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.3872T>C | L1291P 2D  AIThe SynGAP1 missense variant L1291P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs two pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, five tools predict pathogenicity while four predict benignity, giving a slight tilt toward a pathogenic interpretation. Because there is no ClinVar assertion, this prediction does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.827927 | Disordered | 0.863458 | Binding | 0.579 | 0.797 | 0.625 | -3.322 | Likely Benign | 0.243 | Likely Benign | Likely Benign | 0.417 | Likely Benign | -4.32 | Deleterious | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.48 | Pathogenic | 0.01 | Affected | 0.3078 | 0.2162 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3872T>G | L1291R 2D  AIThe SynGAP1 missense variant L1291R is not reported in ClinVar and is present in gnomAD (ID 6‑33447920‑T‑G). Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessment shows AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive and Foldetta results are unavailable. Overall, the majority of conventional predictors indicate a pathogenic effect, whereas the single high‑accuracy tool suggests benign. No ClinVar annotation contradicts these findings. Thus, based on the collective evidence, the variant is most likely pathogenic, though the high‑accuracy prediction introduces uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.827927 | Disordered | 0.863458 | Binding | 0.579 | 0.797 | 0.625 | 6-33447920-T-G | 1 | 6.44e-7 | -3.977 | Likely Benign | 0.302 | Likely Benign | Likely Benign | 0.287 | Likely Benign | -4.29 | Deleterious | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.49 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1160 | 0.1049 | -2 | -3 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||
| c.3961C>A | P1321T 2D  AIThe SynGAP1 missense variant P1321T is catalogued in gnomAD (ID 6‑33451835‑C‑A) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the variant as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and this conclusion is consistent with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.933505 | Binding | 0.463 | 0.828 | 0.875 | 6-33451835-C-A | -4.946 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.058 | Likely Benign | 1.07 | Neutral | 0.115 | Benign | 0.012 | Benign | 4.25 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2016 | 0.5901 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3961C>G | P1321A 2D  AIThe SynGAP1 missense variant P1321A is reported in gnomAD (ID 6‑33451835‑C‑G) and has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.933505 | Binding | 0.463 | 0.828 | 0.875 | 6-33451835-C-G | -4.411 | Likely Benign | 0.051 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.33 | Neutral | 0.001 | Benign | 0.000 | Benign | 4.29 | Benign | 0.42 | Tolerated | 3.77 | 5 | 0.3615 | 0.4716 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||
| c.3961C>T | P1321S 2D  AIThe SynGAP1 missense variant P1321S is listed in ClinVar (ID 1806027.0) with an “Uncertain” clinical significance and is present in the gnomAD database (gnomAD ID 6‑33451835‑C‑T). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic prediction. High‑accuracy assessments corroborate this benign trend: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign effect, which is consistent with the ClinVar “Uncertain” designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.933505 | Binding | 0.463 | 0.828 | 0.875 | Uncertain | 2 | 6-33451835-C-T | 10 | 6.46e-6 | -4.897 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.049 | Likely Benign | 0.68 | Neutral | 0.028 | Benign | 0.004 | Benign | 4.27 | Benign | 0.71 | Tolerated | 3.77 | 5 | 0.3610 | 0.5190 | 1 | -1 | 0.8 | -10.04 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.3962C>A | P1321Q 2D  AIThe SynGAP1 missense variant P1321Q is listed in ClinVar (ID 833687.0) as benign and is present in gnomAD (variant ID 6‑33451836‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification, and AlphaMissense‑Optimized also reports benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence—including the high‑confidence SGM consensus and AlphaMissense‑Optimized—supports a benign impact. This conclusion aligns with the ClinVar benign status, with no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.933505 | Binding | 0.463 | 0.828 | 0.875 | Benign | 1 | 6-33451836-C-A | 1 | 6.58e-7 | -5.594 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.74 | Neutral | 0.659 | Possibly Damaging | 0.034 | Benign | 4.24 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.1839 | 0.4884 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||
| c.3962C>G | P1321R 2D  AIThe SynGAP1 missense variant P1321R is reported in gnomAD (ID 6‑33451836‑C‑G) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool examined—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classifies the substitution as benign. No pathogenic predictions are present. Grouping the results, the benign consensus is unanimous; the pathogenic group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign status. Foldetta stability analysis is not available for this variant. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.933505 | Binding | 0.463 | 0.828 | 0.875 | 6-33451836-C-G | 1 | 6.58e-7 | -5.310 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.034 | Likely Benign | -1.10 | Neutral | 0.389 | Benign | 0.024 | Benign | 4.25 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.1722 | 0.3635 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||
| c.3962C>T | P1321L 2D  AIThe SynGAP1 missense variant P1321L is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.933505 | Binding | 0.463 | 0.828 | 0.875 | -4.892 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -0.81 | Neutral | 0.115 | Benign | 0.009 | Benign | 4.28 | Benign | 0.08 | Tolerated | 0.2626 | 0.6222 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3067T>A | S1023T 2D  AIThe SynGAP1 missense variant S1023T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, and Foldetta results are unavailable. Overall, the majority of high‑confidence tools predict a benign impact, and there is no conflict with ClinVar status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.831250 | Disordered | 0.990262 | Binding | 0.322 | 0.750 | 0.500 | -5.573 | Likely Benign | 0.360 | Ambiguous | Likely Benign | 0.092 | Likely Benign | -1.62 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.49 | Pathogenic | 0.04 | Affected | 0.1299 | 0.5370 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3067T>C | S1023P 2D  AIThe SynGAP1 missense variant S1023P is reported in gnomAD (ID 6‑33443619‑T‑C) but has no ClinVar entry (ClinVar status: not reported). Functional prediction tools are split: benign calls come from REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls come from polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, SGM Consensus remains inconclusive, and Foldetta (combining FoldX‑MD and Rosetta) has no available result. Overall, the majority of standard predictors lean toward pathogenicity, whereas the few high‑accuracy tools do not support a pathogenic verdict. Thus, the variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.831250 | Disordered | 0.990262 | Binding | 0.322 | 0.750 | 0.500 | 6-33443619-T-C | 2 | 1.24e-6 | -5.634 | Likely Benign | 0.679 | Likely Pathogenic | Likely Benign | 0.146 | Likely Benign | -2.11 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.43 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.1818 | 0.4616 | -1 | 1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.3067T>G | S1023A 2D  AIThe SynGAP1 missense variant S1023A is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of pathogenic predictors—polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT—suggest a damaging impact. The AlphaMissense‑Default score is uncertain, and Foldetta stability analysis is unavailable. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy tools therefore lean toward a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus indicates likely benign, and no Foldetta data is available. Overall, the computational evidence supports a benign classification, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.990262 | Binding | 0.322 | 0.750 | 0.500 | -6.031 | Likely Benign | 0.356 | Ambiguous | Likely Benign | 0.098 | Likely Benign | -1.59 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.53 | Benign | 0.04 | Affected | 0.4427 | 0.4386 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3068C>T | S1023L 2D  AIThe SynGAP1 missense variant S1023L is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, while the SGM‑Consensus remains Likely Pathogenic; Foldetta stability analysis is unavailable. Overall, the balance of evidence from the majority of tools and the SGM‑Consensus indicates a pathogenic effect, and this conclusion does not contradict any ClinVar annotation because none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.831250 | Disordered | 0.990262 | Binding | 0.322 | 0.750 | 0.500 | -5.735 | Likely Benign | 0.705 | Likely Pathogenic | Likely Benign | 0.204 | Likely Benign | -3.47 | Deleterious | 0.991 | Probably Damaging | 0.991 | Probably Damaging | 2.47 | Pathogenic | 0.01 | Affected | 0.1080 | 0.4923 | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.3079A>C | N1027H 2D  AIThe SynGAP1 missense variant N1027H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions, including the high‑accuracy tools, indicate that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -4.185 | Likely Benign | 0.193 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -1.44 | Neutral | 0.970 | Probably Damaging | 0.799 | Possibly Damaging | 2.74 | Benign | 0.07 | Tolerated | 0.1345 | 0.7176 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3079A>G | N1027D 2D  AIThe SynGAP1 missense variant N1027D is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all score benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also classifies it as likely benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, and AlphaMissense‑Default remains uncertain. High‑accuracy tools reinforce the benign assessment: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence supports a benign classification, and this is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -2.891 | Likely Benign | 0.458 | Ambiguous | Likely Benign | 0.073 | Likely Benign | -1.27 | Neutral | 0.649 | Possibly Damaging | 0.353 | Benign | 2.74 | Benign | 0.27 | Tolerated | 0.1854 | 0.4004 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3079A>T | N1027Y 2D  AIThe SynGAP1 missense variant N1027Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -5.799 | Likely Benign | 0.626 | Likely Pathogenic | Likely Benign | 0.074 | Likely Benign | -2.15 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.70 | Benign | 0.03 | Affected | 0.0611 | 0.6133 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||||||||||||
| c.3080A>C | N1027T 2D  AIThe SynGAP1 missense variant N1027T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumDiv indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus also reports Likely Benign; Foldetta results are not available. Overall, the consensus of the available predictions points to a benign effect, and this conclusion is consistent with the absence of any ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -3.604 | Likely Benign | 0.199 | Likely Benign | Likely Benign | 0.046 | Likely Benign | -0.71 | Neutral | 0.481 | Possibly Damaging | 0.220 | Benign | 2.75 | Benign | 0.13 | Tolerated | 0.1239 | 0.7188 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||||||||||
| c.3080A>G | N1027S 2D  AIThe SynGAP1 missense variant N1027S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the collective predictions strongly suggest that the variant is most likely benign, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -2.443 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -0.35 | Neutral | 0.068 | Benign | 0.039 | Benign | 2.77 | Benign | 0.50 | Tolerated | 0.3540 | 0.6874 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||||||||||
| c.3080A>T | N1027I 2D  AIThe SynGAP1 missense variant N1027I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -5.847 | Likely Benign | 0.751 | Likely Pathogenic | Likely Benign | 0.065 | Likely Benign | -2.36 | Neutral | 0.970 | Probably Damaging | 0.726 | Possibly Damaging | 2.71 | Benign | 0.02 | Affected | 0.0677 | 0.5724 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3081C>A | N1027K 2D  AIThe SynGAP1 missense variant N1027K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and the SGM‑Consensus result is benign; Foldetta predictions are unavailable. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -3.177 | Likely Benign | 0.841 | Likely Pathogenic | Ambiguous | 0.063 | Likely Benign | -0.64 | Neutral | 0.481 | Possibly Damaging | 0.220 | Benign | 2.81 | Benign | 0.65 | Tolerated | 0.1808 | 0.6079 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3081C>G | N1027K 2D AIThe SynGAP1 missense variant N1027K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and AlphaMissense‑Optimized is uncertain. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -3.177 | Likely Benign | 0.841 | Likely Pathogenic | Ambiguous | 0.063 | Likely Benign | -0.64 | Neutral | 0.481 | Possibly Damaging | 0.220 | Benign | 2.81 | Benign | 0.65 | Tolerated | 0.1808 | 0.6079 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| 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.2995T>A | S999T 2D AIThe SynGAP1 missense variant S999T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.950682 | Binding | 0.262 | 0.897 | 0.625 | -3.961 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -0.94 | Neutral | 0.625 | Possibly Damaging | 0.266 | Benign | 2.69 | Benign | 0.04 | Affected | 0.1469 | 0.6651 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2995T>C | S999P 2D AIThe SynGAP1 missense variant S999P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for S999P, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.950682 | Binding | 0.262 | 0.897 | 0.625 | -2.279 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -1.05 | Neutral | 0.966 | Probably Damaging | 0.773 | Possibly Damaging | 2.65 | Benign | 0.04 | Affected | 0.1963 | 0.6268 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2995T>G | S999A 2D AIThe SynGAP1 missense variant S999A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is that the variant is most likely benign, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.950682 | Binding | 0.262 | 0.897 | 0.625 | -3.719 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -0.83 | Neutral | 0.005 | Benign | 0.016 | Benign | 2.71 | Benign | 0.81 | Tolerated | 0.4516 | 0.5434 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2996C>A | S999Y 2D  AIThe SynGAP1 missense variant S999Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S999Y, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.950682 | Binding | 0.262 | 0.897 | 0.625 | -6.446 | Likely Benign | 0.346 | Ambiguous | Likely Benign | 0.069 | Likely Benign | -1.74 | Neutral | 0.934 | Possibly Damaging | 0.559 | Possibly Damaging | 2.64 | Benign | 0.00 | Affected | 0.0881 | 0.6249 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2996C>G | S999C 2D  AIThe SynGAP1 missense variant S999C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. ESM1b is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S999C, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.950682 | Binding | 0.262 | 0.897 | 0.625 | -7.751 | In-Between | 0.139 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -1.68 | Neutral | 0.991 | Probably Damaging | 0.873 | Possibly Damaging | 2.63 | Benign | 0.01 | Affected | 0.1131 | 0.6212 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2996C>T | S999F 2D  AIThe SynGAP1 missense variant S999F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized independently predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect; this is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.950682 | Binding | 0.262 | 0.897 | 0.625 | -6.206 | Likely Benign | 0.368 | Ambiguous | Likely Benign | 0.072 | Likely Benign | -1.79 | Neutral | 0.966 | Probably Damaging | 0.837 | Possibly Damaging | 2.64 | Benign | 0.01 | Affected | 0.0865 | 0.6337 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.3007A>C | S1003R 2D  AIThe SynGAP1 missense variant S1003R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of evaluated tools (six pathogenic vs. three benign) indicate a pathogenic impact. This prediction aligns with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | -5.113 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.110 | Likely Benign | -1.88 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1151 | 0.3746 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3007A>G | S1003G 2D  AIThe SynGAP1 missense variant S1003G is catalogued in gnomAD (ID 6‑33443559‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for S1003G, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | 6-33443559-A-G | 1 | 6.20e-7 | -5.888 | Likely Benign | 0.542 | Ambiguous | Likely Benign | 0.088 | Likely Benign | -1.72 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2730 | 0.4789 | 0 | 1 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.3007A>T | S1003C 2D AIThe SynGAP1 missense variant S1003C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, PROVEAN, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect include polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and is classified as Likely Pathogenic. AlphaMissense‑Optimized, a high‑accuracy tool, predicts a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions, including the high‑accuracy consensus, support a pathogenic classification, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | -8.058 | Likely Pathogenic | 0.647 | Likely Pathogenic | Likely Benign | 0.141 | Likely Benign | -1.98 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 0.1442 | 0.5966 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.3008G>A | S1003N 2D  AIThe SynGAP1 missense variant S1003N is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, more tools (five) predict pathogenicity than benign (three), and the high‑accuracy methods do not overturn this trend. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | -5.175 | Likely Benign | 0.889 | Likely Pathogenic | Ambiguous | 0.122 | Likely Benign | -1.37 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 0.1798 | 0.5029 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3008G>C | S1003T 2D AIThe SynGAP1 missense variant S1003T is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of pathogenic predictors—polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT—suggest a damaging impact. The AlphaMissense‑Default score is uncertain, and Foldetta stability analysis is unavailable. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments therefore lean toward a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is likely benign, and no Foldetta data is present. Overall, the computational evidence supports a benign classification, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | -5.140 | Likely Benign | 0.493 | Ambiguous | Likely Benign | 0.115 | Likely Benign | -1.04 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.51 | Benign | 0.00 | Affected | 0.1864 | 0.6227 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3008G>T | S1003I 2D  AIThe SynGAP1 missense variant S1003I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus methods give mixed results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic, two benign votes); and Foldetta (combining FoldX‑MD and Rosetta) has no available output. Based on the overall distribution of predictions, the variant is most likely pathogenic. This assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | -8.952 | Likely Pathogenic | 0.954 | Likely Pathogenic | Ambiguous | 0.189 | Likely Benign | -2.31 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.50 | Benign | 0.00 | Affected | 0.1294 | 0.5735 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3009C>A | S1003R 2D AIThe SynGAP1 missense variant S1003R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of evaluated tools (six pathogenic vs. three benign) indicate a pathogenic impact. This prediction aligns with the lack of ClinVar annotation and does not contradict any existing clinical classification. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | -5.113 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.141 | Likely Benign | -1.88 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1151 | 0.3746 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3009C>G | S1003R 2D AIThe SynGAP1 missense variant S1003R (ClinVar ID 1798770.0) is listed as Uncertain in ClinVar and is not present in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and ESM1b, while pathogenic predictions are reported by polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessment shows AlphaMissense‑Optimized classifying the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic), and Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a pathogenic effect, which contrasts with the ClinVar designation of Uncertain. Thus, the variant is most likely pathogenic, contradicting the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | Uncertain | 1 | -5.113 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.141 | Likely Benign | -1.88 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1151 | 0.3746 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| c.3031G>A | G1011R 2D  AIThe SynGAP1 missense variant G1011R is reported in gnomAD (variant ID 6‑33443583‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign, reflecting the majority of benign calls. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign effect for G1011R, and this conclusion does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.898380 | Binding | 0.332 | 0.869 | 0.625 | 6-33443583-G-A | -4.650 | Likely Benign | 0.609 | Likely Pathogenic | Likely Benign | 0.118 | Likely Benign | -0.79 | Neutral | 0.642 | Possibly Damaging | 0.494 | Possibly Damaging | 2.72 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1041 | 0.4415 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||
| c.3031G>C | G1011R 2D AIThe SynGAP1 missense variant G1011R is not reported in ClinVar and is absent from gnomAD, so no population frequency or clinical assertion data are available. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.898380 | Binding | 0.332 | 0.869 | 0.625 | -4.650 | Likely Benign | 0.609 | Likely Pathogenic | Likely Benign | 0.118 | Likely Benign | -0.79 | Neutral | 0.642 | Possibly Damaging | 0.494 | Possibly Damaging | 2.72 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1041 | 0.4415 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.3032G>A | G1011E 2D  AIThe SynGAP1 missense variant G1011E is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM, while those predicting a pathogenic outcome are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the collective predictions point to a benign effect, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.898380 | Binding | 0.332 | 0.869 | 0.625 | -3.870 | Likely Benign | 0.617 | Likely Pathogenic | Likely Benign | 0.091 | Likely Benign | -1.10 | Neutral | 0.642 | Possibly Damaging | 0.252 | Benign | 2.78 | Benign | 0.01 | Affected | 0.1692 | 0.4521 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3032G>C | G1011A 2D  AIThe SynGAP1 missense variant G1011A is catalogued in gnomAD (ID 6‑33443584‑G‑C) and has no ClinVar entry. All evaluated in‑silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic outcome. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.898380 | Binding | 0.332 | 0.869 | 0.625 | 6-33443584-G-C | -4.349 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -0.04 | Neutral | 0.139 | Benign | 0.089 | Benign | 2.89 | Benign | 0.64 | Tolerated | 3.77 | 5 | 0.3641 | 0.4571 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.3032G>T | G1011V 2D  AIThe SynGAP1 missense variant G1011V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.898380 | Binding | 0.332 | 0.869 | 0.625 | -4.883 | Likely Benign | 0.129 | Likely Benign | Likely Benign | 0.133 | Likely Benign | -1.21 | Neutral | 0.473 | Possibly Damaging | 0.192 | Benign | 2.71 | Benign | 0.01 | Affected | 0.1352 | 0.3434 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3034C>A | P1012T 2D AIThe SynGAP1 missense variant P1012T is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.894674 | Binding | 0.319 | 0.866 | 0.625 | -4.788 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.052 | Likely Benign | -0.56 | Neutral | 0.369 | Benign | 0.171 | Benign | 2.84 | Benign | 0.14 | Tolerated | 0.1399 | 0.5730 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3034C>G | P1012A 2D AIThe SynGAP1 missense variant P1012A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.894674 | Binding | 0.319 | 0.866 | 0.625 | -4.038 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -0.55 | Neutral | 0.112 | Benign | 0.084 | Benign | 2.81 | Benign | 0.26 | Tolerated | 0.3272 | 0.4900 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3034C>T | P1012S 2D AIThe SynGAP1 missense variant P1012S is catalogued in gnomAD (ID 6‑33443586‑C‑T) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Overall, the evidence strongly supports a benign classification, and this conclusion is consistent with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.894674 | Binding | 0.319 | 0.866 | 0.625 | 6-33443586-C-T | 2 | 1.24e-6 | -3.342 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.23 | Neutral | 0.224 | Benign | 0.131 | Benign | 2.81 | Benign | 0.22 | Tolerated | 3.77 | 5 | 0.3217 | 0.5300 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3035C>A | P1012H 2D  AIThe SynGAP1 missense variant P1012H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for P1012H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.894674 | Binding | 0.319 | 0.866 | 0.625 | -4.877 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.024 | Likely Benign | -0.38 | Neutral | 0.832 | Possibly Damaging | 0.600 | Possibly Damaging | 2.75 | Benign | 0.08 | Tolerated | 0.1553 | 0.4635 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3035C>G | P1012R 2D AIThe SynGAP1 missense variant P1012R is not reported in ClinVar and is absent from gnomAD, indicating no documented population frequency. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the consensus of all available predictions strongly supports a benign classification, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.894674 | Binding | 0.319 | 0.866 | 0.625 | -4.413 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.034 | Likely Benign | 1.24 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.89 | Benign | 0.88 | Tolerated | 0.1339 | 0.3083 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3035C>T | P1012L 2D AIThe SynGAP1 missense variant P1012L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which contains no pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.894674 | Binding | 0.319 | 0.866 | 0.625 | -4.363 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.014 | Likely Benign | -0.90 | Neutral | 0.224 | Benign | 0.131 | Benign | 2.76 | Benign | 0.12 | Tolerated | 0.2155 | 0.6388 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3373G>A | G1125R 2D AIThe SynGAP1 missense variant G1125R is catalogued in gnomAD (ID 6‑33443925‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. AlphaMissense‑Default remains uncertain. A high‑accuracy consensus (SGM) that aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a benign majority vote. AlphaMissense‑Optimized also reports benign. No Foldetta stability assessment is available. Collectively, the majority of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.835839 | Binding | 0.339 | 0.923 | 0.875 | 6-33443925-G-A | -8.463 | Likely Pathogenic | 0.542 | Ambiguous | Likely Benign | 0.291 | Likely Benign | -0.54 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 4.56 | Benign | 0.04 | Affected | 3.77 | 5 | 0.0980 | 0.4332 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.3373G>C | G1125R 2D AIThe SynGAP1 missense variant G1125R is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443925‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b all predict a pathogenic outcome; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta’s protein‑folding stability result is unavailable. Overall, the balance of evidence, particularly from the high‑accuracy tools, indicates that the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.835839 | Binding | 0.339 | 0.923 | 0.875 | 6-33443925-G-C | 1 | 6.68e-7 | -8.463 | Likely Pathogenic | 0.542 | Ambiguous | Likely Benign | 0.290 | Likely Benign | -0.54 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 4.56 | Benign | 0.04 | Affected | 3.77 | 5 | 0.0980 | 0.4332 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.3373G>T | G1125W 2D  AIThe SynGAP1 missense variant G1125W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors a benign outcome. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the balance of evidence, especially from the high‑accuracy tools, points to a benign classification. This conclusion is not contradicted by any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.835839 | Binding | 0.339 | 0.923 | 0.875 | -11.684 | Likely Pathogenic | 0.372 | Ambiguous | Likely Benign | 0.402 | Likely Benign | -1.10 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 4.50 | Benign | 0.00 | Affected | 0.0924 | 0.4046 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||||||
| c.3374G>A | G1125E 2D AIThe SynGAP1 missense variant G1125E is not reported in ClinVar (ClinVar status: not reported) but is present in gnomAD (gnomAD ID 6‑33443926‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, AlphaMissense‑Optimized, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; AlphaMissense‑Default remains uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome (2 benign vs. 1 pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.835839 | Binding | 0.339 | 0.923 | 0.875 | 6-33443926-G-A | 11 | 7.34e-6 | -9.849 | Likely Pathogenic | 0.353 | Ambiguous | Likely Benign | 0.264 | Likely Benign | -0.32 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 4.58 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.1430 | 0.4063 | -2 | 0 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||
