Tolerated | 0.1658 | 0.1754 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||
| c.3791G>C | G1264A 2D AIThe SynGAP1 missense variant G1264A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumDiv indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign likelihood. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion is consistent with the lack of any ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -3.460 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -0.32 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 2.79 | Benign | 0.91 | Tolerated | 0.3504 | 0.4220 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3791G>T | G1264V 2D AIThe SynGAP1 missense variant G1264V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. 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 | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -6.116 | Likely Benign | 0.488 | Ambiguous | Likely Benign | 0.136 | Likely Benign | -2.33 | Neutral | 0.966 | Probably Damaging | 0.617 | Possibly Damaging | 2.74 | Benign | 0.15 | Tolerated | 0.0972 | 0.3891 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||
| c.3502A>C | I1168L 2D AIThe SynGAP1 missense variant I1168L is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all score the substitution as tolerated, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also classifies it as likely benign. Only AlphaMissense‑Default predicts a pathogenic outcome, but this is an outlier relative to the other tools. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized reports a benign effect, and the SGM‑Consensus (majority vote) concurs. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so it does not influence the overall assessment. Overall, the computational evidence overwhelmingly favors a benign classification, and this is consistent with the absence of a ClinVar pathogenic report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.763262 | Binding | 0.423 | 0.796 | 0.500 | -1.855 | Likely Benign | 0.604 | Likely Pathogenic | Likely Benign | 0.361 | Likely Benign | -0.60 | Neutral | 0.241 | Benign | 0.286 | Benign | 5.48 | Benign | 0.20 | Tolerated | 0.0956 | 0.4465 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3502A>G | I1168V 2D AIThe SynGAP1 missense variant I1168V is listed in ClinVar (ID 936001.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports a “Likely Benign” outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this consensus does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.763262 | Binding | 0.423 | 0.796 | 0.500 | Uncertain | 1 | -3.263 | Likely Benign | 0.524 | Ambiguous | Likely Benign | 0.363 | Likely Benign | -0.14 | Neutral | 0.876 | Possibly Damaging | 0.643 | Possibly Damaging | 5.47 | Benign | 0.84 | Tolerated | 3.88 | 3 | 0.1339 | 0.4374 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.3502A>T | I1168F 2D AIThe SynGAP1 missense variant I1168F is not reported in ClinVar and is absent from gnomAD. Prediction tools show a mixed signal: benign calls come from REVEL, PROVEAN, ESM1b, and FATHMM, while pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments are limited: AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. Considering the majority of individual predictors and the SGM‑Consensus outcome, the variant is most likely benign. This assessment does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.763262 | Binding | 0.423 | 0.796 | 0.500 | -3.422 | Likely Benign | 0.879 | Likely Pathogenic | Ambiguous | 0.440 | Likely Benign | -1.21 | Neutral | 0.998 | Probably Damaging | 0.958 | Probably Damaging | 5.45 | Benign | 0.04 | Affected | 0.0616 | 0.3524 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3503T>A | I1168N 2D AIThe SynGAP1 missense variant I1168N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote) which labels the variant as Likely Benign. In contrast, tools that predict a pathogenic effect are PolyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further show AlphaMissense‑Optimized as Pathogenic, while the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the evidence is split evenly between benign and pathogenic predictions, with no consensus from the most accurate methods. Consequently, the variant’s pathogenicity is uncertain and does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.763262 | Binding | 0.423 | 0.796 | 0.500 | -4.269 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.455 | Likely Benign | -1.79 | Neutral | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 5.53 | Benign | 0.01 | Affected | 0.0943 | 0.0969 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3503T>C | I1168T 2D AIThe SynGAP1 missense variant I1168T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” AlphaMissense‑Optimized is uncertain, and no Foldetta stability result is available. Overall, the high‑accuracy consensus (SGM‑Consensus) points to a benign outcome, whereas AlphaMissense‑Optimized remains inconclusive. Thus, the variant is most likely benign based on the available predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.763262 | Binding | 0.423 | 0.796 | 0.500 | -2.970 | Likely Benign | 0.943 | Likely Pathogenic | Ambiguous | 0.426 | Likely Benign | -1.29 | Neutral | 0.992 | Probably Damaging | 0.933 | Probably Damaging | 5.54 | Benign | 0.04 | Affected | 0.1173 | 0.1647 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||||||||||||