| c.3374G>C | G1125A 2D AIThe SynGAP1 missense variant G1125A is listed in ClinVar with an “Uncertain” status and is present in gnomAD (6‑33443926‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (derived from the four high‑accuracy tools) is 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 | 0.834292 | Disordered | 0.835839 | Binding | 0.339 | 0.923 | 0.875 | Uncertain | 1 | 6-33443926-G-C | 1 | 6.68e-7 | -6.569 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.232 | Likely Benign | -0.60 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 4.60 | Benign | 0.11 | Tolerated | 3.77 | 5 | 0.3395 | 0.5138 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||
| c.3374G>T | G1125V 2D AIThe SynGAP1 missense variant G1125V is reported in gnomAD (variant ID 6-33443926-G-T) but has no ClinVar entry. Functional prediction tools cluster into two groups: six tools (REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score all predict a benign effect, whereas three tools (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT) predict pathogenicity. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) 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 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 | 0.834292 | Disordered | 0.835839 | Binding | 0.339 | 0.923 | 0.875 | 6-33443926-G-T | -6.776 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.320 | Likely Benign | -0.99 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 4.55 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1407 | 0.3688 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||
| c.3742C>A | L1248I 2D  AIThe SynGAP1 missense variant L1248I is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and ESM1b, whereas pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments are less decisive: AlphaMissense‑Optimized returns an uncertain result, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie and thus unavailable, and Foldetta data are missing. Consequently, the overall evidence leans toward pathogenicity, but the lack of definitive high‑accuracy support and the absence of ClinVar annotation mean the prediction is not contradicted by existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.834292 | Disordered | 0.371716 | Uncertain | 0.880 | 0.562 | 0.625 | -6.928 | Likely Benign | 0.872 | Likely Pathogenic | Ambiguous | 0.173 | Likely Benign | -1.56 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.75 | Pathogenic | 0.00 | Affected | 0.0919 | 0.2413 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3742C>G | L1248V 2D  AIThe SynGAP1 missense variant L1248V is not reported 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. AlphaMissense‑Optimized is uncertain. 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 tools (five pathogenic vs three benign) predict a deleterious impact, and no high‑accuracy consensus or folding‑stability evidence contradicts this. Therefore, the variant is most likely pathogenic, and this assessment does not conflict with the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.834292 | Disordered | 0.371716 | Uncertain | 0.880 | 0.562 | 0.625 | -6.460 | Likely Benign | 0.899 | Likely Pathogenic | Ambiguous | 0.181 | Likely Benign | -2.33 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.73 | Pathogenic | 0.00 | Affected | 0.1510 | 0.1883 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3743T>A | L1248Q 2D  AIThe SynGAP1 missense variant L1248Q is not reported in ClinVar and is absent from gnomAD. 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—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 predicts pathogenic, and the SGM‑Consensus (majority vote) confirms this prediction; the Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a pathogenic effect for this variant, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.834292 | Disordered | 0.371716 | Uncertain | 0.880 | 0.562 | 0.625 | -6.471 | Likely Benign | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.364 | Likely Benign | -4.65 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.64 | Pathogenic | 0.00 | Affected | 0.1067 | 0.0688 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||||||
| c.3743T>C | L1248P 2D AIThe SynGAP1 missense variant L1248P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus agrees. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.834292 | Disordered | 0.371716 | Uncertain | 0.880 | 0.562 | 0.625 | -14.647 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.410 | Likely Benign | -5.45 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.64 | Pathogenic | 0.00 | Affected | 0.3596 | 0.0848 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||
| c.3743T>G | L1248R 2D AIThe SynGAP1 missense variant L1248R 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. No Foldetta stability analysis is available for this variant. Based on the preponderance of pathogenic predictions, the variant 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 | 0.834292 | Disordered | 0.371716 | Uncertain | 0.880 | 0.562 | 0.625 | -11.285 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.370 | Likely Benign | -4.69 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.64 | Pathogenic | 0.00 | Affected | 0.1222 | 0.0488 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||
| c.3853C>A | P1285T 2D AIThe SynGAP1 missense variant P1285T is catalogued in gnomAD (ID 6‑33447901‑C‑A) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign outcome: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as tolerated or benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Benign verdict. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no reported result for this variant, so its status is unavailable. Overall, the computational evidence overwhelmingly supports a benign effect, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.821643 | Binding | 0.557 | 0.759 | 0.750 | 6-33447901-C-A | -4.230 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.047 | Likely Benign | -0.35 | Neutral | 0.451 | Benign | 0.193 | Benign | 4.33 | Benign | 0.40 | Tolerated | 4.32 | 2 | 0.1496 | 0.3556 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3853C>G | P1285A 2D AIThe SynGAP1 missense variant P1285A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.821643 | Binding | 0.557 | 0.759 | 0.750 | -3.902 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.052 | Likely Benign | -0.52 | Neutral | 0.264 | Benign | 0.070 | Benign | 4.27 | Benign | 0.71 | Tolerated | 0.2944 | 0.2974 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3853C>T | P1285S 2D AIThe SynGAP1 missense variant P1285S is reported in gnomAD (variant ID 6‑33447901‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags it as pathogenic, creating a single discordant call. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign impact, and this is not in conflict with ClinVar, which currently has no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.821643 | Binding | 0.557 | 0.759 | 0.750 | 6-33447901-C-T | 1 | 6.44e-7 | -3.875 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -1.27 | Neutral | 0.802 | Possibly Damaging | 0.249 | Benign | 4.34 | Benign | 0.29 | Tolerated | 4.32 | 2 | 0.2912 | 0.3319 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3854C>A | P1285Q 2D AIThe SynGAP1 missense variant P1285Q is reported in gnomAD (variant ID 6‑33447902‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also 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 status (none is provided). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.821643 | Binding | 0.557 | 0.759 | 0.750 | 6-33447902-C-A | -4.073 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -1.67 | Neutral | 0.977 | Probably Damaging | 0.632 | Possibly Damaging | 4.22 | Benign | 0.13 | Tolerated | 4.32 | 2 | 0.1476 | 0.3025 | -1 | 0 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||
| c.3854C>G | P1285R 2D AIThe SynGAP1 missense variant P1285R is reported in gnomAD (variant ID 6‑33447902‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the majority of evidence points to a benign impact. There is no ClinVar classification to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.821643 | Binding | 0.557 | 0.759 | 0.750 | 6-33447902-C-G | -3.417 | Likely Benign | 0.157 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -2.10 | Neutral | 0.977 | Probably Damaging | 0.632 | Possibly Damaging | 4.22 | Benign | 0.14 | Tolerated | 4.32 | 2 | 0.1564 | 0.2194 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||
| c.3854C>T | P1285L 2D AIThe SynGAP1 missense variant P1285L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the collective evidence strongly supports a benign classification for P1285L, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.821643 | Binding | 0.557 | 0.759 | 0.750 | -3.663 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.072 | Likely Benign | 0.06 | Neutral | 0.072 | Benign | 0.029 | Benign | 4.31 | Benign | 1.00 | Tolerated | 0.2159 | 0.4539 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3247A>C | K1083Q 2D  AIThe SynGAP1 missense variant K1083Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 HumDiv and HumVar. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign effect. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy tools points to a benign impact for K1083Q, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.978906 | Binding | 0.302 | 0.893 | 1.000 | -2.214 | Likely Benign | 0.390 | Ambiguous | Likely Benign | 0.099 | Likely Benign | -0.50 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 4.06 | Benign | 0.37 | Tolerated | 0.4821 | 0.1647 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3247A>G | K1083E 2D  AIThe SynGAP1 missense variant K1083E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is not available for this variant. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.978906 | Binding | 0.302 | 0.893 | 1.000 | -3.538 | Likely Benign | 0.864 | Likely Pathogenic | Ambiguous | 0.133 | Likely Benign | -0.78 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 4.09 | Benign | 0.27 | Tolerated | 0.4135 | 0.1717 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3248A>C | K1083T 2D  AIThe SynGAP1 missense variant K1083T is reported in gnomAD (ID 6‑33443800‑A‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.978906 | Binding | 0.302 | 0.893 | 1.000 | 6-33443800-A-C | 2 | 1.26e-6 | -2.870 | Likely Benign | 0.690 | Likely Pathogenic | Likely Benign | 0.233 | Likely Benign | -0.76 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 4.05 | Benign | 0.31 | Tolerated | 3.77 | 5 | 0.2192 | 0.4150 | -1 | 0 | 3.2 | -27.07 | ||||||||||||||||||||||||||||||||||
| c.3248A>G | K1083R 2D  AIThe SynGAP1 missense variant K1083R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.978906 | Binding | 0.302 | 0.893 | 1.000 | -2.212 | Likely Benign | 0.132 | Likely Benign | Likely Benign | 0.119 | Likely Benign | -0.53 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 4.06 | Benign | 0.84 | Tolerated | 0.5053 | 0.1903 | Weaken | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||||||||||
| c.3248A>T | K1083I 2D  AIThe SynGAP1 missense variant K1083I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.978906 | Binding | 0.302 | 0.893 | 1.000 | -3.207 | Likely Benign | 0.836 | Likely Pathogenic | Ambiguous | 0.239 | Likely Benign | -1.65 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 4.02 | Benign | 0.30 | Tolerated | 0.1394 | 0.3978 | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||||||||||||||||
| c.3249A>C | K1083N 2D  AIThe SynGAP1 missense variant K1083N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.978906 | Binding | 0.302 | 0.893 | 1.000 | -4.088 | Likely Benign | 0.873 | Likely Pathogenic | Ambiguous | 0.053 | Likely Benign | -0.83 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 4.04 | Benign | 0.21 | Tolerated | 0.3939 | 0.2234 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3249A>T | K1083N 2D AIThe SynGAP1 missense variant K1083N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.978906 | Binding | 0.302 | 0.893 | 1.000 | -4.088 | Likely Benign | 0.873 | Likely Pathogenic | Ambiguous | 0.053 | Likely Benign | -0.83 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 4.04 | Benign | 0.21 | Tolerated | 0.3939 | 0.2234 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3367G>A | G1123S 2D  AIThe SynGAP1 missense variant G1123S is reported in gnomAD (variant ID 6-33443919-G-A) but has no ClinVar entry. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.827246 | Binding | 0.346 | 0.934 | 0.875 | 6-33443919-G-A | -4.918 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.291 | Likely Benign | -0.32 | Neutral | 0.292 | Benign | 0.157 | Benign | 4.66 | Benign | 0.57 | Tolerated | 3.77 | 5 | 0.2554 | 0.5111 | 0 | 1 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||||||
| c.3367G>C | G1123R 2D AIThe SynGAP1 missense variant G1123R is not reported in ClinVar (no entry) and is absent from gnomAD. Consensus from routine in silico predictors shows a split: benign calls come from REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls arise from polyPhen‑2 HumDiv and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessment further supports a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign outcome, and no Foldetta stability data are available. Consequently, the overall evidence points to a benign effect for G1123R. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.837511 | Disordered | 0.827246 | Binding | 0.346 | 0.934 | 0.875 | -9.104 | Likely Pathogenic | 0.525 | Ambiguous | Likely Benign | 0.330 | Likely Benign | -0.46 | Neutral | 0.802 | Possibly Damaging | 0.435 | Benign | 4.34 | Benign | 0.57 | Tolerated | 0.0933 | 0.4342 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3367G>T | G1123C 2D  AIThe SynGAP1 missense variant G1123C is listed in gnomAD (ID 6‑33443919‑G‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and ESM1b predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; Foldetta results are unavailable. Overall, the majority of evidence—including the consensus and high‑accuracy tools—supports a benign classification. This conclusion is not contradicted by ClinVar, which contains no record for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.827246 | Binding | 0.346 | 0.934 | 0.875 | 6-33443919-G-T | 1 | 6.64e-7 | -9.329 | Likely Pathogenic | 0.118 | Likely Benign | Likely Benign | 0.353 | Likely Benign | -1.17 | Neutral | 0.994 | Probably Damaging | 0.840 | Possibly Damaging | 4.34 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.1348 | 0.4227 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||
| c.3368G>A | G1123D 2D  AISynGAP1 missense variant G1123D is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443920‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and ESM1b. AlphaMissense‑Default remains uncertain, and Foldetta stability analysis is unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus also benign, while Foldetta provides no result. Overall, the preponderance of evidence points to a benign effect, which does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.837511 | Disordered | 0.827246 | Binding | 0.346 | 0.934 | 0.875 | Uncertain | 2 | 6-33443920-G-A | 2 | 1.33e-6 | -10.321 | Likely Pathogenic | 0.405 | Ambiguous | Likely Benign | 0.360 | Likely Benign | -0.78 | Neutral | 0.500 | Possibly Damaging | 0.157 | Benign | 4.34 | Benign | 0.19 | Tolerated | 3.77 | 5 | 0.1792 | 0.2035 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||
| c.3368G>C | G1123A 2D AIThe SynGAP1 missense variant G1123A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated methods. High‑accuracy tools 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 | 0.837511 | Disordered | 0.827246 | Binding | 0.346 | 0.934 | 0.875 | -6.720 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.240 | Likely Benign | -0.55 | Neutral | 0.264 | Benign | 0.103 | Benign | 4.38 | Benign | 1.00 | Tolerated | 0.3544 | 0.4944 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3368G>T | G1123V 2D AIThe SynGAP1 missense variant G1123V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; ESM1b is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the collective predictions strongly suggest that G1123V 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 | 0.837511 | Disordered | 0.827246 | Binding | 0.346 | 0.934 | 0.875 | -7.129 | In-Between | 0.091 | Likely Benign | Likely Benign | 0.333 | Likely Benign | -1.03 | Neutral | 0.292 | Benign | 0.157 | Benign | 4.35 | Benign | 0.29 | Tolerated | 0.1362 | 0.3694 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3370G>A | G1124R 2D AISynGAP1 missense variant G1124R is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443922‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and ESM1b, while AlphaMissense‑Default remains uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to benign. High‑accuracy methods give AlphaMissense‑Optimized as benign; the SGM Consensus also supports benign. Foldetta, a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the ensemble of predictions leans toward a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.837511 | Disordered | 0.833401 | Binding | 0.341 | 0.931 | 0.875 | Conflicting | 3 | 6-33443922-G-A | 24 | 1.60e-5 | -8.918 | Likely Pathogenic | 0.534 | Ambiguous | Likely Benign | 0.243 | Likely Benign | -0.58 | Neutral | 0.002 | Benign | 0.002 | Benign | 4.81 | Benign | 0.01 | Affected | 3.77 | 5 | 0.0935 | 0.4332 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||
| c.3370G>C | G1124R 2D AIThe SynGAP1 missense variant G1124R is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors shows a predominance of benign calls: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized all predict a benign effect, while SIFT and ESM1b predict pathogenicity. The AlphaMissense‑Default tool is uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized is benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also returns benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the balance of evidence points to a benign impact for G1124R, and this conclusion is consistent with the absence of any ClinVar annotation or gnomAD observation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.837511 | Disordered | 0.833401 | Binding | 0.341 | 0.931 | 0.875 | -8.918 | Likely Pathogenic | 0.534 | Ambiguous | Likely Benign | 0.239 | Likely Benign | -0.58 | Neutral | 0.002 | Benign | 0.002 | Benign | 4.81 | Benign | 0.01 | Affected | 3.77 | 5 | 0.0935 | 0.4332 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3371G>A | G1124E 2D AIThe SynGAP1 missense variant G1124E is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and ESM1b, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors a benign outcome (2 benign vs. 1 pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.837511 | Disordered | 0.833401 | Binding | 0.341 | 0.931 | 0.875 | -10.403 | Likely Pathogenic | 0.345 | Ambiguous | Likely Benign | 0.301 | Likely Benign | -0.84 | Neutral | 0.126 | Benign | 0.066 | Benign | 4.78 | Benign | 0.02 | Affected | 0.1405 | 0.4063 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3371G>C | G1124A 2D AIThe SynGAP1 missense variant G1124A 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 interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign,” and the Foldetta stability analysis is unavailable. Taken together, the overwhelming majority of computational evidence classifies G1124A as 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 | 0.837511 | Disordered | 0.833401 | Binding | 0.341 | 0.931 | 0.875 | -6.608 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.199 | Likely Benign | -0.39 | Neutral | 0.059 | Benign | 0.041 | Benign | 4.81 | Benign | 0.02 | Affected | 0.3494 | 0.5138 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3371G>T | G1124V 2D AIThe SynGAP1 missense variant G1124V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta results are unavailable, so they do not influence the assessment. Overall, the consensus of available predictions indicates that G1124V is most likely benign, 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 | 0.837511 | Disordered | 0.833401 | Binding | 0.341 | 0.931 | 0.875 | -6.980 | Likely Benign | 0.094 | Likely Benign | Likely Benign | 0.315 | Likely Benign | -0.96 | Neutral | 0.586 | Possibly Damaging | 0.172 | Benign | 4.75 | Benign | 0.00 | Affected | 0.1299 | 0.3888 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3886G>A | E1296K 2D  AIThe SynGAP1 missense variant E1296K is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM; pathogenic predictions come from PROVEAN, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign effect, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence points toward a benign impact, with no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -3.435 | Likely Benign | 0.713 | Likely Pathogenic | Likely Benign | 0.136 | Likely Benign | -2.80 | Deleterious | 0.241 | Benign | 0.210 | Benign | 2.65 | Benign | 0.05 | Affected | 0.1951 | 0.6138 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||||
| c.3886G>C | E1296Q 2D  AIThe SynGAP1 missense variant E1296Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and 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 | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -2.510 | Likely Benign | 0.286 | Likely Benign | Likely Benign | 0.148 | Likely Benign | -2.11 | Neutral | 0.992 | Probably Damaging | 0.868 | Possibly Damaging | 2.60 | Benign | 0.03 | Affected | 0.0978 | 0.5736 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3887A>C | E1296A 2D  AIThe SynGAP1 missense variant E1296A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy predictions therefore indicate a benign outcome: AlphaMissense‑Optimized is benign, the SGM Consensus is benign, and Foldetta data are missing. Consequently, the variant is most likely benign based on the collective 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. | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -2.562 | Likely Benign | 0.372 | Ambiguous | Likely Benign | 0.238 | Likely Benign | -4.08 | Deleterious | 0.980 | Probably Damaging | 0.812 | Possibly Damaging | 2.61 | Benign | 0.02 | Affected | 0.3664 | 0.5506 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3887A>G | E1296G 2D  AIThe SynGAP1 missense variant E1296G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are 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 | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -2.864 | Likely Benign | 0.221 | Likely Benign | Likely Benign | 0.204 | Likely Benign | -5.10 | Deleterious | 0.992 | Probably Damaging | 0.868 | Possibly Damaging | 2.56 | Benign | 0.01 | Affected | 0.2971 | 0.5231 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3887A>T | E1296V 2D  AIThe SynGAP1 missense variant E1296V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. High‑accuracy predictions therefore indicate a benign outcome: AlphaMissense‑Optimized is benign, the SGM Consensus is benign, and no Foldetta data are available. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -3.384 | Likely Benign | 0.443 | Ambiguous | Likely Benign | 0.229 | Likely Benign | -4.24 | Deleterious | 0.992 | Probably Damaging | 0.902 | Possibly Damaging | 2.62 | Benign | 0.01 | Affected | 0.0678 | 0.6040 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||||
| c.3888G>C | E1296D 2D  AIThe SynGAP1 missense variant E1296D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -3.566 | Likely Benign | 0.276 | Likely Benign | Likely Benign | 0.299 | Likely Benign | -2.15 | Neutral | 0.980 | Probably Damaging | 0.812 | Possibly Damaging | 2.59 | Benign | 0.04 | Affected | 0.1906 | 0.3443 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3888G>T | E1296D 2D AIThe SynGAP1 missense variant E1296D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -3.566 | Likely Benign | 0.276 | Likely Benign | Likely Benign | 0.493 | Likely Benign | -2.15 | Neutral | 0.980 | Probably Damaging | 0.812 | Possibly Damaging | 2.59 | Benign | 0.04 | Affected | 0.1906 | 0.3443 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3250C>A | P1084T 2D AIThe SynGAP1 missense variant P1084T is reported in ClinVar as “Not submitted” and is present in gnomAD (ID 6‑33443802‑C‑A). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it as pathogenic, but this is the sole discordant call. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are not available. Overall, the preponderance of evidence indicates the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently contains no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.979020 | Binding | 0.348 | 0.889 | 1.000 | 6-33443802-C-A | -4.665 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.127 | Likely Benign | -2.14 | Neutral | 0.025 | Benign | 0.012 | Benign | 4.11 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1546 | 0.6793 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3250C>G | P1084A 2D AIThe SynGAP1 missense variant P1084A is listed in ClinVar (ID 2827308.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which itself is “Likely Benign”). In contrast, PROVEAN and polyPhen‑2 HumDiv predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.979020 | Binding | 0.348 | 0.889 | 1.000 | Uncertain | 1 | -3.928 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.114 | Likely Benign | -2.54 | Deleterious | 0.649 | Possibly Damaging | 0.157 | Benign | 4.05 | Benign | 0.35 | Tolerated | 3.77 | 5 | 0.3164 | 0.5784 | -1 | 1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||
| c.3250C>T | P1084S 2D AIThe SynGAP1 missense variant P1084S is reported in gnomAD (variant ID 6‑33443802‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.979020 | Binding | 0.348 | 0.889 | 1.000 | 6-33443802-C-T | 1 | 6.31e-7 | -3.987 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.086 | Likely Benign | -2.24 | Neutral | 0.481 | Possibly Damaging | 0.157 | Benign | 4.03 | Benign | 0.03 | Affected | 3.77 | 5 | 0.3102 | 0.6215 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3251C>A | P1084H 2D AIThe SynGAP1 missense variant P1084H is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443803‑C‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which reports “Likely Benign”). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the ClinVar designation of uncertainty rather than a definitive pathogenic claim. Thus, the variant is most likely benign, and its prediction profile does not contradict the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.979020 | Binding | 0.348 | 0.889 | 1.000 | Uncertain | 1 | 6-33443803-C-A | 1 | 6.31e-7 | -4.125 | Likely Benign | 0.323 | Likely Benign | Likely Benign | 0.134 | Likely Benign | -3.16 | Deleterious | 0.997 | Probably Damaging | 0.840 | Possibly Damaging | 3.96 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1751 | 0.5523 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||
| c.3251C>G | P1084R 2D AIThe SynGAP1 missense variant P1084R is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443803‑C‑G). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors a benign outcome (2 benign vs 1 pathogenic vote). Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for P1084R, and this conclusion does not contradict the ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.842060 | Disordered | 0.979020 | Binding | 0.348 | 0.889 | 1.000 | 6-33443803-C-G | 4 | 2.52e-6 | -4.171 | Likely Benign | 0.562 | Ambiguous | Likely Benign | 0.153 | Likely Benign | -2.87 | Deleterious | 0.970 | Probably Damaging | 0.637 | Possibly Damaging | 3.99 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1370 | 0.4153 | -2 | 0 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.3251C>T | P1084L 2D AIThe SynGAP1 missense variant P1084L is reported in gnomAD (ID 6‑33443803‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.979020 | Binding | 0.348 | 0.889 | 1.000 | 6-33443803-C-T | 1 | 6.31e-7 | -4.547 | Likely Benign | 0.175 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -3.33 | Deleterious | 0.649 | Possibly Damaging | 0.157 | Benign | 4.00 | Benign | 0.01 | Affected | 3.77 | 5 | 0.2218 | 0.6470 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| c.3835G>A | A1279T 2D  AIThe SynGAP1 missense variant A1279T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33447883‑G‑A). All available in silico predictors report a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized are benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” No tool predicts pathogenicity. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is benign; Foldetta results are not available. 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 | 0.842060 | Disordered | 0.814139 | Binding | 0.485 | 0.724 | 0.750 | Uncertain | 2 | 6-33447883-G-A | 2 | 1.29e-6 | -4.871 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.178 | Likely Benign | -0.30 | Neutral | 0.001 | Benign | 0.000 | Benign | 2.71 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.1027 | 0.5871 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||
| c.3835G>C | A1279P 2D  AIThe SynGAP1 missense variant A1279P 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 predictor, was not available for this variant. Overall, the collective evidence strongly suggests the variant is most likely benign, 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 | 0.842060 | Disordered | 0.814139 | Binding | 0.485 | 0.724 | 0.750 | -3.999 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.167 | Likely Benign | -0.68 | Neutral | 0.299 | Benign | 0.087 | Benign | 2.67 | Benign | 0.15 | Tolerated | 0.1589 | 0.3938 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3835G>T | A1279S 2D  AIThe SynGAP1 missense variant A1279S is catalogued in gnomAD (ID 6‑33447883‑G‑T) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool listed—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently scores the substitution as benign. No pathogenic predictions are reported. Grouping by agreement, the benign‑predicting tools comprise the entire set, while the pathogenic group is empty. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “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 is unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.814139 | Binding | 0.485 | 0.724 | 0.750 | 6-33447883-G-T | -4.281 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.134 | Likely Benign | 0.37 | Neutral | 0.019 | Benign | 0.019 | Benign | 2.74 | Benign | 0.16 | Tolerated | 3.77 | 5 | 0.2166 | 0.4583 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.3836C>A | A1279D 2D  AIThe SynGAP1 missense variant A1279D is catalogued in gnomAD (ID 6‑33447884‑C‑A) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool listed—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classifies the substitution as benign. No pathogenic predictions are reported. Grouping by agreement, all available tools fall into the benign category, with no tools indicating pathogenicity. High‑accuracy assessments further support 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, has no result for this variant and is therefore considered unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.814139 | Binding | 0.485 | 0.724 | 0.750 | 6-33447884-C-A | -3.914 | Likely Benign | 0.172 | Likely Benign | Likely Benign | 0.087 | Likely Benign | 1.38 | Neutral | 0.000 | Benign | 0.000 | Benign | 2.89 | Benign | 0.35 | Tolerated | 3.77 | 5 | 0.1505 | 0.2062 | -2 | 0 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||
| c.3836C>G | A1279G 2D  AIThe SynGAP1 missense variant A1279G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports “Likely Benign.” No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, SGM‑Consensus reports 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 reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.814139 | Binding | 0.485 | 0.724 | 0.750 | -3.469 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.064 | Likely Benign | -0.97 | Neutral | 0.033 | Benign | 0.017 | Benign | 2.69 | Benign | 0.19 | Tolerated | 0.1884 | 0.3473 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3836C>T | A1279V 2D  AIThe SynGAP1 missense variant A1279V is reported in gnomAD (ID 6‑33447884‑C‑T) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool examined—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classifies the substitution as benign. No pathogenic predictions appear in the dataset, so the pathogenic group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized returns a benign score, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, has no available result for this variant. Taken together, the consensus of all available predictions is that A1279V is most likely benign, and this assessment does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.814139 | Binding | 0.485 | 0.724 | 0.750 | 6-33447884-C-T | -4.892 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -1.23 | Neutral | 0.017 | Benign | 0.017 | Benign | 2.68 | Benign | 0.07 | Tolerated | 3.77 | 5 | 0.0777 | 0.5005 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||
| c.3955G>A | A1319T 2D AIThe SynGAP1 missense variant A1319T is reported in gnomAD (variant ID 6‑33451829‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts a benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT each predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, SGM‑Consensus is benign, and the Foldetta stability analysis is unavailable. Overall, the majority of evidence supports a benign impact for A1319T, and this conclusion does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.960481 | Binding | 0.454 | 0.851 | 0.750 | 6-33451829-G-A | -4.861 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.30 | Neutral | 0.917 | Possibly Damaging | 0.500 | Possibly Damaging | 4.13 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1944 | 0.7174 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||
| c.3955G>C | A1319P 2D AIThe SynGAP1 missense variant A1319P is reported in ClinVar as “Not submitted” and is present in gnomAD (ID 6‑33451829‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently contains no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.960481 | Binding | 0.454 | 0.851 | 0.750 | 6-33451829-G-C | 3 | 1.95e-6 | -2.783 | Likely Benign | 0.057 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -0.81 | Neutral | 0.992 | Probably Damaging | 0.878 | Possibly Damaging | 4.06 | Benign | 0.03 | Affected | 3.77 | 5 | 0.2360 | 0.5715 | -1 | 1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||||||
| c.3955G>T | A1319S 2D AIThe SynGAP1 missense variant A1319S is catalogued in gnomAD (ID 6‑33451829‑G‑T) but has no ClinVar entry. Functional prediction tools uniformly classify it as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign effects. No tool predicts pathogenicity. Grouping by consensus, all listed predictors fall into the benign category, with no pathogenic predictions to counterbalance. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign outcome. Foldetta results are not available for this variant. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.960481 | Binding | 0.454 | 0.851 | 0.750 | 6-33451829-G-T | -4.557 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.094 | Likely Benign | 0.79 | Neutral | 0.174 | Benign | 0.112 | Benign | 4.17 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2957 | 0.5676 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.3956C>A | A1319D 2D AIThe SynGAP1 missense variant A1319D is reported in gnomAD (ID 6‑33451830‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority of the same four tools) is benign. Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for A1319D, and this conclusion is not contradicted by any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.960481 | Binding | 0.454 | 0.851 | 0.750 | 6-33451830-C-A | -5.156 | Likely Benign | 0.297 | Likely Benign | Likely Benign | 0.208 | Likely Benign | -0.85 | Neutral | 0.971 | Probably Damaging | 0.813 | Possibly Damaging | 4.08 | Benign | 0.01 | Affected | 3.77 | 5 | 0.2290 | 0.2702 | -2 | 0 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||
| c.3956C>G | A1319G 2D AIThe SynGAP1 missense variant A1319G is listed in ClinVar (ID 1690510.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451830‑C‑G). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this is consistent with the ClinVar “Uncertain” status rather than contradicting it. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.960481 | Binding | 0.454 | 0.851 | 0.750 | Uncertain | 2 | 6-33451830-C-G | -3.927 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.128 | Likely Benign | -0.74 | Neutral | 0.819 | Possibly Damaging | 0.581 | Possibly Damaging | 4.07 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0.2423 | 0.4541 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.3956C>T | A1319V 2D AIThe SynGAP1 missense variant A1319V is reported in gnomAD (ID 6‑33451830‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority of the same four tools) is benign. Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for A1319V, and this conclusion is not contradicted by any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.960481 | Binding | 0.454 | 0.851 | 0.750 | 6-33451830-C-T | 1 | 7.16e-7 | -5.015 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.167 | Likely Benign | -0.17 | Neutral | 0.971 | Probably Damaging | 0.757 | Possibly Damaging | 4.14 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1583 | 0.6127 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||
| c.2194A>G | R732G 2D  AIThe SynGAP1 R732G missense variant is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (ID 6‑33441659‑A‑G). Prediction tools that agree on a benign effect include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs. 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of standard predictors lean toward pathogenicity, while the most accurate single predictor (AlphaMissense‑Optimized) suggests a benign outcome. Given the lack of ClinVar evidence, there is no contradiction; the variant is most likely pathogenic based on the collective predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.846163 | Disordered | 0.412403 | Uncertain | 0.427 | 0.673 | 0.750 | 6-33441659-A-G | 1 | 6.20e-7 | -9.348 | Likely Pathogenic | 0.295 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -2.98 | Deleterious | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 2.56 | Benign | 0.03 | Affected | 3.59 | 7 | 0.3080 | 0.2942 | -2 | -3 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||
| c.2194A>T | R732W 2D  AIThe SynGAP1 missense variant R732W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, five tools predict pathogenicity versus four predicting benign, with no ClinVar evidence to contradict these computational findings. Thus, the variant is most likely pathogenic based on the current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.846163 | Disordered | 0.412403 | Uncertain | 0.427 | 0.673 | 0.750 | -11.976 | Likely Pathogenic | 0.252 | Likely Benign | Likely Benign | 0.161 | Likely Benign | -3.57 | Deleterious | 1.000 | Probably Damaging | 0.973 | Probably Damaging | 2.53 | Benign | 0.01 | Affected | 0.1332 | 0.2748 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2195G>A | R732K 2D  AIThe SynGAP1 missense variant R732K is listed in ClinVar (ID 537019.0) with an “Uncertain” clinical significance and is present in gnomAD (6‑33441660‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. 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 consensus does not conflict with the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.846163 | Disordered | 0.412403 | Uncertain | 0.427 | 0.673 | 0.750 | Conflicting | 2 | 6-33441660-G-A | 4 | 2.48e-6 | -5.278 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.82 | Neutral | 0.973 | Probably Damaging | 0.943 | Probably Damaging | 2.69 | Benign | 0.21 | Tolerated | 3.59 | 7 | 0.4194 | 0.3923 | 3 | 2 | 0.6 | -28.01 | ||||||||||||||||||||||||||||||||
| c.2195G>C | R732T 2D  AISynGAP1 missense variant R732T is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign (REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Optimized) and pathogenic (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b). AlphaMissense‑Default remains uncertain. The high‑accuracy AlphaMissense‑Optimized predicts a benign effect, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also favors 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 preponderance of evidence from both general and high‑accuracy predictors points to a benign impact, which does not contradict the current ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.846163 | Disordered | 0.412403 | Uncertain | 0.427 | 0.673 | 0.750 | Uncertain | 1 | -8.545 | Likely Pathogenic | 0.434 | Ambiguous | Likely Benign | 0.075 | Likely Benign | -1.96 | Neutral | 0.999 | Probably Damaging | 0.892 | Possibly Damaging | 2.59 | Benign | 0.12 | Tolerated | 3.59 | 7 | 0.1915 | 0.3153 | -1 | -1 | 3.8 | -55.08 | ||||||||||||||||||||||||||||||||||||
| c.2195G>T | R732M 2D  AIThe SynGAP1 missense variant R732M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and ESM1b. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors a benign outcome. Foldetta results are unavailable. Overall, the balance of evidence (5 benign vs 3 pathogenic predictions) indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.846163 | Disordered | 0.412403 | Uncertain | 0.427 | 0.673 | 0.750 | -9.956 | Likely Pathogenic | 0.414 | Ambiguous | Likely Benign | 0.098 | Likely Benign | -1.42 | Neutral | 0.840 | Possibly Damaging | 0.357 | Benign | 2.55 | Benign | 0.01 | Affected | 0.1432 | 0.2980 | 0 | -1 | 6.4 | -24.99 | ||||||||||||||||||||||||||||||||||||||||
| c.2196G>C | R732S 2D  AIThe SynGAP1 missense variant R732S is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the balance of evidence (five benign versus four pathogenic predictions) favors a benign classification. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.846163 | Disordered | 0.412403 | Uncertain | 0.427 | 0.673 | 0.750 | -8.019 | Likely Pathogenic | 0.599 | Likely Pathogenic | Likely Benign | 0.115 | Likely Benign | -1.81 | Neutral | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 2.61 | Benign | 0.14 | Tolerated | 0.2850 | 0.3129 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.2196G>T | R732S 2D AIThe SynGAP1 missense variant R732S is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign impact for R732S, 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. | 0.846163 | Disordered | 0.412403 | Uncertain | 0.427 | 0.673 | 0.750 | -8.019 | Likely Pathogenic | 0.599 | Likely Pathogenic | Likely Benign | 0.115 | Likely Benign | -1.81 | Neutral | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 2.61 | Benign | 0.14 | Tolerated | 0.2850 | 0.3129 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3052A>C | T1018P 2D AIThe SynGAP1 missense variant T1018P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.959985 | Binding | 0.348 | 0.801 | 0.500 | -2.046 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.218 | Likely Benign | -1.39 | Neutral | 0.586 | Possibly Damaging | 0.302 | Benign | 2.24 | Pathogenic | 0.02 | Affected | 0.2155 | 0.3960 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3052A>G | T1018A 2D AIThe SynGAP1 missense variant T1018A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.959985 | Binding | 0.348 | 0.801 | 0.500 | -3.289 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -0.55 | Neutral | 0.001 | Benign | 0.004 | Benign | 2.34 | Pathogenic | 0.53 | Tolerated | 0.3859 | 0.3362 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3052A>T | T1018S 2D AIThe SynGAP1 missense variant T1018S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.959985 | Binding | 0.348 | 0.801 | 0.500 | -2.897 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.090 | Likely Benign | -0.20 | Neutral | 0.004 | Benign | 0.008 | Benign | 2.48 | Pathogenic | 0.06 | Tolerated | 0.3426 | 0.3404 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3053C>A | T1018N 2D  AIThe SynGAP1 missense variant T1018N is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign impact. The predictions do not contradict any ClinVar status, as no ClinVar claim exists for this variant. Thus, based on current computational predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.959985 | Binding | 0.348 | 0.801 | 0.500 | -3.888 | Likely Benign | 0.165 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -1.74 | Neutral | 0.411 | Benign | 0.139 | Benign | 2.25 | Pathogenic | 0.01 | Affected | 0.1537 | 0.3979 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||||||||||||
| c.3053C>G | T1018S 2D AIThe SynGAP1 missense variant T1018S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.959985 | Binding | 0.348 | 0.801 | 0.500 | -2.897 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.026 | Likely Benign | -0.20 | Neutral | 0.004 | Benign | 0.008 | Benign | 2.48 | Pathogenic | 0.06 | Tolerated | 0.3426 | 0.3404 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3053C>T | T1018I 2D AIThe SynGAP1 missense variant T1018I is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443605‑C‑T). Prediction tools that agree on benign impact include REVEL, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized, while those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta results are unavailable. Overall, the predictions are split, with no clear majority leaning toward either benign or pathogenic. Thus, the variant’s impact remains inconclusive, and this uncertainty aligns with ClinVar’s current “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.849326 | Disordered | 0.959985 | Binding | 0.348 | 0.801 | 0.500 | Uncertain | 1 | 6-33443605-C-T | 4 | 2.48e-6 | -3.264 | Likely Benign | 0.524 | Ambiguous | Likely Benign | 0.076 | Likely Benign | -2.55 | Deleterious | 0.586 | Possibly Damaging | 0.304 | Benign | 2.24 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.1022 | 0.4776 | -1 | 0 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||
| c.3088C>A | H1030N 2D  AIThe SynGAP1 missense variant H1030N is not reported in ClinVar and is absent from gnomAD. Consensus prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized returns a benign prediction, and the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign classification, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -3.454 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.033 | Likely Benign | -0.88 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.78 | Benign | 0.04 | Affected | 0.1553 | 0.3195 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3088C>G | H1030D 2D  AIThe SynGAP1 missense variant H1030D is reported in gnomAD (variant ID 6‑33443640‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign. Only SIFT predicts a pathogenic effect, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | 6-33443640-C-G | 1 | 6.19e-7 | -3.500 | Likely Benign | 0.424 | Ambiguous | Likely Benign | 0.189 | Likely Benign | -0.85 | Neutral | 0.126 | Benign | 0.066 | Benign | 2.78 | Benign | 0.05 | Affected | 3.77 | 5 | 0.2273 | 0.2422 | -1 | 1 | -0.3 | -22.05 | ||||||||||||||||||||||||||||||||||
| c.3088C>T | H1030Y 2D  AIThe SynGAP1 missense variant H1030Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for H1030Y, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -5.365 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.026 | Likely Benign | -1.73 | Neutral | 0.812 | Possibly Damaging | 0.298 | Benign | 2.73 | Benign | 0.01 | Affected | 0.0874 | 0.4236 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.3089A>C | H1030P 2D  AIThe SynGAP1 missense variant H1030P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta results are unavailable, so they do not influence the assessment. Overall, the consensus of available predictions indicates that H1030P is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -2.185 | Likely Benign | 0.148 | Likely Benign | Likely Benign | 0.154 | Likely Benign | -0.78 | Neutral | 0.812 | Possibly Damaging | 0.298 | Benign | 2.77 | Benign | 0.02 | Affected | 0.1872 | 0.4225 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3089A>G | H1030R 2D  AIThe SynGAP1 missense variant H1030R is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -2.312 | Likely Benign | 0.340 | Likely Benign | Likely Benign | 0.031 | Likely Benign | -1.08 | Neutral | 0.224 | Benign | 0.066 | Benign | 2.85 | Benign | 0.06 | Tolerated | 0.1872 | 0.2955 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.3089A>T | H1030L 2D  AIThe SynGAP1 missense variant H1030L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods indicates that H1030L is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -3.513 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.108 | Likely Benign | -2.35 | Neutral | 0.224 | Benign | 0.120 | Benign | 2.76 | Benign | 0.02 | Affected | 0.0968 | 0.5710 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||||||
| c.3090C>A | H1030Q 2D  AIThe SynGAP1 missense variant H1030Q is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -2.548 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.01 | Neutral | 0.004 | Benign | 0.004 | Benign | 2.88 | Benign | 0.53 | Tolerated | 0.1538 | 0.4001 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3090C>G | H1030Q 2D AIThe SynGAP1 missense variant H1030Q is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -2.548 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.01 | Neutral | 0.004 | Benign | 0.004 | Benign | 2.88 | Benign | 0.53 | Tolerated | 0.1538 | 0.4001 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3256C>A | P1086T 2D AIThe SynGAP1 missense variant P1086T is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443808‑C‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic impact. The variant is most likely pathogenic based on the available computational evidence, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.849326 | Disordered | 0.977190 | Binding | 0.393 | 0.885 | 1.000 | 6-33443808-C-A | -4.181 | Likely Benign | 0.568 | Likely Pathogenic | Likely Benign | 0.229 | Likely Benign | -2.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.75 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1343 | 0.5848 | -1 | 0 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||
| c.3256C>G | P1086A 2D AIThe SynGAP1 missense variant P1086A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors benign, and Foldetta data are unavailable. Taken together, the balance of evidence points to a benign effect for P1086A. This conclusion does not conflict with the ClinVar status, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.849326 | Disordered | 0.977190 | Binding | 0.393 | 0.885 | 1.000 | -4.317 | Likely Benign | 0.372 | Ambiguous | Likely Benign | 0.206 | Likely Benign | -2.98 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.78 | Benign | 0.00 | Affected | 0.3084 | 0.4463 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3256C>T | P1086S 2D AIThe SynGAP1 missense variant P1086S is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443808‑C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.849326 | Disordered | 0.977190 | Binding | 0.393 | 0.885 | 1.000 | 6-33443808-C-T | -3.165 | Likely Benign | 0.604 | Likely Pathogenic | Likely Benign | 0.212 | Likely Benign | -3.04 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.78 | Benign | 0.00 | Affected | 3.77 | 5 | 0.3067 | 0.4894 | -1 | 1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||
| c.3257C>A | P1086Q 2D AIThe SynGAP1 missense variant P1086Q is not reported in ClinVar (ClinVar status: None) but is present in gnomAD (ID 6‑33443809‑C‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs. two benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (five pathogenic vs. four benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.849326 | Disordered | 0.977190 | Binding | 0.393 | 0.885 | 1.000 | 6-33443809-C-A | -4.668 | Likely Benign | 0.652 | Likely Pathogenic | Likely Benign | 0.185 | Likely Benign | -2.92 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.77 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1285 | 0.4784 | -1 | 0 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||
| c.3257C>G | P1086R 2D AIThe SynGAP1 missense variant P1086R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (two pathogenic vs. two benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, more tools (five) predict pathogenicity than benign (three), and the high‑accuracy consensus is inconclusive. Therefore, the variant is most likely pathogenic based on the current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.849326 | Disordered | 0.977190 | Binding | 0.393 | 0.885 | 1.000 | -5.190 | Likely Benign | 0.848 | Likely Pathogenic | Ambiguous | 0.205 | Likely Benign | -3.42 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.86 | Benign | 0.00 | Affected | 0.1319 | 0.3551 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3257C>T | P1086L 2D AIThe SynGAP1 missense variant P1086L is not reported in ClinVar (ClinVar status: not present) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which simply indicates the variant has not yet been reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.849326 | Disordered | 0.977190 | Binding | 0.393 | 0.885 | 1.000 | -4.694 | Likely Benign | 0.607 | Likely Pathogenic | Likely Benign | 0.166 | Likely Benign | -3.57 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.73 | Benign | 0.00 | Affected | 0.2055 | 0.6326 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2227C>A | P743T 2D AIThe SynGAP1 missense variant P743T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags the variant as pathogenic, creating a single discordant prediction. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized 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 supports a benign classification, 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 | 0.852992 | Disordered | 0.526809 | Binding | 0.317 | 0.862 | 0.875 | -4.892 | Likely Benign | 0.061 | Likely Benign | Likely Benign | 0.050 | Likely Benign | -1.11 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 2.75 | Benign | 0.07 | Tolerated | 0.1461 | 0.4750 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2227C>G | P743A 2D AIThe SynGAP1 missense variant P743A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the evidence strongly supports a benign classification, and this conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.526809 | Binding | 0.317 | 0.862 | 0.875 | -4.253 | Likely Benign | 0.054 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -1.10 | Neutral | 0.005 | Benign | 0.008 | Benign | 2.78 | Benign | 0.12 | Tolerated | 0.3158 | 0.3604 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2227C>T | P743S 2D AIThe SynGAP1 missense variant P743S is listed in gnomAD (ID 6‑33441692‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the change as benign. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is “Likely Benign.” No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence indicates that P743S is most likely benign, and this conclusion is not contradicted by any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.526809 | Binding | 0.317 | 0.862 | 0.875 | 6-33441692-C-T | 1 | 6.19e-7 | -4.286 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -0.33 | Neutral | 0.021 | Benign | 0.015 | Benign | 2.93 | Benign | 0.00 | Affected | 4.32 | 2 | 0.3087 | 0.3948 | -1 | 1 | 0.8 | -10.04 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||||
| c.2228C>A | P743H 2D AIThe SynGAP1 missense variant P743H 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 overall assessment. Overall, the majority of computational evidence points to a benign effect for P743H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.526809 | Binding | 0.317 | 0.862 | 0.875 | -5.649 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.121 | Likely Benign | -1.99 | Neutral | 0.989 | Probably Damaging | 0.870 | Possibly Damaging | 2.70 | Benign | 0.01 | Affected | 0.1653 | 0.3762 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2228C>G | P743R 2D AIThe SynGAP1 missense variant P743R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.526809 | Binding | 0.317 | 0.862 | 0.875 | -4.295 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.087 | Likely Benign | -1.96 | Neutral | 0.966 | Probably Damaging | 0.494 | Possibly Damaging | 2.73 | Benign | 0.02 | Affected | 0.1488 | 0.2819 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2228C>T | P743L 2D AIThe SynGAP1 missense variant P743L is listed in gnomAD (ID 6‑33441693‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; a Foldetta stability analysis is not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status, as none is reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.526809 | Binding | 0.317 | 0.862 | 0.875 | 6-33441693-C-T | 1 | 6.19e-7 | -4.838 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.112 | Likely Benign | -2.21 | Neutral | 0.801 | Possibly Damaging | 0.192 | Benign | 2.73 | Benign | 0.00 | Affected | 4.32 | 2 | 0.2166 | 0.5533 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| c.2230C>A | Q744K 2D  AIThe SynGAP1 missense variant Q744K is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Based on the collective predictions, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.540428 | Binding | 0.316 | 0.866 | 0.875 | -3.929 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.22 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.79 | Benign | 0.07 | Tolerated | 0.1784 | 0.3757 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2230C>G | Q744E 2D  AIThe SynGAP1 missense variant Q744E 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. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.540428 | Binding | 0.316 | 0.866 | 0.875 | -4.053 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -0.57 | Neutral | 0.065 | Benign | 0.038 | Benign | 2.77 | Benign | 0.08 | Tolerated | 0.1453 | 0.1892 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2231A>C | Q744P 2D  AIThe SynGAP1 missense variant Q744P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign impact for Q744P, 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 | 0.852992 | Disordered | 0.540428 | Binding | 0.316 | 0.866 | 0.875 | -2.062 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.080 | Likely Benign | -0.46 | Neutral | 0.784 | Possibly Damaging | 0.206 | Benign | 2.82 | Benign | 0.12 | Tolerated | 0.2584 | 0.4397 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2231A>G | Q744R 2D  AIThe SynGAP1 missense variant Q744R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence indicates that 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 | 0.852992 | Disordered | 0.540428 | Binding | 0.316 | 0.866 | 0.875 | -2.207 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.43 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.80 | Benign | 0.05 | Affected | 0.1437 | 0.1588 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.2231A>T | Q744L 2D  AIThe SynGAP1 missense variant Q744L is not reported in ClinVar (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 preponderance of evidence points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.540428 | Binding | 0.316 | 0.866 | 0.875 | -3.724 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.052 | Likely Benign | -1.96 | Neutral | 0.425 | Benign | 0.158 | Benign | 2.70 | Benign | 0.02 | Affected | 0.0813 | 0.4731 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2232G>C | Q744H 2D  AIThe SynGAP1 missense variant Q744H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q744H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.540428 | Binding | 0.316 | 0.866 | 0.875 | -4.359 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -0.83 | Neutral | 0.975 | Probably Damaging | 0.574 | Possibly Damaging | 2.68 | Benign | 0.01 | Affected | 0.1452 | 0.3443 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2232G>T | Q744H 2D AIThe SynGAP1 missense variant Q744H is not reported 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 Q744H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.540428 | Binding | 0.316 | 0.866 | 0.875 | -4.359 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -0.83 | Neutral | 0.975 | Probably Damaging | 0.574 | Possibly Damaging | 2.68 | Benign | 0.01 | Affected | 0.1452 | 0.3443 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2398G>A | G800S 2D AIThe SynGAP1 missense variant G800S is reported as “Likely Benign” by the SGM‑Consensus method and is absent from ClinVar and gnomAD. All evaluated in‑silico predictors agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. 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) also indicates a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign, and this conclusion is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.852992 | Disordered | 0.588350 | Binding | 0.303 | 0.884 | 0.625 | -3.572 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -0.69 | Neutral | 0.292 | Benign | 0.157 | Benign | 2.78 | Benign | 0.60 | Tolerated | 0.2375 | 0.4923 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||||||||