| c.3503T>G | I1168S 2D AISynGAP1 missense variant I1168S has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, whereas the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the evidence is split, with an equal number of benign and pathogenic calls, and the high‑accuracy predictions are contradictory. Therefore, the variant is not conclusively predicted to be benign or pathogenic, and there is no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.763262 | Binding | 0.423 | 0.796 | 0.500 | -2.212 | Likely Benign | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.442 | Likely Benign | -1.46 | Neutral | 0.998 | Probably Damaging | 0.958 | Probably Damaging | 5.67 | Benign | 0.01 | Affected | 0.3247 | 0.1540 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||||||||||||
| c.3504C>G | I1168M 2D AIThe SynGAP1 missense variant I1168M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for I1168M, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.763262 | Binding | 0.423 | 0.796 | 0.500 | -3.471 | Likely Benign | 0.568 | Likely Pathogenic | Likely Benign | 0.397 | Likely Benign | -0.79 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 5.45 | Benign | 0.04 | Affected | 0.0744 | 0.3335 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2737A>C | T913P 2D AIThe SynGAP1 missense variant T913P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for T913P, 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 | 0.661982 | Disordered | 0.763517 | Binding | 0.339 | 0.899 | 0.375 | -2.029 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.176 | Likely Benign | -1.43 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.65 | Benign | 0.26 | Tolerated | 0.2082 | 0.5786 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2737A>G | T913A 2D AIThe SynGAP1 missense variant T913A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus likewise indicates Likely Benign. Foldetta results are unavailable, so they do not influence the overall assessment. Based on the collective predictions, 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 | 0.661982 | Disordered | 0.763517 | Binding | 0.339 | 0.899 | 0.375 | -2.386 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.098 | Likely Benign | -1.41 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.79 | Benign | 0.15 | Tolerated | 0.4240 | 0.4905 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2737A>T | T913S 2D AIThe SynGAP1 missense variant T913S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are not available for this variant. Overall, the majority of computational evidence points to a benign 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 Benign | 0.661982 | Disordered | 0.763517 | Binding | 0.339 | 0.899 | 0.375 | -2.636 | Likely Benign | 0.106 | Likely Benign | Likely Benign | 0.129 | Likely Benign | -0.74 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.80 | Benign | 0.74 | Tolerated | 0.3541 | 0.5147 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2738C>A | T913K 2D AIThe SynGAP1 missense variant T913K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for T913K, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.763517 | Binding | 0.339 | 0.899 | 0.375 | -4.145 | Likely Benign | 0.619 | Likely Pathogenic | Likely Benign | 0.152 | Likely Benign | -1.46 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.70 | Benign | 0.05 | Affected | 0.1204 | 0.3491 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||||
| c.2738C>G | T913R 2D AIThe SynGAP1 missense variant T913R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.763517 | Binding | 0.339 | 0.899 | 0.375 | -3.218 | Likely Benign | 0.494 | Ambiguous | Likely Benign | 0.152 | Likely Benign | -0.97 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.68 | Benign | 0.03 | Affected | 0.1025 | 0.3373 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||||||||||||