| c.2398G>C | G800R 2D AIThe SynGAP1 missense variant G800R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.852992 | Disordered | 0.588350 | Binding | 0.303 | 0.884 | 0.625 | -3.613 | Likely Benign | 0.405 | Ambiguous | Likely Benign | 0.147 | Likely Benign | -0.27 | Neutral | 0.003 | Benign | 0.004 | Benign | 2.84 | Benign | 0.17 | Tolerated | 0.0868 | 0.3835 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.2398G>T | G800C 2D AIThe SynGAP1 missense variant G800C is not reported in ClinVar and has no allele in 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, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and 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 lack of a ClinVar pathogenic annotation. Based on the aggregate predictions, the variant is most likely benign, and this is consistent with the lack of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.852992 | Disordered | 0.588350 | Binding | 0.303 | 0.884 | 0.625 | -7.074 | In-Between | 0.129 | Likely Benign | Likely Benign | 0.144 | Likely Benign | -1.53 | Neutral | 0.994 | Probably Damaging | 0.840 | Possibly Damaging | 2.70 | Benign | 0.15 | Tolerated | 0.1102 | 0.4189 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||||
| c.2399G>A | G800D 2D AIThe SynGAP1 missense variant G800D is catalogued in gnomAD (6-33442951‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the change as benign or likely benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized reports a benign outcome, and the SGM‑Consensus (derived from the majority of the four high‑accuracy predictors) also yields a benign verdict. Foldetta results are unavailable, so they do not influence the assessment. Overall, the evidence strongly supports a benign classification, 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 | SH3-binding motif | 0.852992 | Disordered | 0.588350 | Binding | 0.303 | 0.884 | 0.625 | 6-33442951-G-A | -5.929 | Likely Benign | 0.400 | Ambiguous | Likely Benign | 0.088 | Likely Benign | -0.84 | Neutral | 0.451 | Benign | 0.265 | Benign | 2.76 | Benign | 0.34 | Tolerated | 4.32 | 2 | 0.1664 | 0.1877 | -1 | 1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||
| c.2399G>C | G800A 2D AIThe SynGAP1 missense variant G800A is listed in gnomAD (6-33442951‑G‑C) but has no ClinVar entry. Across the available in‑silico predictors, every tool reports a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant. Based on the unanimous benign predictions and the absence of any pathogenic calls, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.852992 | Disordered | 0.588350 | Binding | 0.303 | 0.884 | 0.625 | 6-33442951-G-C | 7 | 4.34e-6 | -3.550 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.031 | Likely Benign | -0.48 | Neutral | 0.011 | Benign | 0.006 | Benign | 2.78 | Benign | 1.00 | Tolerated | 4.32 | 2 | 0.3466 | 0.4850 | 0 | 1 | 2.2 | 14.03 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||||||||
| c.2399G>T | G800V 2D AIThe SynGAP1 missense variant G800V is predicted to be benign by all evaluated in‑silico tools. ClinVar contains no entry for this variant, and it is not reported in gnomAD. Consensus predictions from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign effect. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign outcome. Foldetta results are unavailable, so they do not influence the overall assessment. Based on the collective evidence, the variant is most likely benign, and this conclusion is consistent with the absence of a pathogenic ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.852992 | Disordered | 0.588350 | Binding | 0.303 | 0.884 | 0.625 | -4.890 | Likely Benign | 0.113 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.24 | Neutral | 0.451 | Benign | 0.157 | Benign | 2.73 | Benign | 0.25 | Tolerated | 0.1130 | 0.4198 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||
| c.2977C>A | P993T 2D AIThe SynGAP1 missense variant P993T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.923979 | Binding | 0.319 | 0.908 | 0.750 | -4.444 | Likely Benign | 0.061 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -0.65 | Neutral | 0.001 | Benign | 0.010 | Benign | 4.32 | Benign | 0.04 | Affected | 0.1603 | 0.5789 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2977C>G | P993A 2D AIThe SynGAP1 missense variant P993A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign. Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.923979 | Binding | 0.319 | 0.908 | 0.750 | -4.030 | Likely Benign | 0.052 | Likely Benign | Likely Benign | 0.036 | Likely Benign | -0.46 | Neutral | 0.001 | Benign | 0.006 | Benign | 4.26 | Benign | 0.07 | Tolerated | 0.3487 | 0.4991 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2977C>T | P993S 2D AIThe SynGAP1 missense variant P993S is reported in gnomAD (ID 6‑33443529‑C‑T) and has no ClinVar entry. All evaluated in silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Based on the unanimous benign predictions and lack of ClinVar pathogenicity, the variant is most likely benign and does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.923979 | Binding | 0.319 | 0.908 | 0.750 | 6-33443529-C-T | 3 | 1.86e-6 | -3.665 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.13 | Neutral | 0.011 | Benign | 0.023 | Benign | 4.26 | Benign | 0.59 | Tolerated | 4.32 | 2 | 0.3421 | 0.5465 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.2978C>A | P993H 2D AIThe SynGAP1 missense variant P993H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for P993H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.923979 | Binding | 0.319 | 0.908 | 0.750 | -4.535 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -0.93 | Neutral | 0.938 | Possibly Damaging | 0.819 | Possibly Damaging | 4.11 | Benign | 0.00 | Affected | 0.1799 | 0.4591 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2978C>G | P993R 2D AIThe SynGAP1 missense variant P993R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.923979 | Binding | 0.319 | 0.908 | 0.750 | -3.508 | Likely Benign | 0.158 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -0.85 | Neutral | 0.586 | Possibly Damaging | 0.478 | Possibly Damaging | 4.14 | Benign | 0.01 | Affected | 0.1469 | 0.3122 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2978C>T | P993L 2D AIThe SynGAP1 missense variant P993L is reported in ClinVar as “Not listed” and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which contains no pathogenic assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.923979 | Binding | 0.319 | 0.908 | 0.750 | -3.581 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.028 | Likely Benign | -1.37 | Neutral | 0.224 | Benign | 0.138 | Benign | 4.14 | Benign | 0.01 | Affected | 0.2299 | 0.6697 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3058C>G | R1020G 2D AIThe SynGAP1 missense variant R1020G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default all indicate pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.852992 | Disordered | 0.972945 | Binding | 0.340 | 0.777 | 0.500 | -4.898 | Likely Benign | 0.868 | Likely Pathogenic | Ambiguous | 0.162 | Likely Benign | -4.26 | Deleterious | 0.990 | Probably Damaging | 0.894 | Possibly Damaging | 2.48 | Pathogenic | 0.00 | Affected | 0.3394 | 0.3721 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3058C>T | R1020W 2D AIThe SynGAP1 missense variant R1020W is catalogued in gnomAD (ID 6‑33443610‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: the single benign predictor REVEL, and a consensus of pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic,” and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) is not available. Taken together, the preponderance of evidence indicates that R1020W is most likely pathogenic, and this conclusion does not contradict any ClinVar classification because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.852992 | Disordered | 0.972945 | Binding | 0.340 | 0.777 | 0.500 | 6-33443610-C-T | 6 | 3.72e-6 | -9.378 | Likely Pathogenic | 0.829 | Likely Pathogenic | Ambiguous | 0.165 | Likely Benign | -4.14 | Deleterious | 1.000 | Probably Damaging | 0.986 | Probably Damaging | 2.44 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1420 | 0.4373 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.3059G>A | R1020Q 2D  AIThe SynGAP1 missense variant R1020Q is catalogued in gnomAD (6‑33443611‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus also indicates “Likely Benign.” No Foldetta stability analysis is available, so it does not influence the overall assessment. Based on the collective predictions, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.972945 | Binding | 0.340 | 0.777 | 0.500 | 6-33443611-G-A | 2 | 1.24e-6 | -3.753 | Likely Benign | 0.445 | Ambiguous | Likely Benign | 0.137 | Likely Benign | -2.19 | Neutral | 0.995 | Probably Damaging | 0.870 | Possibly Damaging | 2.52 | Benign | 0.00 | Affected | 3.77 | 5 | 0.3050 | 0.2997 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||||
| c.3059G>C | R1020P 2D  AIThe SynGAP1 missense variant R1020P is listed in ClinVar (ID 3700393.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves as “Likely Pathogenic” (3 pathogenic vs. 1 benign votes). High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM‑Consensus as “Likely Pathogenic,” and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.852992 | Disordered | 0.972945 | Binding | 0.340 | 0.777 | 0.500 | Uncertain | 1 | -3.491 | Likely Benign | 0.902 | Likely Pathogenic | Ambiguous | 0.205 | Likely Benign | -3.50 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.46 | Pathogenic | 0.00 | Affected | 0.2077 | 0.5109 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||
| c.3059G>T | R1020L 2D  AISynGAP1 missense variant R1020L is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive; Foldetta stability analysis is unavailable. Overall, the majority of evidence points toward a pathogenic effect, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.972945 | Binding | 0.340 | 0.777 | 0.500 | Uncertain | 1 | -6.031 | Likely Benign | 0.907 | Likely Pathogenic | Ambiguous | 0.216 | Likely Benign | -4.03 | Deleterious | 0.990 | Probably Damaging | 0.921 | Probably Damaging | 2.50 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1898 | 0.5214 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||||
| c.3085C>A | Q1029K 2D AIThe SynGAP1 missense variant Q1029K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. AlphaMissense‑Default remains uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while Foldetta data is missing. Overall, the majority of evidence points to a benign impact for Q1029K, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.995643 | Binding | 0.375 | 0.734 | 0.500 | -3.698 | Likely Benign | 0.516 | Ambiguous | Likely Benign | 0.075 | Likely Benign | -1.18 | Neutral | 0.771 | Possibly Damaging | 0.482 | Possibly Damaging | 2.79 | Benign | 1.00 | Tolerated | 0.1656 | 0.4196 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3085C>G | Q1029E 2D AIThe SynGAP1 missense variant Q1029E is reported in gnomAD (ID 6‑33443637‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags it as pathogenic, creating a single discordant call. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.995643 | Binding | 0.375 | 0.734 | 0.500 | 6-33443637-C-G | 17 | 1.05e-5 | -3.660 | Likely Benign | 0.281 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.92 | Neutral | 0.625 | Possibly Damaging | 0.258 | Benign | 2.83 | Benign | 0.26 | Tolerated | 3.77 | 5 | 0.1327 | 0.2433 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||
| c.3086A>C | Q1029P 2D AIThe SynGAP1 missense variant Q1029P is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available for this variant. Overall, the consensus of all available predictions strongly supports a benign impact, and this conclusion is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.995643 | Binding | 0.375 | 0.734 | 0.500 | -2.940 | Likely Benign | 0.124 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -1.23 | Neutral | 0.005 | Benign | 0.015 | Benign | 2.68 | Benign | 0.15 | Tolerated | 0.1966 | 0.4986 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3086A>G | Q1029R 2D AIThe SynGAP1 missense variant Q1029R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (both HumDiv and HumVar) predict a pathogenic outcome. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign; Foldetta results are unavailable. Based on the preponderance of evidence from both general and high‑accuracy predictors, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.995643 | Binding | 0.375 | 0.734 | 0.500 | -3.437 | Likely Benign | 0.420 | Ambiguous | Likely Benign | 0.073 | Likely Benign | -0.72 | Neutral | 0.961 | Probably Damaging | 0.677 | Possibly Damaging | 2.73 | Benign | 0.88 | Tolerated | 0.1377 | 0.2420 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.3086A>T | Q1029L 2D AIThe SynGAP1 missense variant Q1029L is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome (2 benign vs. 1 pathogenic, with one uncertain). AlphaMissense‑Default remains uncertain, and Foldetta results are unavailable. High‑accuracy predictions therefore point to a benign impact: AlphaMissense‑Optimized is benign, SGM Consensus is benign, and no Foldetta data are available. Overall, the computational evidence indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.995643 | Binding | 0.375 | 0.734 | 0.500 | -3.984 | Likely Benign | 0.364 | Ambiguous | Likely Benign | 0.067 | Likely Benign | -2.65 | Deleterious | 0.891 | Possibly Damaging | 0.587 | Possibly Damaging | 2.70 | Benign | 0.16 | Tolerated | 0.0685 | 0.5866 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||||||||||||
| c.3087G>C | Q1029H 2D AIThe SynGAP1 missense variant Q1029H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar classification, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.995643 | Binding | 0.375 | 0.734 | 0.500 | -3.984 | Likely Benign | 0.308 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -0.83 | Neutral | 0.989 | Probably Damaging | 0.879 | Possibly Damaging | 2.74 | Benign | 0.15 | Tolerated | 0.1268 | 0.4184 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3087G>T | Q1029H 2D AIThe SynGAP1 missense variant Q1029H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the consensus of the available predictions indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.995643 | Binding | 0.375 | 0.734 | 0.500 | -3.984 | Likely Benign | 0.308 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -0.83 | Neutral | 0.989 | Probably Damaging | 0.879 | Possibly Damaging | 2.74 | Benign | 0.15 | Tolerated | 0.1268 | 0.4184 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3253C>G | R1085G 2D AIThe SynGAP1 missense variant R1085G is reported in gnomAD (ID 6‑33443805‑C‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions from REVEL, ESM1b, and FATHMM; pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. A high‑accuracy consensus (SGM) that aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a 2‑to‑2 split, leaving the consensus inconclusive. No Foldetta stability assessment is available. Overall, the majority of evidence (five pathogenic versus three benign) points to a pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.978838 | Binding | 0.270 | 0.888 | 1.000 | 6-33443805-C-G | -4.225 | Likely Benign | 0.846 | Likely Pathogenic | Ambiguous | 0.179 | Likely Benign | -2.79 | Deleterious | 0.997 | Probably Damaging | 0.993 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | 3.77 | 5 | 0.3310 | 0.3693 | -2 | -3 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||
| c.3253C>T | R1085W 2D AISynGAP1 missense variant R1085W is listed in ClinVar as Uncertain and is present in gnomAD (ID 6‑33443805‑C‑T). Prediction tools that classify the variant as benign include REVEL, ESM1b, and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is Uncertain, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta stability assessment are unavailable. Overall, the majority of available predictions (five pathogenic vs. three benign) indicate a pathogenic effect. Thus, the variant is most likely pathogenic, which contradicts the ClinVar designation of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.978838 | Binding | 0.270 | 0.888 | 1.000 | Uncertain | 1 | 6-33443805-C-T | 2 | 1.26e-6 | -6.339 | Likely Benign | 0.821 | Likely Pathogenic | Ambiguous | 0.202 | Likely Benign | -3.15 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.70 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1238 | 0.3700 | -3 | 2 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||
| c.3254G>A | R1085Q 2D AIThe SynGAP1 missense variant R1085Q (ClinVar ID 1729448.0) is listed as ClinVar status Uncertain and is present in gnomAD (6‑33443806‑G‑A). Functional prediction tools show a split opinion: benign predictions come from REVEL, PROVEAN, ESM1b, and FATHMM, whereas pathogenic predictions are reported by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also favors benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, which is consistent with the ClinVar uncertain designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.978838 | Binding | 0.270 | 0.888 | 1.000 | Uncertain | 1 | 6-33443806-G-A | 5 | 3.16e-6 | -3.843 | Likely Benign | 0.589 | Likely Pathogenic | Likely Benign | 0.224 | Likely Benign | -1.43 | Neutral | 0.998 | Probably Damaging | 0.988 | Probably Damaging | 2.73 | Benign | 0.02 | Affected | 3.77 | 5 | 0.2962 | 0.2751 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.3254G>C | R1085P 2D AIThe SynGAP1 missense variant R1085P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2). Foldetta results are unavailable. Overall, the majority of standard predictors (five pathogenic vs. four benign) lean toward a pathogenic interpretation, but the high‑accuracy AlphaMissense‑Optimized prediction and the inconclusive SGM Consensus temper this view. The variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.978838 | Binding | 0.270 | 0.888 | 1.000 | -2.527 | Likely Benign | 0.759 | Likely Pathogenic | Likely Benign | 0.260 | Likely Benign | -2.55 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.71 | Benign | 0.01 | Affected | 0.1988 | 0.4524 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3254G>T | R1085L 2D AIThe SynGAP1 missense variant R1085L is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for R1085L, and this conclusion does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.978838 | Binding | 0.270 | 0.888 | 1.000 | -3.674 | Likely Benign | 0.734 | Likely Pathogenic | Likely Benign | 0.243 | Likely Benign | -2.38 | Neutral | 0.997 | Probably Damaging | 0.993 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | 0.1909 | 0.4568 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3322A>C | S1108R 2D AISynGAP1 missense variant S1108R is not reported in ClinVar (status: None) and is absent from gnomAD (no entry). Prediction tools that classify the variant as benign include REVEL, polyPhen‑2 HumVar, ESM1b, and FATHMM. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN is inconclusive, as it yields a 2‑vs‑2 split. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, has no available result for this variant. Overall, the computational evidence is mixed, with an equal number of benign and pathogenic calls and no high‑confidence consensus. Thus, the variant is most likely pathogenic based on the current predictions, and this assessment does not contradict the ClinVar status, which is unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -5.878 | Likely Benign | 0.912 | Likely Pathogenic | Ambiguous | 0.130 | Likely Benign | -2.75 | Deleterious | 0.611 | Possibly Damaging | 0.329 | Benign | 2.54 | Benign | 0.04 | Affected | 0.0864 | 0.3492 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3322A>G | S1108G 2D AIThe SynGAP1 missense variant S1108G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence (six benign vs three pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Thus, the variant is most likely benign based on current predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -6.496 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.084 | Likely Benign | -2.59 | Deleterious | 0.568 | Possibly Damaging | 0.239 | Benign | 2.46 | Pathogenic | 0.16 | Tolerated | 0.2268 | 0.3975 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3322A>T | S1108C 2D AIThe SynGAP1 missense variant S1108C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains Likely Pathogenic; Foldetta results are unavailable. Overall, the majority of predictions (seven pathogenic vs. three benign) support a pathogenic classification, and this conclusion does not contradict any ClinVar status because none is available. Thus, the variant is most likely pathogenic based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -9.189 | Likely Pathogenic | 0.183 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -3.30 | Deleterious | 0.992 | Probably Damaging | 0.820 | Possibly Damaging | 2.42 | Pathogenic | 0.04 | Affected | 0.0992 | 0.5299 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.3323G>A | S1108N 2D AIThe SynGAP1 missense variant S1108N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S1108N, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -6.488 | Likely Benign | 0.250 | Likely Benign | Likely Benign | 0.070 | Likely Benign | -2.02 | Neutral | 0.611 | Possibly Damaging | 0.239 | Benign | 2.47 | Pathogenic | 0.06 | Tolerated | 0.1283 | 0.3952 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| c.3323G>C | S1108T 2D AIThe SynGAP1 missense variant S1108T is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -5.710 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.49 | Neutral | 0.393 | Benign | 0.239 | Benign | 2.56 | Benign | 0.25 | Tolerated | 0.1304 | 0.5365 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3323G>T | S1108I 2D AIThe SynGAP1 missense variant S1108I is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443875‑G‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, has no reported result for this variant. Overall, the balance of evidence (five benign versus four pathogenic predictions) suggests the variant is most likely benign, and this conclusion does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | Uncertain | 1 | 6-33443875-G-T | -3.666 | Likely Benign | 0.292 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -3.73 | Deleterious | 0.971 | Probably Damaging | 0.604 | Possibly Damaging | 2.44 | Pathogenic | 0.10 | Tolerated | 3.77 | 5 | 0.0949 | 0.4602 | -2 | -1 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||
| c.3324C>A | S1108R 2D AISynGAP1 missense variant S1108R has no ClinVar record and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, ESM1b, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a 2‑to‑2 split and therefore unavailable; Foldetta, which would combine FoldX‑MD and Rosetta outputs, has no reported result. Consequently, the evidence is evenly divided, leaving the variant’s functional impact uncertain. The predictions do not contradict any ClinVar status, as none is available. Overall, the variant is most likely of uncertain significance rather than definitively benign or pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -5.878 | Likely Benign | 0.912 | Likely Pathogenic | Ambiguous | 0.109 | Likely Benign | -2.75 | Deleterious | 0.611 | Possibly Damaging | 0.329 | Benign | 2.54 | Benign | 0.04 | Affected | 0.0864 | 0.3492 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3324C>G | S1108R 2D AIThe SynGAP1 missense variant S1108R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, and FATHMM, while those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign). Foldetta, which would assess protein‑folding stability, has no available result for this variant. Overall, the computational evidence is balanced, providing no clear bias toward benign or pathogenic. Thus, the variant’s likely impact remains uncertain, and there is no contradiction with the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -5.878 | Likely Benign | 0.912 | Likely Pathogenic | Ambiguous | 0.108 | Likely Benign | -2.75 | Deleterious | 0.611 | Possibly Damaging | 0.329 | Benign | 2.54 | Benign | 0.04 | Affected | 0.0864 | 0.3492 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3856G>A | E1286K 2D AIThe SynGAP1 missense variant E1286K is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33447904‑G‑A). 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 is 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 classified there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.817022 | Binding | 0.544 | 0.765 | 0.750 | 6-33447904-G-A | -3.784 | Likely Benign | 0.395 | Ambiguous | Likely Benign | 0.195 | Likely Benign | -2.36 | Neutral | 0.770 | Possibly Damaging | 0.242 | Benign | 2.47 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.2069 | 0.5117 | 1 | 0 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||
| c.3856G>C | E1286Q 2D AIThe SynGAP1 missense variant E1286Q is 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 | 0.852992 | Disordered | 0.817022 | Binding | 0.544 | 0.765 | 0.750 | -3.858 | Likely Benign | 0.170 | Likely Benign | Likely Benign | 0.158 | Likely Benign | -1.84 | Neutral | 0.872 | Possibly Damaging | 0.478 | Possibly Damaging | 2.47 | Pathogenic | 0.03 | Affected | 0.1185 | 0.4829 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3857A>C | E1286A 2D AIThe SynGAP1 missense variant E1286A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. 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 | 0.852992 | Disordered | 0.817022 | Binding | 0.544 | 0.765 | 0.750 | -3.136 | Likely Benign | 0.153 | Likely Benign | Likely Benign | 0.190 | Likely Benign | -2.37 | Neutral | 0.770 | Possibly Damaging | 0.303 | Benign | 2.46 | Pathogenic | 0.02 | Affected | 0.3820 | 0.5016 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3857A>G | E1286G 2D AIThe SynGAP1 missense variant E1286G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the balance of evidence (five benign vs four pathogenic predictions) suggests the variant is most likely benign. This conclusion does not contradict ClinVar status, as the variant has not been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.817022 | Binding | 0.544 | 0.765 | 0.750 | -3.763 | Likely Benign | 0.171 | Likely Benign | Likely Benign | 0.217 | Likely Benign | -3.36 | Deleterious | 0.770 | Possibly Damaging | 0.327 | Benign | 2.45 | Pathogenic | 0.01 | Affected | 0.2904 | 0.4942 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3857A>T | E1286V 2D AIThe SynGAP1 missense variant E1286V is not 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, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it yields a 2‑benign/2‑pathogenic split. High‑accuracy methods show AlphaMissense‑Optimized as benign; Foldetta results are unavailable. Overall, the majority of available predictions (five pathogenic vs. four benign) indicate that the variant is most likely pathogenic. This assessment 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. | 0.852992 | Disordered | 0.817022 | Binding | 0.544 | 0.765 | 0.750 | -4.195 | Likely Benign | 0.275 | Likely Benign | Likely Benign | 0.259 | Likely Benign | -3.90 | Deleterious | 0.960 | Probably Damaging | 0.679 | Possibly Damaging | 2.42 | Pathogenic | 0.00 | Affected | 0.0828 | 0.5614 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||||
| c.3858A>C | E1286D 2D AIThe SynGAP1 missense variant E1286D is not reported in ClinVar and is absent from gnomAD. All available in silico predictors classify it as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments 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 results are not available. Based on the unanimous benign predictions and lack of ClinVar evidence, the variant is most likely benign and does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.817022 | Binding | 0.544 | 0.765 | 0.750 | -4.010 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.036 | Likely Benign | 1.02 | Neutral | 0.001 | Benign | 0.004 | Benign | 2.96 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2114 | 0.3141 | 3 | 2 | 0.0 | -14.03 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||||||||||||
| c.3858A>T | E1286D 2D AIThe SynGAP1 missense variant E1286D is listed in ClinVar (ID 469159.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33447906‑A‑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 all return benign scores. No tool in the set predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign effect, and this conclusion does not contradict the current ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.817022 | Binding | 0.544 | 0.765 | 0.750 | Conflicting | 4 | 6-33447906-A-T | 143 | 9.22e-5 | -4.010 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.036 | Likely Benign | 1.02 | Neutral | 0.001 | Benign | 0.004 | Benign | 2.96 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2114 | 0.3141 | 3 | 2 | 0.0 | -14.03 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.3883C>A | Q1295K 2D AIThe SynGAP1 missense variant Q1295K is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID: 6‑33447931‑C‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic prediction (2 pathogenic vs. 1 benign vs. 1 uncertain). AlphaMissense‑Optimized remains benign, while Foldetta (combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the majority of predictions (five pathogenic vs. three benign) point to a pathogenic effect. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.892719 | Binding | 0.499 | 0.801 | 0.625 | 6-33447931-C-A | -3.419 | Likely Benign | 0.343 | Ambiguous | Likely Benign | 0.313 | Likely Benign | -3.30 | Deleterious | 0.843 | Possibly Damaging | 0.893 | Possibly Damaging | 2.38 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1782 | 0.3517 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||
| c.3883C>G | Q1295E 2D AIThe SynGAP1 missense variant Q1295E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.892719 | Binding | 0.499 | 0.801 | 0.625 | -3.192 | Likely Benign | 0.177 | Likely Benign | Likely Benign | 0.264 | Likely Benign | -2.46 | Neutral | 0.843 | Possibly Damaging | 0.848 | Possibly Damaging | 2.29 | Pathogenic | 0.00 | Affected | 0.1428 | 0.1492 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3884A>C | Q1295P 2D AIThe SynGAP1 missense variant Q1295P is not 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. 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 (5/9) indicate pathogenicity, while 4/9 suggest benignity. Thus, the variant is most likely pathogenic based on the current computational evidence, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.892719 | Binding | 0.499 | 0.801 | 0.625 | -2.511 | Likely Benign | 0.168 | Likely Benign | Likely Benign | 0.372 | Likely Benign | -4.95 | Deleterious | 0.968 | Probably Damaging | 0.954 | Probably Damaging | 2.23 | Pathogenic | 0.00 | Affected | 0.2299 | 0.4738 | 0 | -1 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||||||||||||
| c.3884A>G | Q1295R 2D AIThe SynGAP1 missense variant Q1295R is catalogued in gnomAD (ID 6‑33447932‑A‑G) but has no ClinVar entry. Functional prediction tools show discordant results: benign calls come from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments are mixed: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta data are unavailable. Overall, the balance of evidence slightly favors a pathogenic interpretation, though the presence of several benign predictions and the lack of a ClinVar classification mean the variant’s clinical significance remains uncertain. No contradiction exists with ClinVar status, as no ClinVar claim is present. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.892719 | Binding | 0.499 | 0.801 | 0.625 | 6-33447932-A-G | -3.342 | Likely Benign | 0.300 | Likely Benign | Likely Benign | 0.351 | Likely Benign | -3.30 | Deleterious | 0.925 | Possibly Damaging | 0.932 | Probably Damaging | 2.44 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1432 | 0.1348 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||
| c.3884A>T | Q1295L 2D AIThe SynGAP1 missense variant Q1295L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact for Q1295L, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.892719 | Binding | 0.499 | 0.801 | 0.625 | -2.862 | Likely Benign | 0.348 | Ambiguous | Likely Benign | 0.379 | Likely Benign | -5.63 | Deleterious | 0.925 | Possibly Damaging | 0.932 | Probably Damaging | 2.25 | Pathogenic | 0.00 | Affected | 0.0810 | 0.5672 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||||||||||||
| c.3885G>C | Q1295H 2D AIThe SynGAP1 missense variant Q1295H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show discordant results: benign calls come from REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further highlight this split: AlphaMissense‑Optimized predicts a benign effect, whereas the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome. No Foldetta stability analysis is available for this residue. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict any existing ClinVar annotation, as none is present. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.852992 | Disordered | 0.892719 | Binding | 0.499 | 0.801 | 0.625 | -4.851 | Likely Benign | 0.588 | Likely Pathogenic | Likely Benign | 0.349 | Likely Benign | -4.08 | Deleterious | 0.991 | Probably Damaging | 0.986 | Probably Damaging | 2.24 | Pathogenic | 0.00 | Affected | 0.1345 | 0.3203 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3885G>T | Q1295H 2D AIThe SynGAP1 missense variant Q1295H is catalogued in gnomAD (ID 6‑33447933‑G‑T) but has no ClinVar submission. Functional prediction tools show a split: benign calls come from REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. When predictions are grouped, 3 tools predict benign and 6 predict pathogenic. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains benign, while 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 substitution. Overall, the preponderance of evidence points to a pathogenic effect, and this assessment does not conflict with ClinVar, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.852992 | Disordered | 0.892719 | Binding | 0.499 | 0.801 | 0.625 | 6-33447933-G-T | -4.851 | Likely Benign | 0.588 | Likely Pathogenic | Likely Benign | 0.349 | Likely Benign | -4.08 | Deleterious | 0.991 | Probably Damaging | 0.986 | Probably Damaging | 2.24 | Pathogenic | 0.00 | Affected | 0.1345 | 0.3203 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||
| c.4018A>C | T1340P 2D AIThe SynGAP1 missense variant T1340P is catalogued in gnomAD (ID 6‑33451892‑A‑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 report benign or tolerated outcomes, while only SIFT predicts 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 this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that T1340P is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.977899 | Binding | 0.444 | 0.697 | 0.750 | 6-33451892-A-C | -2.681 | Likely Benign | 0.102 | Likely Benign | Likely Benign | 0.190 | Likely Benign | -1.81 | Neutral | 0.334 | Benign | 0.099 | Benign | 4.08 | Benign | 0.01 | Affected | 3.77 | 5 | 0.2268 | 0.4983 | -1 | 0 | -0.9 | -3.99 | ||||||||||||||||||||||||||||||||||||
| c.4018A>G | T1340A 2D AIThe SynGAP1 missense variant T1340A 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, 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 unavailable. Overall, the consensus of the majority of tools, including the high‑accuracy methods, supports a benign classification. This prediction is consistent with the lack of ClinVar evidence and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.977899 | Binding | 0.444 | 0.697 | 0.750 | -3.192 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -1.01 | Neutral | 0.010 | Benign | 0.011 | Benign | 4.20 | Benign | 0.02 | Affected | 0.3984 | 0.4288 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.4018A>T | T1340S 2D AIThe SynGAP1 missense variant T1340S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the variant is most likely benign based on the available predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.977899 | Binding | 0.444 | 0.697 | 0.750 | -2.698 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.116 | Likely Benign | 0.62 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.87 | Benign | 1.00 | Tolerated | 0.3436 | 0.4521 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.4019C>A | T1340N 2D AIThe SynGAP1 missense variant T1340N is reported in gnomAD (ID 6‑33451893‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact for T1340N. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.977899 | Binding | 0.444 | 0.697 | 0.750 | 6-33451893-C-A | -3.664 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -0.95 | Neutral | 0.092 | Benign | 0.026 | Benign | 4.09 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1755 | 0.5309 | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||||||||||||||||
| c.4019C>G | T1340S 2D AIThe SynGAP1 missense variant T1340S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the variant is most likely benign based on the available predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.977899 | Binding | 0.444 | 0.697 | 0.750 | -2.698 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.083 | Likely Benign | 0.62 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.87 | Benign | 1.00 | Tolerated | 0.3436 | 0.4521 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.4019C>T | T1340I 2D AIThe SynGAP1 missense variant T1340I is not reported in ClinVar (ClinVar status: “None”) but is present in gnomAD (ID 6‑33451893‑C‑T). 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 and SIFT. AlphaMissense‑Default is uncertain, while AlphaMissense‑Optimized predicts benign. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to benign (two benign versus one pathogenic, with the uncertain result treated as unavailable). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the high‑accuracy predictions (AlphaMissense‑Optimized, SGM Consensus) both indicate a benign impact, and no evidence contradicts this assessment with the ClinVar status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.977899 | Binding | 0.444 | 0.697 | 0.750 | 6-33451893-C-T | -3.476 | Likely Benign | 0.402 | Ambiguous | Likely Benign | 0.089 | Likely Benign | -2.57 | Deleterious | 0.334 | Benign | 0.099 | Benign | 4.08 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1163 | 0.5848 | -1 | 0 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||
| c.3055C>A | R1019S 2D AIThe SynGAP1 missense variant R1019S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and ESM1b, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, while the SGM‑Consensus (majority vote) remains Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for R1019S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.856457 | Disordered | 0.966400 | Binding | 0.315 | 0.794 | 0.500 | -3.818 | Likely Benign | 0.871 | Likely Pathogenic | Ambiguous | 0.113 | Likely Benign | -2.59 | Deleterious | 0.800 | Possibly Damaging | 0.410 | Benign | 2.43 | Pathogenic | 0.01 | Affected | 0.2441 | 0.3979 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3055C>G | R1019G 2D AIThe SynGAP1 missense variant R1019G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas tools predicting a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and the Foldetta stability analysis is unavailable. Overall, the majority of predictions support a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation (none is available). Thus, the variant is most likely pathogenic based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.856457 | Disordered | 0.966400 | Binding | 0.315 | 0.794 | 0.500 | -4.325 | Likely Benign | 0.614 | Likely Pathogenic | Likely Benign | 0.115 | Likely Benign | -3.34 | Deleterious | 0.800 | Possibly Damaging | 0.496 | Possibly Damaging | 2.39 | Pathogenic | 0.00 | Affected | 0.2946 | 0.3489 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3055C>T | R1019C 2D  AIThe SynGAP1 missense variant R1019C is listed in ClinVar with an “Uncertain” status (ClinVar ID 1676922.0) and is present in gnomAD (ID 6‑33443607‑C‑T). Prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact; ESM1b remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote) remains pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.856457 | Disordered | 0.966400 | Binding | 0.315 | 0.794 | 0.500 | Conflicting | 2 | 6-33443607-C-T | 10 | 6.19e-6 | -7.386 | In-Between | 0.646 | Likely Pathogenic | Likely Benign | 0.168 | Likely Benign | -4.00 | Deleterious | 0.999 | Probably Damaging | 0.880 | Possibly Damaging | 2.36 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.3016 | 0.3664 | -4 | -3 | 7.0 | -53.05 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.3056G>A | R1019H 2D  AIThe SynGAP1 missense variant R1019H is listed in ClinVar (ID 1195115.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443608‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) also benign; Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact for R1019H, and this conclusion does not contradict the current ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.856457 | Disordered | 0.966400 | Binding | 0.315 | 0.794 | 0.500 | Conflicting | 2 | 6-33443608-G-A | 67 | 4.15e-5 | -4.610 | Likely Benign | 0.258 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -1.95 | Neutral | 0.995 | Probably Damaging | 0.845 | Possibly Damaging | 2.39 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.2400 | 0.1903 | 2 | 0 | 1.3 | -19.05 | ||||||||||||||||||||||||||||||||
| c.3056G>C | R1019P 2D AIThe SynGAP1 missense variant R1019P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on benign impact include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized, whereas those that predict pathogenicity are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign), and Foldetta results are unavailable. Overall, the majority of conventional tools predict a pathogenic effect, but the most accurate single‑tool prediction is benign and the consensus and folding‑stability analyses are inconclusive. Thus, the variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.856457 | Disordered | 0.966400 | Binding | 0.315 | 0.794 | 0.500 | -3.737 | Likely Benign | 0.697 | Likely Pathogenic | Likely Benign | 0.143 | Likely Benign | -2.48 | Neutral | 0.966 | Probably Damaging | 0.811 | Possibly Damaging | 2.38 | Pathogenic | 0.01 | Affected | 0.1899 | 0.4521 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3056G>T | R1019L 2D AIThe SynGAP1 missense variant R1019L is listed in ClinVar with an “Uncertain” status (ClinVar ID 3364537.0) and is present in gnomAD (gnomAD ID 6‑33443608‑G‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote) remains pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a pathogenic impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.856457 | Disordered | 0.966400 | Binding | 0.315 | 0.794 | 0.500 | Uncertain | 1 | 6-33443608-G-T | 2 | 1.24e-6 | -5.194 | Likely Benign | 0.752 | Likely Pathogenic | Likely Benign | 0.110 | Likely Benign | -3.57 | Deleterious | 0.800 | Possibly Damaging | 0.573 | Possibly Damaging | 2.40 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.1850 | 0.4886 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||
| c.3325C>A | L1109I 2D AIThe SynGAP1 missense variant L1109I is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign, and this conclusion is consistent with the lack of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.856457 | Disordered | 0.948334 | Binding | 0.343 | 0.893 | 0.875 | -5.475 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.40 | Neutral | 0.126 | Benign | 0.040 | Benign | 2.70 | Benign | 0.23 | Tolerated | 0.1087 | 0.4703 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3325C>G | L1109V 2D AIThe SynGAP1 missense variant L1109V is catalogued in gnomAD (ID 6‑33443877‑C‑G) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Benign verdict. Foldetta results are not available for this variant. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status, as none is reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.856457 | Disordered | 0.948334 | Binding | 0.343 | 0.893 | 0.875 | 6-33443877-C-G | -5.490 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -0.52 | Neutral | 0.001 | Benign | 0.005 | Benign | 2.72 | Benign | 0.19 | Tolerated | 4.32 | 2 | 0.1676 | 0.4353 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.3325C>T | L1109F 2D  AIThe SynGAP1 missense variant L1109F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to the variant being most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.856457 | Disordered | 0.948334 | Binding | 0.343 | 0.893 | 0.875 | -3.459 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -1.04 | Neutral | 0.832 | Possibly Damaging | 0.324 | Benign | 2.74 | Benign | 0.12 | Tolerated | 0.0780 | 0.4540 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3326T>A | L1109H 2D  AIThe SynGAP1 missense variant L1109H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.856457 | Disordered | 0.948334 | Binding | 0.343 | 0.893 | 0.875 | -4.353 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.134 | Likely Benign | -0.56 | Neutral | 0.832 | Possibly Damaging | 0.499 | Possibly Damaging | 2.70 | Benign | 0.04 | Affected | 0.1250 | 0.1845 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||||||
| c.3326T>C | L1109P 2D AIThe SynGAP1 missense variant L1109P is listed in ClinVar with an uncertain significance (ClinVar ID 1730257.0) and is not reported in gnomAD. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized indicates a benign effect, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign classification, which does not contradict the ClinVar uncertain status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.856457 | Disordered | 0.948334 | Binding | 0.343 | 0.893 | 0.875 | Conflicting | 2 | -5.313 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.151 | Likely Benign | -0.52 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.65 | Benign | 0.07 | Tolerated | 4.32 | 2 | 0.3159 | 0.2330 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||
| c.3326T>G | L1109R 2D AIThe SynGAP1 missense variant L1109R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.856457 | Disordered | 0.948334 | Binding | 0.343 | 0.893 | 0.875 | -5.440 | Likely Benign | 0.408 | Ambiguous | Likely Benign | 0.139 | Likely Benign | -0.70 | Neutral | 0.586 | Possibly Damaging | 0.225 | Benign | 2.68 | Benign | 0.34 | Tolerated | 0.1352 | 0.1919 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.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.3064C>A | L1022I 2D AIThe SynGAP1 missense variant L1022I is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions strongly supports a benign classification, and this conclusion is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.986981 | Binding | 0.339 | 0.752 | 0.500 | -4.624 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.025 | Likely Benign | -0.91 | Neutral | 0.114 | Benign | 0.072 | Benign | 2.58 | Benign | 0.11 | Tolerated | 0.1081 | 0.4395 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3064C>G | L1022V 2D AIThe SynGAP1 missense variant L1022V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags the variant as pathogenic, creating a single discordant prediction. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.986981 | Binding | 0.339 | 0.752 | 0.500 | -3.957 | Likely Benign | 0.174 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -1.22 | Neutral | 0.664 | Possibly Damaging | 0.260 | Benign | 2.66 | Benign | 0.07 | Tolerated | 0.1702 | 0.4045 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3064C>T | L1022F 2D AIThe SynGAP1 missense variant L1022F is reported in gnomAD (variant ID 6‑33443616‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion is not contradicted by any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.986981 | Binding | 0.339 | 0.752 | 0.500 | 6-33443616-C-T | 2 | 1.24e-6 | -5.035 | Likely Benign | 0.351 | Ambiguous | Likely Benign | 0.072 | Likely Benign | -1.84 | Neutral | 0.971 | Probably Damaging | 0.801 | Possibly Damaging | 2.51 | Benign | 0.07 | Tolerated | 3.77 | 5 | 0.0730 | 0.4231 | 0 | 2 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||||
| c.3065T>A | L1022H 2D AIThe SynGAP1 missense variant L1022H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie (2 pathogenic, 2 benign) and is therefore inconclusive. Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the majority of conventional predictors lean toward pathogenicity, whereas the single high‑accuracy tool predicts benign and the consensus is unresolved. Thus, the variant is most likely pathogenic based on the current predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.859585 | Disordered | 0.986981 | Binding | 0.339 | 0.752 | 0.500 | -2.473 | Likely Benign | 0.589 | Likely Pathogenic | Likely Benign | 0.140 | Likely Benign | -2.21 | Neutral | 0.999 | Probably Damaging | 0.944 | Probably Damaging | 2.49 | Pathogenic | 0.00 | Affected | 0.1165 | 0.1313 | -2 | -3 | -7.0 | 23.98 | ||||||||||||||||||||||||||||||||||||||||
| c.3065T>C | L1022P 2D AIThe SynGAP1 missense variant L1022P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic, two benign), and Foldetta data are unavailable. Overall, the balance of evidence favors a pathogenic interpretation, and this assessment does not conflict with ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.859585 | Disordered | 0.986981 | Binding | 0.339 | 0.752 | 0.500 | -2.532 | Likely Benign | 0.643 | Likely Pathogenic | Likely Benign | 0.177 | Likely Benign | -2.22 | Neutral | 0.995 | Probably Damaging | 0.925 | Probably Damaging | 2.49 | Pathogenic | 0.01 | Affected | 0.3332 | 0.1589 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3065T>G | L1022R 2D AIThe SynGAP1 missense variant L1022R is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict the ClinVar status, which currently contains no classification for L1022R. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.986981 | Binding | 0.339 | 0.752 | 0.500 | -2.875 | Likely Benign | 0.659 | Likely Pathogenic | Likely Benign | 0.183 | Likely Benign | -1.96 | Neutral | 0.986 | Probably Damaging | 0.894 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.1279 | 0.1387 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3889A>G | R1297G 2D AIThe SynGAP1 missense variant R1297G is reported in gnomAD (ID 6‑33451763‑A‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus itself is Benign; Foldetta results are unavailable. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that R1297G is most likely benign, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | 6-33451763-A-G | 3 | 1.86e-6 | -2.833 | Likely Benign | 0.168 | Likely Benign | Likely Benign | 0.215 | Likely Benign | -3.65 | Deleterious | 0.224 | Benign | 0.171 | Benign | 2.56 | Benign | 0.01 | Affected | 3.77 | 5 | 0.3089 | 0.2400 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||
| c.3889A>T | R1297W 2D AIThe SynGAP1 missense variant R1297W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of evaluated predictors (five pathogenic vs. three benign) indicate a pathogenic impact. This conclusion is consistent with the lack of ClinVar reporting; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | -6.039 | Likely Benign | 0.358 | Ambiguous | Likely Benign | 0.262 | Likely Benign | -4.45 | Deleterious | 0.983 | Probably Damaging | 0.868 | Possibly Damaging | 2.44 | Pathogenic | 0.01 | Affected | 0.1260 | 0.2587 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3890G>A | R1297K 2D AIThe SynGAP1 missense variant R1297K is catalogued in gnomAD (ID 6‑33451764‑G‑A) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as tolerated or benign. Grouping by consensus, all listed predictors fall into the benign category, with no tool reporting a pathogenic outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign classification. Foldetta stability analysis is unavailable for this variant. Consequently, the aggregate evidence strongly supports a benign interpretation, and this assessment does not conflict with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | 6-33451764-G-A | 1 | 6.20e-7 | -3.780 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.074 | Likely Benign | 0.55 | Neutral | 0.000 | Benign | 0.004 | Benign | 2.80 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.4109 | 0.2801 | 2 | 3 | 0.6 | -28.01 | ||||||||||||||||||||||||||||||||||
| c.3890G>C | R1297T 2D AIThe SynGAP1 missense variant R1297T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Functional prediction tools cluster into two groups: seven tools (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a benign effect, while two tools (PROVEAN, FATHMM) predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | -3.941 | Likely Benign | 0.287 | Likely Benign | Likely Benign | 0.151 | Likely Benign | -2.95 | Deleterious | 0.224 | Benign | 0.171 | Benign | 2.49 | Pathogenic | 0.08 | Tolerated | 0.1634 | 0.2972 | -1 | -1 | 3.8 | -55.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3890G>T | R1297M 2D AIThe SynGAP1 missense variant R1297M is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | -4.286 | Likely Benign | 0.383 | Ambiguous | Likely Benign | 0.139 | Likely Benign | -3.00 | Deleterious | 0.938 | Possibly Damaging | 0.690 | Possibly Damaging | 2.45 | Pathogenic | 0.02 | Affected | 0.1294 | 0.2449 | 0 | -1 | 6.4 | -24.99 | ||||||||||||||||||||||||||||||||||||||||
| c.3891G>C | R1297S 2D AIThe SynGAP1 missense variant R1297S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the consensus of available predictions indicates that R1297S is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | -3.468 | Likely Benign | 0.401 | Ambiguous | Likely Benign | 0.139 | Likely Benign | -2.39 | Neutral | 0.224 | Benign | 0.096 | Benign | 2.50 | Benign | 0.07 | Tolerated | 0.2863 | 0.2347 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3891G>T | R1297S 2D AIThe SynGAP1 missense variant R1297S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign classification. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions strongly suggests that R1297S is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | -3.468 | Likely Benign | 0.401 | Ambiguous | Likely Benign | 0.139 | Likely Benign | -2.39 | Neutral | 0.224 | Benign | 0.096 | Benign | 2.50 | Benign | 0.07 | Tolerated | 0.2863 | 0.2347 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2980A>C | K994Q 2D AIThe SynGAP1 missense variant K994Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.930054 | Binding | 0.289 | 0.912 | 0.750 | -1.947 | Likely Benign | 0.124 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -0.45 | Neutral | 0.002 | Benign | 0.004 | Benign | 4.16 | Benign | 0.03 | Affected | 0.4975 | 0.1889 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2980A>G | K994E 2D AIThe SynGAP1 missense variant K994E is reported in gnomAD (variant ID 6‑33443532‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of tools, including the high‑accuracy methods, points to a benign impact. This prediction does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.930054 | Binding | 0.289 | 0.912 | 0.750 | 6-33443532-A-G | 1 | 6.20e-7 | -2.587 | Likely Benign | 0.339 | Likely Benign | Likely Benign | 0.057 | Likely Benign | -0.58 | Neutral | 0.036 | Benign | 0.039 | Benign | 4.14 | Benign | 0.02 | Affected | 4.32 | 2 | 0.4148 | 0.1699 | 1 | 0 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||||||
| c.2981A>C | K994T 2D AIThe SynGAP1 missense variant K994T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Taken together, the majority of evidence points to a benign effect. There is no conflict with ClinVar status, as no ClinVar classification exists for this variant. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.930054 | Binding | 0.289 | 0.912 | 0.750 | -2.346 | Likely Benign | 0.226 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -1.22 | Neutral | 0.144 | Benign | 0.085 | Benign | 4.09 | Benign | 0.01 | Affected | 0.2503 | 0.4248 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||||||
| c.2981A>G | K994R 2D AIThe SynGAP1 missense variant K994R is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.930054 | Binding | 0.289 | 0.912 | 0.750 | -1.990 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.071 | Likely Benign | 0.02 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.21 | Benign | 0.47 | Tolerated | 0.5064 | 0.1657 | Weaken | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||||||||||
| c.2981A>T | K994M 2D  AIThe SynGAP1 missense variant K994M is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign. Pathogenicity is suggested only by polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as likely benign, and AlphaMissense‑Optimized also predicts benign. No Foldetta stability analysis is available. Overall, the majority of evidence points to a benign impact, and this assessment does not conflict with ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.930054 | Binding | 0.289 | 0.912 | 0.750 | -2.974 | Likely Benign | 0.424 | Ambiguous | Likely Benign | 0.057 | Likely Benign | -1.21 | Neutral | 0.589 | Possibly Damaging | 0.187 | Benign | 4.04 | Benign | 0.00 | Affected | 0.1612 | 0.4395 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.2982G>C | K994N 2D AIThe SynGAP1 missense variant K994N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the only pathogenic call comes from SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, SGM‑Consensus confirms a Likely Benign status, and Foldetta data are unavailable. Taken together, the preponderance of evidence indicates that K994N is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.930054 | Binding | 0.289 | 0.912 | 0.750 | -3.724 | Likely Benign | 0.519 | Ambiguous | Likely Benign | 0.011 | Likely Benign | -0.73 | Neutral | 0.255 | Benign | 0.113 | Benign | 4.09 | Benign | 0.01 | Affected | 0.4010 | 0.2376 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2982G>T | K994N 2D AIThe SynGAP1 missense variant K994N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the only pathogenic call comes from SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, SGM‑Consensus confirms a Likely Benign status, and Foldetta data are unavailable. Taken together, the preponderance of evidence indicates that K994N is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.930054 | Binding | 0.289 | 0.912 | 0.750 | -3.724 | Likely Benign | 0.519 | Ambiguous | Likely Benign | 0.009 | Likely Benign | -0.73 | Neutral | 0.255 | Benign | 0.113 | Benign | 4.09 | Benign | 0.01 | Affected | 0.4010 | 0.2376 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2983C>A | P995T 2D AIThe SynGAP1 missense variant P995T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for P995T, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.935305 | Binding | 0.338 | 0.902 | 0.750 | -5.148 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.034 | Likely Benign | -1.15 | Neutral | 0.224 | Benign | 0.096 | Benign | 4.19 | Benign | 0.00 | Affected | 0.1467 | 0.5667 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2983C>G | P995A 2D AIThe SynGAP1 missense variant P995A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) indicates likely benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the majority of evidence points to a benign impact for P995A, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.935305 | Binding | 0.338 | 0.902 | 0.750 | -4.465 | Likely Benign | 0.051 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -1.02 | Neutral | 0.001 | Benign | 0.008 | Benign | 4.22 | Benign | 0.00 | Affected | 0.3287 | 0.4841 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2983C>T | P995S 2D AIThe SynGAP1 missense variant P995S is listed in ClinVar (ID 436929.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). The only tool that predicts a pathogenic outcome is SIFT. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates “Likely Benign.” No Foldetta (FoldX‑MD/Rosetta) stability result is available, so it does not influence the assessment. Overall, the majority of predictions, including the high‑accuracy tools, point to a benign effect, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.935305 | Binding | 0.338 | 0.902 | 0.750 | Uncertain | 1 | -4.457 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.042 | Likely Benign | -1.03 | Neutral | 0.011 | Benign | 0.015 | Benign | 4.24 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3204 | 0.5236 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||