| c.2738C>T | T913I 2D AIThe SynGAP1 missense variant T913I is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for T913I, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.763517 | Binding | 0.339 | 0.899 | 0.375 | -4.030 | Likely Benign | 0.600 | Likely Pathogenic | Likely Benign | 0.144 | Likely Benign | -2.01 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.70 | Benign | 0.04 | Affected | 0.0903 | 0.6119 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.3814G>A | E1272K 2D AIThe SynGAP1 E1272K missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions are made by REVEL and ESM1b, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic, and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.483068 | Structured | 0.766082 | Binding | 0.799 | 0.677 | 0.500 | -4.227 | Likely Benign | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.312 | Likely Benign | -3.37 | Deleterious | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.28 | Pathogenic | 0.00 | Affected | 0.1544 | 0.5488 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3814G>C | E1272Q 2D AIThe SynGAP1 E1272Q missense variant is catalogued in gnomAD (variant ID 6‑33447862‑G‑C) but has no ClinVar entry. Prediction tools cluster into two groups: benign calls come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, a majority‑vote aggregator of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Pathogenic, and Foldetta (a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the preponderance of evidence (seven pathogenic versus three benign predictions) 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 | 0.483068 | Structured | 0.766082 | Binding | 0.799 | 0.677 | 0.500 | 6-33447862-G-C | 1 | 6.45e-7 | -3.000 | Likely Benign | 0.651 | Likely Pathogenic | Likely Benign | 0.207 | Likely Benign | -2.53 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.25 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.0746 | 0.5258 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||
| c.3815A>C | E1272A 2D AIThe SynGAP1 missense variant E1272A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus indicates a likely pathogenic outcome; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points toward a pathogenic impact for E1272A. 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 | 0.483068 | Structured | 0.766082 | Binding | 0.799 | 0.677 | 0.500 | -0.783 | Likely Benign | 0.779 | Likely Pathogenic | Likely Benign | 0.261 | Likely Benign | -5.05 | Deleterious | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.26 | Pathogenic | 0.00 | Affected | 0.3243 | 0.5547 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3815A>G | E1272G 2D AIThe SynGAP1 missense variant E1272G is catalogued in gnomAD (ID 6‑33447863‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score, which is labeled Likely Pathogenic. The high‑accuracy AlphaMissense‑Optimized assessment is uncertain, and the Foldetta protein‑folding stability analysis is not available for this residue. Overall, the majority of evidence points toward a deleterious effect, so the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar, as no ClinVar classification exists for E1272G. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.483068 | Structured | 0.766082 | Binding | 0.799 | 0.677 | 0.500 | 6-33447863-A-G | -1.919 | Likely Benign | 0.863 | Likely Pathogenic | Ambiguous | 0.287 | Likely Benign | -5.89 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.22 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2804 | 0.5072 | -2 | 0 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||
| c.3815A>T | E1272V 2D AIThe SynGAP1 missense variant E1272V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all indicate pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. AlphaMissense‑Optimized returns an uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available prediction for this variant. Based on the preponderance of pathogenic predictions and the SGM‑Consensus outcome, 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 | 0.483068 | Structured | 0.766082 | Binding | 0.799 | 0.677 | 0.500 | -3.628 | Likely Benign | 0.934 | Likely Pathogenic | Ambiguous | 0.278 | Likely Benign | -5.90 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.22 | Pathogenic | 0.00 | Affected | 0.0424 | 0.5894 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.3816G>C | E1272D 2D AIThe SynGAP1 missense variant E1272D has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas the remaining tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) all predict a pathogenic impact. High‑accuracy assessments further show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely pathogenic; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a pathogenic effect. There is no ClinVar classification to contradict this conclusion, so the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.483068 | Structured | 0.766082 | Binding | 0.799 | 0.677 | 0.500 | -4.781 | Likely Benign | 0.751 | Likely Pathogenic | Likely Benign | 0.189 | Likely Benign | -2.53 | Deleterious | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 2.27 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1450 | 0.3471 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||