| c.2984C>A | P995H 2D AIThe SynGAP1 missense variant P995H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for P995H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.935305 | Binding | 0.338 | 0.902 | 0.750 | -5.347 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.75 | Neutral | 0.832 | Possibly Damaging | 0.600 | Possibly Damaging | 4.16 | Benign | 0.00 | Affected | 0.1618 | 0.4571 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2984C>G | P995R 2D AIThe SynGAP1 missense variant P995R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv and SIFT predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.935305 | Binding | 0.338 | 0.902 | 0.750 | -4.605 | Likely Benign | 0.141 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -1.06 | Neutral | 0.586 | Possibly Damaging | 0.304 | Benign | 4.18 | Benign | 0.00 | Affected | 0.1370 | 0.3424 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2984C>T | P995L 2D AIThe SynGAP1 missense variant P995L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.935305 | Binding | 0.338 | 0.902 | 0.750 | -4.948 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -1.03 | Neutral | 0.411 | Benign | 0.096 | Benign | 4.16 | Benign | 0.00 | Affected | 0.2294 | 0.6324 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3070C>A | L1024I 2D AIThe SynGAP1 missense variant L1024I is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.992699 | Binding | 0.327 | 0.753 | 0.500 | -4.794 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.99 | Neutral | 0.959 | Probably Damaging | 0.642 | Possibly Damaging | 2.45 | Pathogenic | 0.11 | Tolerated | 0.0992 | 0.3735 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3070C>G | L1024V 2D AIThe SynGAP1 missense variant L1024V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for the variant. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.992699 | Binding | 0.327 | 0.753 | 0.500 | -3.758 | Likely Benign | 0.244 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -1.33 | Neutral | 0.907 | Possibly Damaging | 0.642 | Possibly Damaging | 2.47 | Pathogenic | 0.08 | Tolerated | 0.1459 | 0.3185 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3070C>T | L1024F 2D AIThe SynGAP1 missense variant L1024F is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. AlphaMissense‑Default is uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it contains both benign and pathogenic calls. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence favors a benign interpretation, and this assessment does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.862302 | Disordered | 0.992699 | Binding | 0.327 | 0.753 | 0.500 | -5.133 | Likely Benign | 0.544 | Ambiguous | Likely Benign | 0.059 | Likely Benign | -2.08 | Neutral | 0.994 | Probably Damaging | 0.924 | Probably Damaging | 2.40 | Pathogenic | 0.07 | Tolerated | 0.0706 | 0.3708 | 2 | 0 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.3071T>A | L1024H 2D AIThe SynGAP1 missense variant L1024H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL and ESM1b, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized returns an Uncertain result, SGM‑Consensus indicates Likely Pathogenic, and Foldetta data are unavailable. Overall, the majority of evidence points toward a deleterious effect, suggesting the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar, which contains no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.862302 | Disordered | 0.992699 | Binding | 0.327 | 0.753 | 0.500 | -3.271 | Likely Benign | 0.868 | Likely Pathogenic | Ambiguous | 0.123 | Likely Benign | -3.09 | Deleterious | 1.000 | Probably Damaging | 0.981 | Probably Damaging | 2.38 | Pathogenic | 0.01 | Affected | 0.1198 | 0.1483 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||||||
| c.3071T>C | L1024P 2D AIThe SynGAP1 missense variant L1024P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of standard prediction tools lean toward pathogenicity, while high‑accuracy methods are inconclusive. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.862302 | Disordered | 0.992699 | Binding | 0.327 | 0.753 | 0.500 | -4.385 | Likely Benign | 0.730 | Likely Pathogenic | Likely Benign | 0.149 | Likely Benign | -2.42 | Neutral | 0.999 | Probably Damaging | 0.974 | Probably Damaging | 2.43 | Pathogenic | 0.03 | Affected | 0.3187 | 0.2033 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3071T>G | L1024R 2D AIThe SynGAP1 missense variant L1024R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (5 pathogenic vs. 3 benign) lean toward a pathogenic interpretation. This assessment does not contradict ClinVar status, as the variant is not yet catalogued there. Thus, based on current computational evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.862302 | Disordered | 0.992699 | Binding | 0.327 | 0.753 | 0.500 | -3.434 | Likely Benign | 0.841 | Likely Pathogenic | Ambiguous | 0.148 | Likely Benign | -2.41 | Neutral | 0.997 | Probably Damaging | 0.962 | Probably Damaging | 2.40 | Pathogenic | 0.02 | Affected | 0.1335 | 0.1557 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3937C>A | P1313T 2D AIThe SynGAP1 missense variant P1313T is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.970301 | Binding | 0.452 | 0.902 | 0.750 | -4.666 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.149 | Likely Benign | 0.03 | Neutral | 0.000 | Benign | 0.002 | Benign | 4.26 | Benign | 0.14 | Tolerated | 0.1889 | 0.7040 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3937C>G | P1313A 2D AIThe SynGAP1 missense variant P1313A 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 benign classification: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions strongly suggests that P1313A 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 | 0.862302 | Disordered | 0.970301 | Binding | 0.452 | 0.902 | 0.750 | -3.855 | Likely Benign | 0.054 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -0.37 | Neutral | 0.021 | Benign | 0.028 | Benign | 4.27 | Benign | 0.25 | Tolerated | 0.3529 | 0.5842 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3937C>T | P1313S 2D AIThe SynGAP1 missense variant P1313S 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. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign.” Foldetta results are not available, so they do not influence the assessment. Overall, the collective evidence strongly suggests that the variant is most likely benign, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.970301 | Binding | 0.452 | 0.902 | 0.750 | -4.279 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.03 | Neutral | 0.047 | Benign | 0.066 | Benign | 4.33 | Benign | 0.13 | Tolerated | 0.3520 | 0.6153 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3938C>A | P1313Q 2D AIThe SynGAP1 missense variant P1313Q is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the consensus of all available predictions strongly supports a benign classification, and this conclusion is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.970301 | Binding | 0.452 | 0.902 | 0.750 | -4.533 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.063 | Likely Benign | 0.99 | Neutral | 0.324 | Benign | 0.287 | Benign | 4.31 | Benign | 0.15 | Tolerated | 0.1748 | 0.5651 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3938C>G | P1313R 2D AIThe SynGAP1 missense variant P1313R is not reported in ClinVar and has no entry in gnomAD. Prediction tools that assess pathogenicity are unanimous: all listed algorithms (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a benign effect, while none predict pathogenicity. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized scores the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign,” and the protein‑folding stability tool Foldetta provides no result, so it does not influence the assessment. Based on the collective predictions, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.970301 | Binding | 0.452 | 0.902 | 0.750 | -4.634 | Likely Benign | 0.161 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -0.52 | Neutral | 0.324 | Benign | 0.172 | Benign | 4.25 | Benign | 0.22 | Tolerated | 0.1659 | 0.4742 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3938C>T | P1313L 2D AIThe SynGAP1 missense variant P1313L 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, 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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.970301 | Binding | 0.452 | 0.902 | 0.750 | -4.588 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.082 | Likely Benign | 1.90 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.30 | Benign | 1.00 | Tolerated | 0.2489 | 0.6948 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3091A>C | M1031L 2D  AIThe SynGAP1 missense variant M1031L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | -2.213 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -0.82 | Neutral | 0.044 | Benign | 0.018 | Benign | 2.84 | Benign | 0.33 | Tolerated | 0.1220 | 0.4050 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3091A>G | M1031V 2D  AIThe SynGAP1 missense variant M1031V is catalogued in gnomAD (ID 6‑33443643‑A‑G) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool listed—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently scores the variant as benign. No pathogenic predictions are reported. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the uniform benign predictions and the lack of any ClinVar pathogenic classification, the variant is most likely benign and does not contradict existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | 6-33443643-A-G | 7 | 4.34e-6 | -2.815 | Likely Benign | 0.198 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.81 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.72 | Benign | 0.44 | Tolerated | 3.77 | 5 | 0.2305 | 0.3388 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||||||||||||||
| c.3091A>T | M1031L 2D AIThe SynGAP1 missense variant M1031L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | -2.213 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -0.82 | Neutral | 0.044 | Benign | 0.018 | Benign | 2.84 | Benign | 0.33 | Tolerated | 0.1220 | 0.4050 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3092T>A | M1031K 2D  AIThe SynGAP1 missense variant M1031K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | -1.940 | Likely Benign | 0.709 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | -0.80 | Neutral | 0.325 | Benign | 0.098 | Benign | 2.66 | Benign | 0.18 | Tolerated | 0.1224 | 0.1412 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||||||
| c.3092T>C | M1031T 2D  AIThe SynGAP1 missense variant M1031T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443644‑T‑C). In silico prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts a pathogenic outcome; the only inconclusive result is AlphaMissense‑Default, which is treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus is “Likely Benign,” and Foldetta data are not available. **Thus, the variant is most likely benign, and this conclusion does not contradict the ClinVar “Uncertain” status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | Uncertain | 1 | 6-33443644-T-C | 2 | 1.24e-6 | -1.863 | Likely Benign | 0.540 | Ambiguous | Likely Benign | 0.085 | Likely Benign | -0.24 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.67 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.1587 | 0.2264 | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||||||||||||||
| c.3092T>G | M1031R 2D  AIThe SynGAP1 missense variant M1031R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Taken together, the majority of evidence points to a benign impact for M1031R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | -1.365 | Likely Benign | 0.673 | Likely Pathogenic | Likely Benign | 0.117 | Likely Benign | -0.85 | Neutral | 0.325 | Benign | 0.129 | Benign | 2.64 | Benign | 0.12 | Tolerated | 0.1368 | 0.1212 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||||||
| c.3093G>A | M1031I 2D  AIThe SynGAP1 missense variant M1031I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Taken together, the overwhelming majority of evidence points to a benign impact for M1031I. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | -3.312 | Likely Benign | 0.739 | Likely Pathogenic | Likely Benign | 0.026 | Likely Benign | -0.99 | Neutral | 0.095 | Benign | 0.027 | Benign | 2.71 | Benign | 0.25 | Tolerated | 0.1128 | 0.3324 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3093G>C | M1031I 2D AIThe SynGAP1 missense variant M1031I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Taken together, the overwhelming majority of evidence points to a benign impact for M1031I. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | -3.312 | Likely Benign | 0.739 | Likely Pathogenic | Likely Benign | 0.025 | Likely Benign | -0.99 | Neutral | 0.095 | Benign | 0.027 | Benign | 2.71 | Benign | 0.25 | Tolerated | 0.1128 | 0.3324 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3093G>T | M1031I 2D AIThe SynGAP1 missense variant M1031I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Taken together, the overwhelming majority of evidence points to a benign impact for M1031I. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | -3.312 | Likely Benign | 0.739 | Likely Pathogenic | Likely Benign | 0.026 | Likely Benign | -0.99 | Neutral | 0.095 | Benign | 0.027 | Benign | 2.71 | Benign | 0.25 | Tolerated | 0.1128 | 0.3324 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3094C>A | L1032M 2D  AIThe SynGAP1 missense variant L1032M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of any ClinVar pathogenic annotation. Thus, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995318 | Binding | 0.365 | 0.735 | 0.500 | -4.353 | Likely Benign | 0.219 | Likely Benign | Likely Benign | 0.064 | Likely Benign | -0.09 | Neutral | 0.995 | Probably Damaging | 0.892 | Possibly Damaging | 2.66 | Benign | 0.10 | Tolerated | 0.0935 | 0.4719 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3094C>G | L1032V 2D AIThe SynGAP1 missense variant L1032V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and polyPhen‑2 HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995318 | Binding | 0.365 | 0.735 | 0.500 | -4.123 | Likely Benign | 0.176 | Likely Benign | Likely Benign | 0.075 | Likely Benign | 0.16 | Neutral | 0.889 | Possibly Damaging | 0.514 | Possibly Damaging | 2.78 | Benign | 0.78 | Tolerated | 0.1637 | 0.4353 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3095T>A | L1032Q 2D AIThe SynGAP1 missense variant L1032Q is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the aggregate evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995318 | Binding | 0.365 | 0.735 | 0.500 | -2.992 | Likely Benign | 0.467 | Ambiguous | Likely Benign | 0.134 | Likely Benign | -0.78 | Neutral | 0.995 | Probably Damaging | 0.892 | Possibly Damaging | 2.66 | Benign | 0.03 | Affected | 0.1217 | 0.1677 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3095T>C | L1032P 2D AIThe SynGAP1 missense variant L1032P has no ClinVar entry and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and the SGM‑Consensus score all classify the change as benign or likely benign. AlphaMissense‑Optimized also predicts a benign outcome, whereas SIFT uniquely flags the variant as pathogenic. The AlphaMissense‑Default assessment is uncertain, and no Foldetta stability data are available. High‑accuracy analyses reinforce the benign consensus: AlphaMissense‑Optimized reports a benign effect, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign. Foldetta results are missing, so they do not influence the interpretation. Overall, the majority of computational evidence supports a benign classification, which is consistent with the absence of a ClinVar pathogenic annotation. Thus, the variant is most likely benign, and this conclusion does not contradict ClinVar status, as no ClinVar pathogenic claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995318 | Binding | 0.365 | 0.735 | 0.500 | -2.560 | Likely Benign | 0.449 | Ambiguous | Likely Benign | 0.142 | Likely Benign | -0.71 | Neutral | 0.012 | Benign | 0.017 | Benign | 2.64 | Benign | 0.05 | Affected | 0.3024 | 0.2330 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3095T>G | L1032R 2D AIThe SynGAP1 missense variant L1032R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995318 | Binding | 0.365 | 0.735 | 0.500 | -2.658 | Likely Benign | 0.707 | Likely Pathogenic | Likely Benign | 0.099 | Likely Benign | -1.03 | Neutral | 0.995 | Probably Damaging | 0.892 | Possibly Damaging | 2.66 | Benign | 0.02 | Affected | 0.1350 | 0.1919 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.4006G>A | E1336K 2D AIThe SynGAP1 missense variant E1336K is listed in ClinVar (ID 984837) with an “Uncertain” status and is present in gnomAD (6‑33451880‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM. Those that predict a pathogenic impact are polyPhen‑2 HumDiv, 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” classification. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains likely benign; Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign effect, and this conclusion does not contradict the ClinVar designation, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.973342 | Binding | 0.336 | 0.717 | 0.750 | Conflicting | 3 | 6-33451880-G-A | 6 | 4.20e-6 | -4.697 | Likely Benign | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.272 | Likely Benign | -2.44 | Neutral | 0.748 | Possibly Damaging | 0.079 | Benign | 3.23 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2630 | 0.7501 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||
| c.4006G>C | E1336Q 2D AIThe SynGAP1 missense change E1336Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, 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 | 0.865454 | Disordered | 0.973342 | Binding | 0.336 | 0.717 | 0.750 | -4.113 | Likely Benign | 0.769 | Likely Pathogenic | Likely Benign | 0.159 | Likely Benign | -1.88 | Neutral | 0.731 | Possibly Damaging | 0.301 | Benign | 3.21 | Benign | 0.00 | Affected | 0.1432 | 0.7427 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.4007A>C | E1336A 2D AIThe SynGAP1 missense variant E1336A is not 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: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, the majority of evidence (five benign vs. three pathogenic) supports a benign classification. This prediction does not contradict any ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.865454 | Disordered | 0.973342 | Binding | 0.336 | 0.717 | 0.750 | -3.545 | Likely Benign | 0.879 | Likely Pathogenic | Ambiguous | 0.191 | Likely Benign | -3.78 | Deleterious | 0.345 | Benign | 0.099 | Benign | 3.22 | Benign | 0.00 | Affected | 0.4000 | 0.7385 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.4007A>G | E1336G 2D AIThe SynGAP1 missense variant E1336G is not 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. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2). Foldetta, which would assess protein‑folding stability, has no available result for this variant. Overall, the balance of evidence (five benign vs three pathogenic predictions) suggests the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.865454 | Disordered | 0.973342 | Binding | 0.336 | 0.717 | 0.750 | -3.574 | Likely Benign | 0.932 | Likely Pathogenic | Ambiguous | 0.211 | Likely Benign | -4.36 | Deleterious | 0.345 | Benign | 0.109 | Benign | 3.20 | Benign | 0.00 | Affected | 0.3092 | 0.6170 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.4007A>T | E1336V 2D AIThe SynGAP1 missense variant E1336V has no ClinVar record (ClinVar status: None) and is not present in gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, and FATHMM, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is reported as uncertain. High‑accuracy assessments are inconclusive: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a tie (2 pathogenic vs. 2 benign), and Foldetta results are unavailable. Consequently, the variant’s predicted impact is ambiguous, with an equal split between benign and pathogenic calls and no evidence from ClinVar to contradict this uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.865454 | Disordered | 0.973342 | Binding | 0.336 | 0.717 | 0.750 | -3.367 | Likely Benign | 0.932 | Likely Pathogenic | Ambiguous | 0.221 | Likely Benign | -4.46 | Deleterious | 0.789 | Possibly Damaging | 0.348 | Benign | 3.18 | Benign | 0.00 | Affected | 0.0991 | 0.7425 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||||
| c.4008G>C | E1336D 2D AIThe SynGAP1 missense variant E1336D is listed in ClinVar (ID 3323942.0) as benign and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The SGM‑Consensus result is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yielding a 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, consistent with the ClinVar benign designation. Thus, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.973342 | Binding | 0.336 | 0.717 | 0.750 | Likely Benign | 1 | -3.344 | Likely Benign | 0.596 | Likely Pathogenic | Likely Benign | 0.062 | Likely Benign | -1.92 | Neutral | 0.001 | Benign | 0.003 | Benign | 3.30 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1995 | 0.5101 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.4008G>T | E1336D 2D AIThe SynGAP1 missense variant E1336D is catalogued in gnomAD (ID 6‑33451882‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a benign or likely benign outcome. Only two tools—SIFT and AlphaMissense‑Default—predict pathogenicity. High‑accuracy assessments further support benignity: 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 classification, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.973342 | Binding | 0.336 | 0.717 | 0.750 | 6-33451882-G-T | -3.344 | Likely Benign | 0.596 | Likely Pathogenic | Likely Benign | 0.065 | Likely Benign | -1.92 | Neutral | 0.001 | Benign | 0.003 | Benign | 3.30 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1995 | 0.5101 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.2224C>G | R742G 2D AIThe SynGAP1 missense variant R742G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.509587 | Binding | 0.309 | 0.856 | 0.875 | -4.065 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -1.25 | Neutral | 0.524 | Possibly Damaging | 0.259 | Benign | 2.70 | Benign | 0.02 | Affected | 0.3974 | 0.2805 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2224C>T | R742W 2D AIThe SynGAP1 missense variant R742W is listed in ClinVar (ID 2581888.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33441689‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign. 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 impact, which is consistent with the ClinVar “Uncertain” classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.509587 | Binding | 0.309 | 0.856 | 0.875 | Uncertain | 1 | 6-33441689-C-T | 6 | 3.72e-6 | -7.725 | In-Between | 0.133 | Likely Benign | Likely Benign | 0.079 | Likely Benign | -1.71 | Neutral | 0.992 | Probably Damaging | 0.684 | Possibly Damaging | 2.66 | Benign | 0.01 | Affected | 4.32 | 2 | 0.1638 | 0.2839 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||
| c.2225G>A | R742Q 2D AIThe SynGAP1 missense variant R742Q is listed in ClinVar (ID 928481.0) with an uncertain significance annotation and is observed in gnomAD (variant ID 6‑33441690‑G‑A). Consensus from multiple in‑silico predictors—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—uniformly classify the change as benign. No tool in the dataset reports a pathogenic prediction. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. A protein‑folding stability analysis via Foldetta is not available for this variant. Overall, the computational evidence strongly favors a benign interpretation, which is consistent with the ClinVar uncertain status rather than contradicting it. The variant is most likely benign, and this assessment does not contradict its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.509587 | Binding | 0.309 | 0.856 | 0.875 | Uncertain | 2 | 6-33441690-G-A | 24 | 1.49e-5 | -4.090 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.19 | Neutral | 0.032 | Benign | 0.007 | Benign | 2.73 | Benign | 0.07 | Tolerated | 4.32 | 2 | 0.3660 | 0.1530 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.2225G>C | R742P 2D AIThe SynGAP1 missense variant R742P is catalogued in gnomAD (6-33441690‑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, 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 the sole discordant prediction. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise reports likely benign. The Foldetta protein‑folding stability analysis is not available for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.509587 | Binding | 0.309 | 0.856 | 0.875 | 6-33441690-G-C | 1 | 6.20e-7 | -2.920 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -0.51 | Neutral | 0.001 | Benign | 0.004 | Benign | 2.84 | Benign | 0.03 | Affected | 4.32 | 2 | 0.2598 | 0.3637 | -2 | 0 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||
| c.2225G>T | R742L 2D AIThe SynGAP1 missense variant R742L 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 | 0.871313 | Disordered | 0.509587 | Binding | 0.309 | 0.856 | 0.875 | -3.778 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.064 | Likely Benign | -0.77 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.71 | Benign | 0.16 | Tolerated | 0.2342 | 0.3831 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2392C>A | P798T 2D AIThe SynGAP1 missense variant P798T is not reported 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 P798T, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.871313 | Disordered | 0.492709 | Uncertain | 0.426 | 0.899 | 0.875 | -5.926 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -0.38 | Neutral | 0.901 | Possibly Damaging | 0.534 | Possibly Damaging | 4.24 | Benign | 0.00 | Affected | 0.1293 | 0.4854 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||||
| c.2392C>G | P798A 2D AIThe SynGAP1 missense variant P798A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas only polyPhen‑2 HumDiv and SIFT 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 view: AlphaMissense‑Optimized reports benign, and the SGM‑Consensus also indicates benign. Foldetta results are not available, so they do not influence the assessment. Overall, the consensus of available predictions indicates that P798A 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 | 0.871313 | Disordered | 0.492709 | Uncertain | 0.426 | 0.899 | 0.875 | -4.841 | Likely Benign | 0.050 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.57 | Neutral | 0.790 | Possibly Damaging | 0.353 | Benign | 4.27 | Benign | 0.00 | Affected | 0.3060 | 0.4030 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||||
| c.2392C>T | P798S 2D AIThe SynGAP1 missense variant P798S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports benign, and the SGM‑Consensus (majority vote) also indicates 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 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 | SH3-binding motif | 0.871313 | Disordered | 0.492709 | Uncertain | 0.426 | 0.899 | 0.875 | -5.382 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.058 | Likely Benign | 0.14 | Neutral | 0.818 | Possibly Damaging | 0.353 | Benign | 4.28 | Benign | 0.00 | Affected | 0.2950 | 0.4425 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||||
| c.2393C>A | P798Q 2D AIThe SynGAP1 missense variant P798Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for P798Q, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.871313 | Disordered | 0.492709 | Uncertain | 0.426 | 0.899 | 0.875 | -5.944 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -0.53 | Neutral | 0.988 | Probably Damaging | 0.780 | Possibly Damaging | 4.25 | Benign | 0.00 | Affected | 0.1290 | 0.3864 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||||
| c.2393C>G | P798R 2D AIThe SynGAP1 missense variant P798R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for P798R, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.871313 | Disordered | 0.492709 | Uncertain | 0.426 | 0.899 | 0.875 | -5.232 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -0.83 | Neutral | 0.976 | Probably Damaging | 0.780 | Possibly Damaging | 4.25 | Benign | 0.00 | Affected | 0.1397 | 0.2840 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||
| c.2393C>T | P798L 2D AIThe SynGAP1 missense variant P798L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33442945‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (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 (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign; a Foldetta stability prediction is not available. 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 | SH3-binding motif | 0.871313 | Disordered | 0.492709 | Uncertain | 0.426 | 0.899 | 0.875 | Uncertain | 2 | 6-33442945-C-T | 6 | 3.72e-6 | -5.640 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.042 | Likely Benign | -0.86 | Neutral | 0.981 | Probably Damaging | 0.631 | Possibly Damaging | 4.21 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2039 | 0.5555 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||
| c.2395C>A | P799T 2D AIThe SynGAP1 missense variant P799T 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. Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for P799T, 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 | 0.871313 | Disordered | 0.537892 | Binding | 0.400 | 0.894 | 0.750 | -5.470 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.033 | Likely Benign | -0.82 | Neutral | 0.951 | Possibly Damaging | 0.738 | Possibly Damaging | 4.24 | Benign | 0.00 | Affected | 0.1522 | 0.5257 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||||
| c.2395C>G | P799A 2D AIThe SynGAP1 missense variant P799A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign) score; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the conclusion. Overall, the majority of evidence points to a benign effect for P799A, and this assessment is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, and this conclusion does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.871313 | Disordered | 0.537892 | Binding | 0.400 | 0.894 | 0.750 | -4.660 | Likely Benign | 0.048 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.72 | Neutral | 0.798 | Possibly Damaging | 0.489 | Possibly Damaging | 4.27 | Benign | 0.00 | Affected | 0.3488 | 0.4279 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||||
| c.2395C>T | P799S 2D AIThe SynGAP1 missense variant P799S 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 (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 P799S, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.871313 | Disordered | 0.537892 | Binding | 0.400 | 0.894 | 0.750 | -4.635 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -0.73 | Neutral | 0.951 | Possibly Damaging | 0.593 | Possibly Damaging | 4.26 | Benign | 0.00 | Affected | 0.3411 | 0.4464 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||||