| c.3816G>T | E1272D 2D AIThe SynGAP1 missense variant E1272D is listed in ClinVar with no submitted interpretation and is present in gnomAD (variant ID 6‑33447864‑G‑T). Functional prediction tools show mixed results: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. The high‑accuracy AlphaMissense‑Optimized tool classifies the change as benign, while the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect. No Foldetta stability assessment is available for this variant. Overall, the majority of conventional predictors and the consensus score lean toward pathogenicity, which is consistent with the SGM‑Consensus designation but contradicts the benign calls from AlphaMissense‑Optimized and a few other tools. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion aligns with the SGM‑Consensus prediction rather than the 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 | 0.766082 | Binding | 0.799 | 0.677 | 0.500 | 6-33447864-G-T | -4.781 | Likely Benign | 0.751 | Likely Pathogenic | Likely Benign | 0.188 | Likely Benign | -2.53 | Deleterious | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 2.27 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1450 | 0.3471 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.3811G>A | E1271K 2D AIThe SynGAP1 missense variant E1271K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further reveal AlphaMissense‑Optimized as benign, whereas Foldetta (combining FoldX‑MD and Rosetta) has no available result. Overall, the preponderance of evidence—both from general predictors and the SGM Consensus—leans toward pathogenicity. 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 | 0.483068 | Structured | 0.767529 | Binding | 0.832 | 0.666 | 0.375 | -2.295 | Likely Benign | 0.689 | Likely Pathogenic | Likely Benign | 0.192 | Likely Benign | -3.24 | Deleterious | 0.905 | Possibly Damaging | 0.433 | Benign | 2.07 | Pathogenic | 0.00 | Affected | 0.1780 | 0.5888 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3811G>C | E1271Q 2D AIThe SynGAP1 missense variant E1271Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. Overall, the majority of predictions (six benign vs. four pathogenic) support a benign classification. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Thus, based on the available computational evidence, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.767529 | Binding | 0.832 | 0.666 | 0.375 | -3.085 | Likely Benign | 0.282 | Likely Benign | Likely Benign | 0.175 | Likely Benign | -2.40 | Neutral | 0.951 | Possibly Damaging | 0.617 | Possibly Damaging | 2.06 | Pathogenic | 0.00 | Affected | 0.0955 | 0.5470 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3812A>C | E1271A 2D AIThe SynGAP1 missense variant E1271A is not 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 AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. AlphaMissense‑Default remains uncertain. High‑accuracy assessment shows AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of conventional tools and the high‑accuracy consensus favor a pathogenic interpretation. 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. | 0.483068 | Structured | 0.767529 | Binding | 0.832 | 0.666 | 0.375 | -3.817 | Likely Benign | 0.375 | Ambiguous | Likely Benign | 0.298 | Likely Benign | -4.79 | Deleterious | 0.951 | Possibly Damaging | 0.433 | Benign | 2.06 | Pathogenic | 0.00 | Affected | 0.2985 | 0.4959 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3812A>G | E1271G 2D AIThe SynGAP1 missense variant E1271G is catalogued in gnomAD (ID 6‑33447860‑A‑G) but has no entry in ClinVar. Functional prediction tools show a split consensus: benign calls come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts a benign effect, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans pathogenic (two pathogenic versus one benign vote). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence, including the SGM Consensus, indicates a pathogenic impact. This prediction is not contradicted by ClinVar, as no ClinVar classification exists for E1271G. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.483068 | Structured | 0.767529 | Binding | 0.832 | 0.666 | 0.375 | 6-33447860-A-G | -4.857 | Likely Benign | 0.393 | Ambiguous | Likely Benign | 0.288 | Likely Benign | -5.37 | Deleterious | 0.905 | Possibly Damaging | 0.538 | Possibly Damaging | 2.05 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2513 | 0.5485 | -2 | 0 | 3.1 | -72.06 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||||||||||||