| c.2396C>A | P799H 2D AIThe SynGAP1 missense variant P799H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the substitution is benign: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a benign effect. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence supports a benign classification for P799H, and this conclusion does not contradict any ClinVar annotation, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.871313 | Disordered | 0.537892 | Binding | 0.400 | 0.894 | 0.750 | -5.611 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -0.80 | Neutral | 0.999 | Probably Damaging | 0.933 | Probably Damaging | 4.20 | Benign | 0.00 | Affected | 0.1684 | 0.4192 | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||||
| c.2396C>G | P799R 2D AIThe SynGAP1 missense variant P799R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a “Likely Benign” outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) likewise indicates benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the preponderance of evidence points to the variant being most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.871313 | Disordered | 0.537892 | Binding | 0.400 | 0.894 | 0.750 | -5.100 | Likely Benign | 0.141 | Likely Benign | Likely Benign | 0.029 | Likely Benign | -0.49 | Neutral | 0.029 | Benign | 0.022 | Benign | 4.27 | Benign | 0.00 | Affected | 0.1425 | 0.2905 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||
| c.2396C>T | P799L 2D AIThe SynGAP1 missense variant P799L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for P799L, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.871313 | Disordered | 0.537892 | Binding | 0.400 | 0.894 | 0.750 | -5.296 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -0.93 | Neutral | 0.905 | Possibly Damaging | 0.670 | Possibly Damaging | 4.27 | Benign | 0.00 | Affected | 0.2078 | 0.6285 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||||
| c.2923A>C | T975P 2D AIThe SynGAP1 missense variant T975P has no ClinVar entry and is not reported in gnomAD. All evaluated in‑silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign effect, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no 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 | 0.871313 | Disordered | 0.969331 | Binding | 0.332 | 0.890 | 0.625 | -2.181 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.286 | Likely Benign | -1.21 | Neutral | 0.000 | Benign | 0.002 | Benign | 4.14 | Benign | 0.06 | Tolerated | 0.2047 | 0.4758 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2923A>G | T975A 2D AIThe SynGAP1 missense change T975A is not reported in ClinVar and is absent from gnomAD. All evaluated 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. 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) indicates a likely benign outcome. Foldetta, a protein‑folding stability method, 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 | 0.871313 | Disordered | 0.969331 | Binding | 0.332 | 0.890 | 0.625 | -2.866 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.110 | Likely Benign | -0.71 | Neutral | 0.000 | Benign | 0.002 | Benign | 4.19 | Benign | 0.18 | Tolerated | 0.3821 | 0.4275 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2923A>T | T975S 2D AIThe SynGAP1 missense variant T975S 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, is not available for this variant. Overall, the predictions strongly suggest that T975S is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.969331 | Binding | 0.332 | 0.890 | 0.625 | -2.743 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.127 | Likely Benign | -0.57 | Neutral | 0.059 | Benign | 0.061 | Benign | 4.16 | Benign | 0.20 | Tolerated | 0.3228 | 0.4366 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2924C>A | T975N 2D AIThe SynGAP1 missense variant T975N is listed in ClinVar (ID 942242.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33443476‑C‑A). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated outcomes. Only polyPhen‑2 HumDiv predicts a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, 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 | 0.871313 | Disordered | 0.969331 | Binding | 0.332 | 0.890 | 0.625 | Uncertain | 1 | 6-33443476-C-A | 1 | 6.20e-7 | -4.671 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.100 | Likely Benign | -0.58 | Neutral | 0.586 | Possibly Damaging | 0.302 | Benign | 4.13 | Benign | 0.07 | Tolerated | 4.32 | 2 | 0.1379 | 0.4772 | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||||||||||||
| c.2924C>G | T975S 2D AIThe SynGAP1 missense variant T975S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, 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 interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the available predictions strongly suggest that T975S is most likely benign, 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 | 0.871313 | Disordered | 0.969331 | Binding | 0.332 | 0.890 | 0.625 | Uncertain | 1 | -2.743 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.109 | Likely Benign | -0.57 | Neutral | 0.059 | Benign | 0.061 | Benign | 4.16 | Benign | 0.20 | Tolerated | 0.3228 | 0.4366 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||
| c.2924C>T | T975I 2D AIThe SynGAP1 missense variant T975I is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33443476‑C‑T). 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 predicts pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a “Likely Benign” classification. 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 computational evidence overwhelmingly supports a benign effect, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.969331 | Binding | 0.332 | 0.890 | 0.625 | Uncertain | 1 | 6-33443476-C-T | 6 | 3.72e-6 | -3.912 | Likely Benign | 0.164 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -1.66 | Neutral | 0.411 | Benign | 0.239 | Benign | 4.11 | Benign | 0.66 | Tolerated | 4.32 | 2 | 0.1107 | 0.5198 | 0 | -1 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||||
| c.3358G>A | G1120S 2D AIThe SynGAP1 missense variant G1120S is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions strongly suggests that G1120S 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 | 0.871313 | Disordered | 0.804931 | Binding | 0.335 | 0.925 | 0.875 | -4.959 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.286 | Likely Benign | -0.27 | Neutral | 0.451 | Benign | 0.209 | Benign | 3.69 | Benign | 0.77 | Tolerated | 0.2515 | 0.5311 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3358G>C | G1120R 2D AIThe SynGAP1 missense variant G1120R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign impact for G1120R, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.871313 | Disordered | 0.804931 | Binding | 0.335 | 0.925 | 0.875 | -8.784 | Likely Pathogenic | 0.565 | Likely Pathogenic | Likely Benign | 0.333 | Likely Benign | -0.77 | Neutral | 0.666 | Possibly Damaging | 0.221 | Benign | 3.60 | Benign | 0.05 | Affected | 0.0994 | 0.4142 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3358G>T | G1120C 2D AIThe SynGAP1 missense variant G1120C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. 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.” No Foldetta stability result is available. Overall, the majority of evidence points to a benign impact for G1120C, 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 | 0.871313 | Disordered | 0.804931 | Binding | 0.335 | 0.925 | 0.875 | -9.324 | Likely Pathogenic | 0.112 | Likely Benign | Likely Benign | 0.311 | Likely Benign | -1.32 | Neutral | 0.994 | Probably Damaging | 0.840 | Possibly Damaging | 3.60 | Benign | 0.03 | Affected | 0.1271 | 0.4227 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.3359G>A | G1120D 2D AIThe SynGAP1 missense variant G1120D is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443911‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) resolves to a benign majority (2 benign vs. 1 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.871313 | Disordered | 0.804931 | Binding | 0.335 | 0.925 | 0.875 | 6-33443911-G-A | 4 | 2.65e-6 | -9.244 | Likely Pathogenic | 0.378 | Ambiguous | Likely Benign | 0.351 | Likely Benign | -0.82 | Neutral | 0.666 | Possibly Damaging | 0.355 | Benign | 3.60 | Benign | 0.19 | Tolerated | 3.77 | 5 | 0.1659 | 0.1835 | -1 | 1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||
| c.3359G>C | G1120A 2D AIThe SynGAP1 missense variant G1120A is not reported in ClinVar (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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; ESM1b is 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 a benign likelihood. Foldetta results are unavailable. Overall, the consensus of available predictions indicates that G1120A is most likely benign, and this conclusion does not contradict any ClinVar status because none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.804931 | Binding | 0.335 | 0.925 | 0.875 | -7.192 | In-Between | 0.082 | Likely Benign | Likely Benign | 0.243 | Likely Benign | -0.39 | Neutral | 0.264 | Benign | 0.139 | Benign | 3.64 | Benign | 0.28 | Tolerated | 0.3435 | 0.4944 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3359G>T | G1120V 2D AIThe SynGAP1 missense variant G1120V is catalogued in gnomAD (6‑33443911‑G‑T) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the variant as benign, while ESM1b remains uncertain. No tool predicts pathogenicity. The high‑accuracy consensus, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), classifies the variant as “Likely Benign.” AlphaMissense‑Optimized also reports a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and this assessment does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.804931 | Binding | 0.335 | 0.925 | 0.875 | 6-33443911-G-T | -7.659 | In-Between | 0.081 | Likely Benign | Likely Benign | 0.355 | Likely Benign | -1.20 | Neutral | 0.292 | Benign | 0.157 | Benign | 3.61 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0.1360 | 0.3694 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||
| c.3907G>A | G1303S 2D AIThe SynGAP1 missense variant G1303S is listed in ClinVar (ID 1736068.0) with an “Uncertain” clinical significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only polyPhen‑2 HumDiv predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this 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 | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | Uncertain | 1 | -2.271 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.155 | Likely Benign | -0.19 | Neutral | 0.649 | Possibly Damaging | 0.433 | Benign | 2.84 | Benign | 0.18 | Tolerated | 0.2605 | 0.4197 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||
| c.3907G>C | G1303R 2D AIThe SynGAP1 missense variant G1303R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic effect, whereas REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict a benign outcome. Grouping by consensus, the benign‑predicating tools outnumber the pathogenic ones. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized classifies the variant as benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b, FATHMM, and PROVEAN—also reports a likely benign status. No Foldetta stability analysis is available for this residue. Overall, the preponderance of evidence points to a benign effect for G1303R, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | -3.093 | Likely Benign | 0.536 | Ambiguous | Likely Benign | 0.364 | Likely Benign | -1.84 | Neutral | 0.970 | Probably Damaging | 0.787 | Possibly Damaging | 2.81 | Benign | 0.05 | Affected | 0.1024 | 0.3596 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3907G>T | G1303C 2D AIThe SynGAP1 missense variant G1303C 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 | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | -5.286 | Likely Benign | 0.257 | Likely Benign | Likely Benign | 0.377 | Likely Benign | -2.49 | Neutral | 0.997 | Probably Damaging | 0.961 | Probably Damaging | 2.76 | Benign | 0.02 | Affected | 0.1319 | 0.3681 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.3908G>A | G1303D 2D AIThe SynGAP1 missense variant G1303D is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | -3.825 | Likely Benign | 0.329 | Likely Benign | Likely Benign | 0.103 | Likely Benign | 2.64 | Neutral | 0.002 | Benign | 0.008 | Benign | 3.22 | Benign | 1.00 | Tolerated | 0.1784 | 0.1452 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3908G>C | G1303A 2D AIThe SynGAP1 missense variant G1303A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumDiv indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the consensus of the available predictions points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | -2.637 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -1.29 | Neutral | 0.790 | Possibly Damaging | 0.433 | Benign | 2.83 | Benign | 0.11 | Tolerated | 0.3822 | 0.4092 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3908G>T | G1303V 2D AIThe SynGAP1 missense variant G1303V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | -3.513 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.147 | Likely Benign | -2.44 | Neutral | 0.990 | Probably Damaging | 0.846 | Possibly Damaging | 2.79 | Benign | 0.02 | Affected | 0.1511 | 0.3508 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.2197C>A | Q733K 2D AIThe SynGAP1 missense variant Q733K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for Q733K, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.410831 | Uncertain | 0.331 | 0.686 | 0.875 | -6.779 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.112 | Likely Benign | -1.66 | Neutral | 0.797 | Possibly Damaging | 0.312 | Benign | 2.61 | Benign | 0.05 | Affected | 0.1572 | 0.2790 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2197C>G | Q733E 2D AIThe SynGAP1 missense variant Q733E is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign predictions from REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar) and SIFT; ESM1b is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus itself is 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 ClinVar pathogenic reports. Thus, the variant is most likely benign, and this is not contradictory to ClinVar, which has no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.410831 | Uncertain | 0.331 | 0.686 | 0.875 | -7.651 | In-Between | 0.152 | Likely Benign | Likely Benign | 0.117 | Likely Benign | -1.38 | Neutral | 0.983 | Probably Damaging | 0.637 | Possibly Damaging | 2.60 | Benign | 0.03 | Affected | 0.1363 | 0.1130 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2198A>C | Q733P 2D AIThe SynGAP1 missense variant Q733P is not reported in ClinVar (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 (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.410831 | Uncertain | 0.331 | 0.686 | 0.875 | -4.249 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.172 | Likely Benign | -1.91 | Neutral | 0.220 | Benign | 0.308 | Benign | 2.52 | Benign | 0.04 | Affected | 0.2182 | 0.3894 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2198A>G | Q733R 2D AIThe SynGAP1 missense variant Q733R 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 for Q733R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.410831 | Uncertain | 0.331 | 0.686 | 0.875 | -5.986 | Likely Benign | 0.291 | Likely Benign | Likely Benign | 0.117 | Likely Benign | -1.96 | Neutral | 0.950 | Possibly Damaging | 0.612 | Possibly Damaging | 2.57 | Benign | 0.04 | Affected | 0.1419 | 0.1279 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.2198A>T | Q733L 2D AIThe SynGAP1 missense variant Q733L 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. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. 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 | 0.874069 | Disordered | 0.410831 | Uncertain | 0.331 | 0.686 | 0.875 | -3.465 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.128 | Likely Benign | -2.04 | Neutral | 0.905 | Possibly Damaging | 0.408 | Benign | 2.55 | Benign | 1.00 | Tolerated | 0.0736 | 0.4291 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2199G>C | Q733H 2D AIThe SynGAP1 missense variant Q733H is not reported 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 show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; the Foldetta stability analysis is 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 | 0.874069 | Disordered | 0.410831 | Uncertain | 0.331 | 0.686 | 0.875 | -5.741 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -2.47 | Neutral | 0.990 | Probably Damaging | 0.780 | Possibly Damaging | 2.52 | Benign | 0.02 | Affected | 0.1341 | 0.2263 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2199G>T | Q733H 2D AIThe SynGAP1 missense variant Q733H is not reported 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 Q733H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.410831 | Uncertain | 0.331 | 0.686 | 0.875 | -5.741 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -2.47 | Neutral | 0.990 | Probably Damaging | 0.780 | Possibly Damaging | 2.52 | Benign | 0.02 | Affected | 0.1341 | 0.2263 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| 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.2821C>A | P941T 2D AIThe SynGAP1 missense variant P941T is listed in gnomAD (ID 6‑33443373‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.900790 | Binding | 0.403 | 0.906 | 0.625 | 6-33443373-C-A | 2 | 1.24e-6 | -6.193 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.19 | Neutral | 0.144 | Benign | 0.085 | Benign | 2.77 | Benign | 0.05 | Affected | 4.32 | 4 | 0.1612 | 0.5607 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||
| c.2821C>G | P941A 2D AIThe SynGAP1 missense variant P941A is reported in gnomAD (variant ID 6-33443373-C-G) but has no ClinVar entry. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign effect. No tool predicts pathogenicity. The high‑accuracy consensus, SGM‑Consensus, also reports the variant as Likely Benign, and AlphaMissense‑Optimized concurs with a benign prediction. Foldetta, a protein‑folding stability method, did not provide a result for this variant, so its status remains unavailable. Overall, the collective evidence strongly supports a benign classification, and this assessment is consistent with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.900790 | Binding | 0.403 | 0.906 | 0.625 | 6-33443373-C-G | 2 | 1.24e-6 | -4.313 | Likely Benign | 0.054 | Likely Benign | Likely Benign | 0.046 | Likely Benign | 0.10 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.80 | Benign | 0.10 | Tolerated | 4.32 | 4 | 0.2844 | 0.5190 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.2821C>T | P941S 2D AIThe SynGAP1 missense variant P941S is reported in gnomAD (ID 6‑33443373‑C‑T) but has no ClinVar entry. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, which evaluates protein‑folding stability via FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of all available predictions indicates that P941S is most likely benign, and this assessment does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.900790 | Binding | 0.403 | 0.906 | 0.625 | 6-33443373-C-T | 1 | 6.20e-7 | -5.099 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.039 | Likely Benign | 0.58 | Neutral | 0.036 | Benign | 0.039 | Benign | 3.05 | Benign | 0.95 | Tolerated | 4.32 | 4 | 0.2759 | 0.5576 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.2822C>A | P941H 2D AIThe SynGAP1 missense variant P941H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. In contrast, two tools—polyPhen‑2 HumDiv and SIFT—classify the change as pathogenic. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; no Foldetta stability data are available. Overall, the majority of evidence points to a benign effect, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.900790 | Binding | 0.403 | 0.906 | 0.625 | -4.439 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.09 | Neutral | 0.589 | Possibly Damaging | 0.309 | Benign | 2.71 | Benign | 0.00 | Affected | 0.1621 | 0.4826 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2822C>G | P941R 2D AIThe SynGAP1 missense variant P941R is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the only pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta results are not available, so they do not influence the assessment. Overall, the majority of evidence points to a benign impact for P941R, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.900790 | Binding | 0.403 | 0.906 | 0.625 | -5.463 | Likely Benign | 0.181 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -0.34 | Neutral | 0.144 | Benign | 0.062 | Benign | 2.75 | Benign | 0.01 | Affected | 0.1487 | 0.3775 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2822C>T | P941L 2D AIThe SynGAP1 missense variant P941L is listed in ClinVar (ID 3451960.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). The only tool that predicts a pathogenic outcome is SIFT. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates “Likely Benign.” No Foldetta (FoldX‑MD/Rosetta) stability result is available, so it does not influence the assessment. Overall, the majority of predictions, including the high‑accuracy tools, point to a benign effect, which is consistent with the ClinVar “Uncertain” designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.900790 | Binding | 0.403 | 0.906 | 0.625 | Uncertain | 2 | -5.692 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.44 | Neutral | 0.144 | Benign | 0.039 | Benign | 2.76 | Benign | 0.01 | Affected | 0.2196 | 0.5931 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||
| c.3241G>A | A1081T 2D AIThe SynGAP1 missense variant A1081T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign effect. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.979759 | Binding | 0.288 | 0.895 | 0.750 | -3.887 | Likely Benign | 0.129 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.07 | Neutral | 0.440 | Benign | 0.184 | Benign | 4.01 | Benign | 0.15 | Tolerated | 0.1567 | 0.6112 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3241G>C | A1081P 2D AIThe SynGAP1 missense variant A1081P is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the collective evidence strongly supports a benign classification, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.979759 | Binding | 0.288 | 0.895 | 0.750 | -2.967 | Likely Benign | 0.178 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -1.07 | Neutral | 0.005 | Benign | 0.010 | Benign | 4.00 | Benign | 0.14 | Tolerated | 0.1878 | 0.4540 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3241G>T | A1081S 2D AIThe SynGAP1 missense variant A1081S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Consequently, the variant is most likely benign, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.979759 | Binding | 0.288 | 0.895 | 0.750 | -3.536 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -0.29 | Neutral | 0.021 | Benign | 0.031 | Benign | 4.02 | Benign | 0.23 | Tolerated | 0.2268 | 0.4915 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3242C>A | A1081D 2D AIThe SynGAP1 missense variant A1081D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized result is Uncertain, and the Foldetta protein‑folding stability assessment is unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.979759 | Binding | 0.288 | 0.895 | 0.750 | -4.603 | Likely Benign | 0.892 | Likely Pathogenic | Ambiguous | 0.095 | Likely Benign | -1.84 | Neutral | 0.611 | Possibly Damaging | 0.404 | Benign | 3.97 | Benign | 0.04 | Affected | 0.2069 | 0.2600 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.3242C>G | A1081G 2D AIThe missense variant A1081G in SynGAP1 has no entry in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as likely benign. Foldetta results are unavailable. Overall, the computational evidence strongly supports a benign classification, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.979759 | Binding | 0.288 | 0.895 | 0.750 | -3.174 | Likely Benign | 0.191 | Likely Benign | Likely Benign | 0.033 | Likely Benign | -1.43 | Neutral | 0.393 | Benign | 0.184 | Benign | 3.99 | Benign | 0.23 | Tolerated | 0.1751 | 0.4348 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3242C>T | A1081V 2D AIThe SynGAP1 missense variant A1081V is reported in gnomAD (ID 6‑33443794‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, creating a single discordant signal. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that A1081V is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.979759 | Binding | 0.288 | 0.895 | 0.750 | 6-33443794-C-T | -3.973 | Likely Benign | 0.172 | Likely Benign | Likely Benign | 0.036 | Likely Benign | -1.32 | Neutral | 0.611 | Possibly Damaging | 0.399 | Benign | 4.04 | Benign | 0.37 | Tolerated | 3.77 | 5 | 0.1353 | 0.4884 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||
| c.3301C>A | P1101T 2D AIThe SynGAP1 missense variant P1101T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.968967 | Binding | 0.457 | 0.861 | 0.875 | -4.161 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.126 | Likely Benign | -1.60 | Neutral | 0.115 | Benign | 0.031 | Benign | 4.22 | Benign | 0.04 | Affected | 0.1729 | 0.5860 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3301C>G | P1101A 2D AIThe SynGAP1 missense variant P1101A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess pathogenicity uniformly predict a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Consequently, the variant is most likely benign based on the collective predictions, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.968967 | Binding | 0.457 | 0.861 | 0.875 | -3.825 | Likely Benign | 0.057 | Likely Benign | Likely Benign | 0.095 | Likely Benign | -1.34 | Neutral | 0.010 | Benign | 0.010 | Benign | 4.26 | Benign | 0.08 | Tolerated | 0.3154 | 0.5218 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3301C>T | P1101S 2D AIThe SynGAP1 missense variant P1101S is reported in gnomAD (variant ID 6‑33443853‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags it as pathogenic, creating a single discordant call. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.968967 | Binding | 0.457 | 0.861 | 0.875 | 6-33443853-C-T | 1 | 6.52e-7 | -3.845 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -1.31 | Neutral | 0.626 | Possibly Damaging | 0.255 | Benign | 4.25 | Benign | 0.07 | Tolerated | 3.77 | 5 | 0.3265 | 0.5400 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3302C>A | P1101H 2D AIThe SynGAP1 missense variant P1101H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign effect for P1101H, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.968967 | Binding | 0.457 | 0.861 | 0.875 | -5.370 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.167 | Likely Benign | -1.87 | Neutral | 0.996 | Probably Damaging | 0.864 | Possibly Damaging | 4.18 | Benign | 0.02 | Affected | 0.2046 | 0.4597 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3302C>G | P1101R 2D AIThe SynGAP1 missense variant P1101R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy methods further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of evidence points to a benign effect, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.968967 | Binding | 0.457 | 0.861 | 0.875 | -4.772 | Likely Benign | 0.227 | Likely Benign | Likely Benign | 0.103 | Likely Benign | -1.28 | Neutral | 0.960 | Probably Damaging | 0.761 | Possibly Damaging | 4.27 | Benign | 0.36 | Tolerated | 0.1497 | 0.4644 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3302C>T | P1101L 2D AIThe SynGAP1 missense variant P1101L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for P1101L, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.874069 | Disordered | 0.968967 | Binding | 0.457 | 0.861 | 0.875 | -4.335 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.109 | Likely Benign | -2.19 | Neutral | 0.770 | Possibly Damaging | 0.255 | Benign | 4.27 | Benign | 0.04 | Affected | 0.2310 | 0.6050 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2926T>A | F976I 2D  AIThe SynGAP1 missense variant F976I 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, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (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, 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 | 0.876521 | Disordered | 0.975061 | Binding | 0.311 | 0.894 | 0.625 | -4.595 | Likely Benign | 0.364 | Ambiguous | Likely Benign | 0.148 | Likely Benign | -1.16 | Neutral | 0.666 | Possibly Damaging | 0.265 | Benign | 4.16 | Benign | 0.21 | Tolerated | 0.2790 | 0.2714 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2926T>C | F976L 2D  AIThe SynGAP1 missense variant F976L is not reported in ClinVar (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 the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which classifies the variant as “Likely Benign.” In contrast, AlphaMissense‑Default predicts a pathogenic effect, while AlphaMissense‑Optimized is uncertain. No Foldetta (FoldX‑MD/ Rosetta) stability result is available, so it does not contribute to the assessment. Overall, the majority of high‑confidence predictors indicate a benign impact, and this is consistent with the lack of ClinVar evidence. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.975061 | Binding | 0.311 | 0.894 | 0.625 | -2.432 | Likely Benign | 0.825 | Likely Pathogenic | Ambiguous | 0.237 | Likely Benign | -0.87 | Neutral | 0.264 | Benign | 0.102 | Benign | 4.20 | Benign | 0.53 | Tolerated | 4.32 | 2 | 0.2829 | 0.3082 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||
| c.2926T>G | F976V 2D  AIThe SynGAP1 missense variant F976V 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 | 0.876521 | Disordered | 0.975061 | Binding | 0.311 | 0.894 | 0.625 | -3.328 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.190 | Likely Benign | -1.32 | Neutral | 0.451 | Benign | 0.157 | Benign | 4.18 | Benign | 0.23 | Tolerated | 0.2696 | 0.2902 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||||||||||||
| c.2927T>A | F976Y 2D  AIThe SynGAP1 missense variant F976Y is not reported 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 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 | 0.876521 | Disordered | 0.975061 | Binding | 0.311 | 0.894 | 0.625 | -3.902 | Likely Benign | 0.225 | Likely Benign | Likely Benign | 0.172 | Likely Benign | -0.50 | Neutral | 0.925 | Possibly Damaging | 0.529 | Possibly Damaging | 4.11 | Benign | 0.80 | Tolerated | 0.1942 | 0.2257 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2927T>C | F976S 2D  AIThe SynGAP1 missense variant F976S is not reported in ClinVar (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, 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 because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.975061 | Binding | 0.311 | 0.894 | 0.625 | -2.393 | Likely Benign | 0.432 | Ambiguous | Likely Benign | 0.217 | Likely Benign | -0.73 | Neutral | 0.292 | Benign | 0.102 | Benign | 4.16 | Benign | 0.49 | Tolerated | 0.4432 | 0.1134 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||||||||||||