| c.3812A>T | E1271V 2D AISynGAP1 missense variant E1271V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. AlphaMissense‑Optimized yields an uncertain result, and no Foldetta stability assessment is available. Considering the majority of high‑confidence tools and the consensus score, the variant is most likely pathogenic. This assessment does not contradict any ClinVar annotation, as no ClinVar entry exists for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.483068 | Structured | 0.767529 | Binding | 0.832 | 0.666 | 0.375 | -6.961 | Likely Benign | 0.848 | Likely Pathogenic | Ambiguous | 0.303 | Likely Benign | -5.64 | Deleterious | 0.995 | Probably Damaging | 0.846 | Possibly Damaging | 2.02 | Pathogenic | 0.00 | Affected | 0.0620 | 0.6106 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.3813G>C | E1271D 2D AIThe SynGAP1 missense variant E1271D is not reported in ClinVar and has no entry in gnomAD, indicating it is not catalogued in these databases. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign; the Foldetta stability prediction is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.767529 | Binding | 0.832 | 0.666 | 0.375 | -4.816 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -1.59 | Neutral | 0.004 | Benign | 0.008 | Benign | 2.26 | Pathogenic | 0.00 | Affected | 0.1729 | 0.3471 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3813G>T | E1271D 2D AIThe SynGAP1 missense variant E1271D is not reported in ClinVar and has no entry in gnomAD, indicating it is not catalogued in these databases. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign; the Foldetta stability prediction is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.767529 | Binding | 0.832 | 0.666 | 0.375 | -4.816 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.121 | Likely Benign | -1.59 | Neutral | 0.004 | Benign | 0.008 | Benign | 2.26 | Pathogenic | 0.00 | Affected | 0.1729 | 0.3471 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2344G>A | D782N 2D AIThe SynGAP1 missense variant D782N is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs four benign) lean toward a pathogenic impact. This conclusion does not contradict ClinVar status, as the variant has no existing ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.604312 | Disordered | 0.768342 | Binding | 0.285 | 0.883 | 0.625 | -6.857 | Likely Benign | 0.766 | Likely Pathogenic | Likely Benign | 0.131 | Likely Benign | -2.26 | Neutral | 0.995 | Probably Damaging | 0.950 | Probably Damaging | 1.98 | Pathogenic | 0.02 | Affected | 0.1167 | 0.6884 | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||||
| c.2344G>C | D782H 2D AIThe SynGAP1 missense variant D782H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Only REVEL predicts a benign outcome, while AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show the SGM‑Consensus as Likely Pathogenic, whereas AlphaMissense‑Optimized remains inconclusive and Foldetta data are unavailable. Taken together, the majority of evidence supports a pathogenic interpretation, and this is consistent with the absence of a ClinVar assertion. Therefore, 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. | Likely Pathogenic | 0.604312 | Disordered | 0.768342 | Binding | 0.285 | 0.883 | 0.625 | -8.528 | Likely Pathogenic | 0.937 | Likely Pathogenic | Ambiguous | 0.311 | Likely Benign | -2.63 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 1.93 | Pathogenic | 0.00 | Affected | 0.1333 | 0.7286 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2344G>T | D782Y 2D AIThe SynGAP1 missense variant D782Y is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools largely converge on a deleterious effect: pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default, while only REVEL predicts a benign outcome. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized is uncertain, but the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is classified as Likely Pathogenic. Foldetta, a protein‑folding stability predictor that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.604312 | Disordered | 0.768342 | Binding | 0.285 | 0.883 | 0.625 | -8.785 | Likely Pathogenic | 0.919 | Likely Pathogenic | Ambiguous | 0.382 | Likely Benign | -3.75 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 1.91 | Pathogenic | 0.00 | Affected | 0.0559 | 0.6202 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| c.2345A>C | D782A 2D AIThe SynGAP1 missense variant D782A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all classify the variant as damaging. Uncertain predictions come from ESM1b and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, reports the variant as Likely Pathogenic, while AlphaMissense‑Optimized remains uncertain and Foldetta results are unavailable. Taken together, the preponderance of evidence from multiple in silico predictors and the SGM‑Consensus suggests that D782A is most likely pathogenic. 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 | 0.604312 | Disordered | 0.768342 | Binding | 0.285 | 0.883 | 0.625 | -7.054 | In-Between | 0.892 | Likely Pathogenic | Ambiguous | 0.345 | Likely Benign | -3.33 | Deleterious | 0.990 | Probably Damaging | 0.932 | Probably Damaging | 1.95 | Pathogenic | 0.01 | Affected | 0.3819 | 0.6121 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||||||
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