| c.2927T>G | F976C 2D  AIThe SynGAP1 missense variant F976C is not reported in ClinVar and is absent from gnomAD. In silico predictors cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from polyPhen‑2 HumDiv and polyPhen‑2 HumVar. 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 impact for F976C, and this conclusion is not in conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.975061 | Binding | 0.311 | 0.894 | 0.625 | -5.490 | Likely Benign | 0.490 | Ambiguous | Likely Benign | 0.103 | Likely Benign | -1.10 | Neutral | 0.977 | Probably Damaging | 0.840 | Possibly Damaging | 4.09 | Benign | 0.10 | Tolerated | 0.2961 | 0.2505 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||||||||||||
| c.2928T>A | F976L 2D AIThe SynGAP1 missense variant F976L is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33443480‑T‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Only AlphaMissense‑Default predicts a pathogenic outcome, while AlphaMissense‑Optimized is uncertain. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from high‑accuracy predictors and consensus analysis indicates that F976L 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 | 0.876521 | Disordered | 0.975061 | Binding | 0.311 | 0.894 | 0.625 | 6-33443480-T-A | 2 | 1.24e-6 | -2.432 | Likely Benign | 0.825 | Likely Pathogenic | Ambiguous | 0.212 | Likely Benign | -0.87 | Neutral | 0.264 | Benign | 0.102 | Benign | 4.20 | Benign | 0.53 | Tolerated | 4.32 | 2 | 0.2829 | 0.3082 | 2 | 0 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||
| c.2928T>G | F976L 2D AIThe SynGAP1 missense variant F976L is listed in ClinVar (ID 624245.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Only AlphaMissense‑Default predicts a pathogenic outcome. The high‑accuracy consensus predictor SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. AlphaMissense‑Optimized is inconclusive, and no Foldetta (FoldX‑MD/Rosetta stability) result is available. Overall, the majority of evidence points to a benign impact, and this is consistent with the ClinVar designation of uncertainty rather than a definitive pathogenic claim. Thus, the variant is most likely benign, and its predictions do not contradict the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.975061 | Binding | 0.311 | 0.894 | 0.625 | Uncertain | 1 | -2.432 | Likely Benign | 0.825 | Likely Pathogenic | Ambiguous | 0.212 | Likely Benign | -0.87 | Neutral | 0.264 | Benign | 0.102 | Benign | 4.20 | Benign | 0.53 | Tolerated | 4.32 | 2 | 0.2829 | 0.3082 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||
| c.3319C>A | Q1107K 2D AIThe SynGAP1 missense variant Q1107K is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools largely support a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. Only polyPhen‑2 HumDiv predicts a pathogenic effect, and AlphaMissense‑Default remains uncertain. High‑accuracy assessments further reinforce the benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion is not in conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -4.066 | Likely Benign | 0.400 | Ambiguous | Likely Benign | 0.095 | Likely Benign | -1.99 | Neutral | 0.920 | Possibly Damaging | 0.425 | Benign | 2.60 | Benign | 0.30 | Tolerated | 0.1805 | 0.5276 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3319C>G | Q1107E 2D AIThe SynGAP1 missense variant Q1107E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -3.875 | Likely Benign | 0.231 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -1.54 | Neutral | 0.920 | Possibly Damaging | 0.425 | Benign | 2.59 | Benign | 0.02 | Affected | 0.1453 | 0.2932 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3320A>C | Q1107P 2D AIThe SynGAP1 missense variant Q1107P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence—including the high‑accuracy tools—points to a benign effect for Q1107P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -2.643 | Likely Benign | 0.047 | Likely Benign | Likely Benign | 0.135 | Likely Benign | -2.35 | Neutral | 0.965 | Probably Damaging | 0.611 | Possibly Damaging | 2.57 | Benign | 0.01 | Affected | 0.2109 | 0.5767 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3320A>G | Q1107R 2D AIThe SynGAP1 missense variant Q1107R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. AlphaMissense‑Default is uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” AlphaMissense‑Optimized also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -2.837 | Likely Benign | 0.394 | Ambiguous | Likely Benign | 0.126 | Likely Benign | -1.76 | Neutral | 0.965 | Probably Damaging | 0.425 | Benign | 2.55 | Benign | 0.04 | Affected | 0.1482 | 0.3319 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.3320A>T | Q1107L 2D AIThe SynGAP1 missense variant Q1107L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, PROVEAN and SIFT predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -3.785 | Likely Benign | 0.116 | Likely Benign | Likely Benign | 0.119 | Likely Benign | -3.27 | Deleterious | 0.006 | Benign | 0.004 | Benign | 2.53 | Benign | 0.01 | Affected | 0.0820 | 0.6447 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3321G>C | Q1107H 2D AIThe SynGAP1 missense variant Q1107H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -3.546 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -2.58 | Deleterious | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.1514 | 0.4683 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3321G>T | Q1107H 2D AIThe SynGAP1 missense variant Q1107H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, while Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -3.546 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -2.58 | Deleterious | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.1514 | 0.4683 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3352A>C | S1118R 2D AIThe SynGAP1 missense variant S1118R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that S1118R is most likely benign, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.828802 | Binding | 0.310 | 0.919 | 0.750 | -2.670 | Likely Benign | 0.553 | Ambiguous | Likely Benign | 0.175 | Likely Benign | -0.74 | Neutral | 0.034 | Benign | 0.023 | Benign | 5.17 | Benign | 0.05 | Affected | 4.32 | 2 | 0.1314 | 0.3431 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.3352A>G | S1118G 2D AIThe SynGAP1 missense variant S1118G is reported in gnomAD (ID 6‑33443904‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic. 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, SGM‑Consensus is likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the preponderance of evidence indicates that S1118G 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 | 0.876521 | Disordered | 0.828802 | Binding | 0.310 | 0.919 | 0.750 | 6-33443904-A-G | 1 | 6.98e-7 | -1.615 | Likely Benign | 0.057 | Likely Benign | Likely Benign | 0.146 | Likely Benign | -0.61 | Neutral | 0.790 | Possibly Damaging | 0.433 | Benign | 5.82 | Benign | 0.08 | Tolerated | 4.32 | 2 | 0.2737 | 0.4657 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||
| c.3352A>T | S1118C 2D AIThe SynGAP1 missense variant S1118C is listed in gnomAD (ID 6‑33443904‑A‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT, while ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.828802 | Binding | 0.310 | 0.919 | 0.750 | 6-33443904-A-T | -7.402 | In-Between | 0.096 | Likely Benign | Likely Benign | 0.311 | Likely Benign | -1.05 | Neutral | 0.997 | Probably Damaging | 0.889 | Possibly Damaging | 5.15 | Benign | 0.01 | Affected | 4.32 | 2 | 0.1648 | 0.5695 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||
| c.3353G>A | S1118N 2D AIThe SynGAP1 missense variant S1118N 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 prediction tools and the high‑accuracy methods indicates that the variant is most likely benign, and this assessment is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.828802 | Binding | 0.310 | 0.919 | 0.750 | -6.551 | Likely Benign | 0.102 | Likely Benign | Likely Benign | 0.223 | Likely Benign | -0.53 | Neutral | 0.901 | Possibly Damaging | 0.433 | Benign | 5.26 | Benign | 0.06 | Tolerated | 0.1924 | 0.4215 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| c.3353G>C | S1118T 2D AIThe SynGAP1 missense variant S1118T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.828802 | Binding | 0.310 | 0.919 | 0.750 | -6.063 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.196 | Likely Benign | -0.67 | Neutral | 0.790 | Possibly Damaging | 0.433 | Benign | 5.18 | Benign | 0.10 | Tolerated | 0.2066 | 0.5587 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3353G>T | S1118I 2D AIThe SynGAP1 missense variant S1118I 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 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 | 0.876521 | Disordered | 0.828802 | Binding | 0.310 | 0.919 | 0.750 | -5.710 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.309 | Likely Benign | -1.09 | Neutral | 0.990 | Probably Damaging | 0.798 | Possibly Damaging | 5.16 | Benign | 0.01 | Affected | 0.1486 | 0.4580 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.3354C>A | S1118R 2D AIThe SynGAP1 missense variant S1118R (ClinVar ID 2656489.0) is listed as ClinVar status Uncertain and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only SIFT predicts a pathogenic effect, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the ClinVar Uncertain designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.828802 | Binding | 0.310 | 0.919 | 0.750 | Uncertain | 1 | -2.670 | Likely Benign | 0.553 | Ambiguous | Likely Benign | 0.166 | Likely Benign | -0.74 | Neutral | 0.034 | Benign | 0.023 | Benign | 5.17 | Benign | 0.05 | Affected | 4.32 | 2 | 0.1314 | 0.3431 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||
| c.3354C>G | S1118R 2D AIThe SynGAP1 missense variant S1118R is listed in gnomAD (ID 6‑33443906‑C‑G) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.828802 | Binding | 0.310 | 0.919 | 0.750 | 6-33443906-C-G | -2.670 | Likely Benign | 0.553 | Ambiguous | Likely Benign | 0.165 | Likely Benign | -0.74 | Neutral | 0.034 | Benign | 0.023 | Benign | 5.17 | Benign | 0.05 | Affected | 4.32 | 2 | 0.1314 | 0.3431 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| c.3973C>A | P1325T 2D AIThe SynGAP1 missense variant P1325T is reported in gnomAD (ID 6‑33451847‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign effect for P1325T, 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 | 0.876521 | Disordered | 0.893621 | Binding | 0.439 | 0.791 | 0.875 | 6-33451847-C-A | -5.880 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.135 | Likely Benign | -0.14 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.07 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1814 | 0.5150 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3973C>G | P1325A 2D AIThe SynGAP1 missense variant P1325A is reported in gnomAD (ID 6‑33451847‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only SIFT predicts a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy methods 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 P1325A, 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 | 0.876521 | Disordered | 0.893621 | Binding | 0.439 | 0.791 | 0.875 | 6-33451847-C-G | -3.786 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -0.95 | Neutral | 0.019 | Benign | 0.004 | Benign | 4.10 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3650 | 0.4016 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||
| c.3973C>T | P1325S 2D AIThe SynGAP1 missense variant P1325S is reported in gnomAD (ID 6‑33451847‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.893621 | Binding | 0.439 | 0.791 | 0.875 | 6-33451847-C-T | 1 | 6.43e-7 | -5.273 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.053 | Likely Benign | 0.29 | Neutral | 0.010 | Benign | 0.007 | Benign | 4.10 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3657 | 0.4360 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3974C>A | P1325H 2D AIThe SynGAP1 missense variant P1325H is reported in gnomAD (variant ID 6‑33451848‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv and SIFT. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” No result is available from the Foldetta stability analysis. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.893621 | Binding | 0.439 | 0.791 | 0.875 | 6-33451848-C-A | -6.970 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.056 | Likely Benign | 0.10 | Neutral | 0.704 | Possibly Damaging | 0.187 | Benign | 4.04 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2103 | 0.4364 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||
| c.3974C>G | P1325R 2D AIThe SynGAP1 missense variant P1325R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and there is no conflict with ClinVar status, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.893621 | Binding | 0.439 | 0.791 | 0.875 | -5.427 | Likely Benign | 0.173 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -0.33 | Neutral | 0.182 | Benign | 0.029 | Benign | 4.06 | Benign | 0.00 | Affected | 0.1668 | 0.3081 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3974C>T | P1325L 2D AIThe SynGAP1 missense variant P1325L is listed in ClinVar (ID 1720534.0) with an uncertain significance designation and is present in gnomAD (variant ID 6‑33451848‑C‑T). Functional 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 further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for P1325L, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.893621 | Binding | 0.439 | 0.791 | 0.875 | Uncertain | 1 | 6-33451848-C-T | -5.256 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.146 | Likely Benign | -1.05 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.05 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2616 | 0.6073 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| c.2200C>A | P734T 2D AIThe SynGAP1 missense variant P734T is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. The high‑accuracy consensus (SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports 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 result available for this variant. Based on the unanimous benign predictions and the lack of any pathogenic evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.411273 | Uncertain | 0.368 | 0.721 | 0.875 | -4.469 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.042 | Likely Benign | -2.08 | Neutral | 0.040 | Benign | 0.013 | Benign | 2.78 | Benign | 0.09 | Tolerated | 0.1764 | 0.4076 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2200C>G | P734A 2D AIThe SynGAP1 missense variant P734A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect. Consensus predictors such as SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and high‑accuracy methods including AlphaMissense‑Optimized all classify the variant as benign. Additional in silico assessments—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—also predict a benign outcome. No tool in the dataset suggests pathogenicity. Protein‑stability analysis via Foldetta is unavailable 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 | 0.879233 | Disordered | 0.411273 | Uncertain | 0.368 | 0.721 | 0.875 | -3.907 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.031 | Likely Benign | -2.19 | Neutral | 0.022 | Benign | 0.074 | Benign | 2.74 | Benign | 0.24 | Tolerated | 0.3801 | 0.3306 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2200C>T | P734S 2D AIThe SynGAP1 missense variant P734S is listed in ClinVar with an uncertain significance (ClinVar ID 2283225.0) and is present in the gnomAD database (gnomAD ID 6‑33441665‑C‑T). Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign effects. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this benign assessment: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign classification, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.411273 | Uncertain | 0.368 | 0.721 | 0.875 | Uncertain | 2 | 6-33441665-C-T | 2 | 1.24e-6 | -4.291 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -2.44 | Neutral | 0.344 | Benign | 0.048 | Benign | 2.77 | Benign | 0.11 | Tolerated | 3.64 | 6 | 0.3775 | 0.3650 | 1 | -1 | 0.8 | -10.04 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.2201C>A | P734Q 2D AIThe SynGAP1 missense variant P734Q 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 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, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.411273 | Uncertain | 0.368 | 0.721 | 0.875 | -4.392 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.080 | Likely Benign | -1.92 | Neutral | 0.959 | Probably Damaging | 0.569 | Possibly Damaging | 2.87 | Benign | 0.06 | Tolerated | 0.1608 | 0.3364 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2201C>G | P734R 2D AIThe SynGAP1 missense variant P734R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.411273 | Uncertain | 0.368 | 0.721 | 0.875 | -6.099 | Likely Benign | 0.288 | Likely Benign | Likely Benign | 0.115 | Likely Benign | -3.00 | Deleterious | 0.984 | Probably Damaging | 0.682 | Possibly Damaging | 2.71 | Benign | 0.07 | Tolerated | 0.1664 | 0.2464 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2201C>T | P734L 2D AIThe SynGAP1 missense variant P734L is reported in gnomAD (variant ID 6‑33441666‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags it as pathogenic, creating a single discordant call. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Overall, the preponderance of evidence indicates 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 | 0.879233 | Disordered | 0.411273 | Uncertain | 0.368 | 0.721 | 0.875 | 6-33441666-C-T | 3 | 1.86e-6 | -3.472 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -2.11 | Neutral | 0.897 | Possibly Damaging | 0.330 | Benign | 2.69 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.2390 | 0.5059 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| c.2920G>A | D974N 2D  AIThe SynGAP1 missense variant D974N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect. Consensus predictors such as SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and high‑accuracy methods including AlphaMissense‑Optimized all classify the variant as benign. Additional in silico assessments—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—also predict a benign outcome. No tool in the dataset suggests pathogenicity. Protein‑stability analysis via Foldetta is unavailable 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 | 0.879233 | Disordered | 0.964377 | Binding | 0.389 | 0.897 | 0.625 | -4.051 | Likely Benign | 0.145 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -0.35 | Neutral | 0.144 | Benign | 0.085 | Benign | 4.20 | Benign | 0.09 | Tolerated | 0.1972 | 0.7698 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2920G>C | D974H 2D  AIThe SynGAP1 missense variant D974H is not reported in ClinVar (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 | 0.879233 | Disordered | 0.964377 | Binding | 0.389 | 0.897 | 0.625 | -3.034 | Likely Benign | 0.333 | Likely Benign | Likely Benign | 0.109 | Likely Benign | -0.95 | Neutral | 0.744 | Possibly Damaging | 0.382 | Benign | 4.14 | Benign | 0.02 | Affected | 0.2249 | 0.7803 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2920G>T | D974Y 2D  AIThe SynGAP1 missense variant D974Y 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, 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, did not provide a result for this variant. Overall, the majority of computational evidence points to a benign impact, which is consistent with the absence of ClinVar pathogenic classification and gnomAD observations. Thus, the variant is most likely benign, 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 | 0.879233 | Disordered | 0.964377 | Binding | 0.389 | 0.897 | 0.625 | -4.290 | Likely Benign | 0.384 | Ambiguous | Likely Benign | 0.130 | Likely Benign | -1.85 | Neutral | 0.716 | Possibly Damaging | 0.284 | Benign | 4.13 | Benign | 0.01 | Affected | 0.1072 | 0.6627 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| c.2921A>C | D974A 2D  AIThe SynGAP1 missense variant D974A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) indicates likely benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the consensus of available predictions indicates that D974A 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 | 0.879233 | Disordered | 0.964377 | Binding | 0.389 | 0.897 | 0.625 | -2.619 | Likely Benign | 0.224 | Likely Benign | Likely Benign | 0.242 | Likely Benign | -0.96 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.22 | Benign | 0.04 | Affected | 0.3398 | 0.7129 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2921A>G | D974G 2D  AIThe SynGAP1 missense variant D974G 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 | 0.879233 | Disordered | 0.964377 | Binding | 0.389 | 0.897 | 0.625 | -1.638 | Likely Benign | 0.188 | Likely Benign | Likely Benign | 0.203 | Likely Benign | -0.72 | Neutral | 0.036 | Benign | 0.026 | Benign | 4.18 | Benign | 0.06 | Tolerated | 0.3379 | 0.6771 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2921A>T | D974V 2D  AIThe SynGAP1 missense variant D974V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the collective predictions strongly suggest that D974V 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 | 0.879233 | Disordered | 0.964377 | Binding | 0.389 | 0.897 | 0.625 | -3.629 | Likely Benign | 0.351 | Ambiguous | Likely Benign | 0.211 | Likely Benign | -1.49 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.16 | Benign | 0.01 | Affected | 0.1449 | 0.7286 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.2922C>A | D974E 2D  AIThe SynGAP1 missense variant D974E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.964377 | Binding | 0.389 | 0.897 | 0.625 | -3.617 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -0.63 | Neutral | 0.036 | Benign | 0.026 | Benign | 4.26 | Benign | 0.05 | Affected | 0.2119 | 0.7516 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2922C>G | D974E 2D AIThe SynGAP1 missense variant D974E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.964377 | Binding | 0.389 | 0.897 | 0.625 | -3.617 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -0.63 | Neutral | 0.036 | Benign | 0.026 | Benign | 4.26 | Benign | 0.05 | Affected | 0.2119 | 0.7516 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3073C>A | Q1025K 2D AIThe SynGAP1 missense variant Q1025K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: benign calls come from REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, whereas the only pathogenic call is from polyPhen‑2 HumDiv. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign consensus. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Thus, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which has no pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.993410 | Binding | 0.363 | 0.746 | 0.500 | -4.510 | Likely Benign | 0.529 | Ambiguous | Likely Benign | 0.041 | Likely Benign | -1.09 | Neutral | 0.649 | Possibly Damaging | 0.353 | Benign | 2.78 | Benign | 0.22 | Tolerated | 0.1690 | 0.4438 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3073C>G | Q1025E 2D AIThe SynGAP1 missense variant Q1025E is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only polyPhen‑2 HumDiv predicts it as pathogenic. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.993410 | Binding | 0.363 | 0.746 | 0.500 | -3.010 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -0.60 | Neutral | 0.649 | Possibly Damaging | 0.353 | Benign | 2.79 | Benign | 1.00 | Tolerated | 0.1391 | 0.2269 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3074A>C | Q1025P 2D AIThe SynGAP1 missense variant Q1025P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.993410 | Binding | 0.363 | 0.746 | 0.500 | -2.151 | Likely Benign | 0.211 | Likely Benign | Likely Benign | 0.153 | Likely Benign | -1.22 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.72 | Benign | 0.11 | Tolerated | 0.2211 | 0.5196 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3074A>G | Q1025R 2D AIThe SynGAP1 missense variant Q1025R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (both HumDiv and HumVar) predict a pathogenic outcome. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.993410 | Binding | 0.363 | 0.746 | 0.500 | -4.435 | Likely Benign | 0.480 | Ambiguous | Likely Benign | 0.101 | Likely Benign | -1.28 | Neutral | 0.818 | Possibly Damaging | 0.453 | Possibly Damaging | 2.72 | Benign | 0.10 | Tolerated | 0.1342 | 0.2656 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.3074A>T | Q1025L 2D AIThe SynGAP1 missense variant Q1025L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.993410 | Binding | 0.363 | 0.746 | 0.500 | -6.460 | Likely Benign | 0.463 | Ambiguous | Likely Benign | 0.117 | Likely Benign | -2.48 | Neutral | 0.901 | Possibly Damaging | 0.534 | Possibly Damaging | 2.70 | Benign | 0.05 | Affected | 0.0798 | 0.5497 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3075G>C | Q1025H 2D AIThe SynGAP1 missense variant Q1025H is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the variant as benign. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence supports a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.993410 | Binding | 0.363 | 0.746 | 0.500 | -4.976 | Likely Benign | 0.405 | Ambiguous | Likely Benign | 0.051 | Likely Benign | -1.43 | Neutral | 0.014 | Benign | 0.012 | Benign | 2.68 | Benign | 0.05 | Affected | 0.1332 | 0.3852 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3075G>T | Q1025H 2D AIThe SynGAP1 missense variant Q1025H is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the variant as benign. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence supports a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.993410 | Binding | 0.363 | 0.746 | 0.500 | -4.976 | Likely Benign | 0.405 | Ambiguous | Likely Benign | 0.051 | Likely Benign | -1.43 | Neutral | 0.014 | Benign | 0.012 | Benign | 2.68 | Benign | 0.05 | Affected | 0.1332 | 0.3852 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| 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.2929G>A | A977T 2D AIThe SynGAP1 missense variant A977T 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 | 0.882776 | Disordered | 0.975330 | Binding | 0.306 | 0.884 | 0.625 | -3.814 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 0.106 | Likely Benign | -0.84 | Neutral | 0.965 | Probably Damaging | 0.782 | Possibly Damaging | 4.00 | Benign | 0.02 | Affected | 0.2155 | 0.6185 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2929G>C | A977P 2D AIThe SynGAP1 missense variant A977P is not reported 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 A977P, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.975330 | Binding | 0.306 | 0.884 | 0.625 | -2.665 | Likely Benign | 0.135 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -1.12 | Neutral | 0.990 | Probably Damaging | 0.892 | Possibly Damaging | 3.94 | Benign | 0.02 | Affected | 0.2405 | 0.5212 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2929G>T | A977S 2D AIThe SynGAP1 missense variant A977S 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 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 further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence indicates that A977S is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.975330 | Binding | 0.306 | 0.884 | 0.625 | -2.909 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -0.38 | Neutral | 0.965 | Probably Damaging | 0.702 | Possibly Damaging | 4.02 | Benign | 0.45 | Tolerated | 0.2820 | 0.5373 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2930C>A | A977D 2D AIThe SynGAP1 missense variant A977D 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy methods give a consistent benign signal: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign, while Foldetta’s protein‑folding stability assessment is unavailable. Overall, the majority of evidence points to a benign impact for A977D, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.975330 | Binding | 0.306 | 0.884 | 0.625 | -4.007 | Likely Benign | 0.717 | Likely Pathogenic | Likely Benign | 0.130 | Likely Benign | -1.15 | Neutral | 0.990 | Probably Damaging | 0.892 | Possibly Damaging | 3.96 | Benign | 0.01 | Affected | 0.2253 | 0.2651 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2930C>G | A977G 2D AIThe SynGAP1 missense variant A977G is not reported 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 A977G, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.975330 | Binding | 0.306 | 0.884 | 0.625 | -3.250 | Likely Benign | 0.138 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -0.79 | Neutral | 0.965 | Probably Damaging | 0.702 | Possibly Damaging | 4.03 | Benign | 0.05 | Affected | 0.2180 | 0.4408 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2930C>T | A977V 2D AIThe SynGAP1 missense variant A977V is not reported 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 A977V, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.975330 | Binding | 0.306 | 0.884 | 0.625 | -3.542 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.064 | Likely Benign | -1.15 | Neutral | 0.818 | Possibly Damaging | 0.457 | Possibly Damaging | 4.01 | Benign | 0.01 | Affected | 0.1966 | 0.5727 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.3232G>A | V1078I 2D  AIThe SynGAP1 missense variant V1078I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as likely benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and consensus methods suggests that V1078I is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.986989 | Binding | 0.294 | 0.898 | 0.750 | -3.652 | Likely Benign | 0.200 | Likely Benign | Likely Benign | 0.120 | Likely Benign | -0.16 | Neutral | 0.625 | Possibly Damaging | 0.266 | Benign | 3.98 | Benign | 0.07 | Tolerated | 0.0771 | 0.4693 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3232G>C | V1078L 2D  AIThe SynGAP1 missense variant V1078L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign classification. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is likely benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the collective evidence strongly suggests that V1078L is most likely benign, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.986989 | Binding | 0.294 | 0.898 | 0.750 | -2.547 | Likely Benign | 0.523 | Ambiguous | Likely Benign | 0.091 | Likely Benign | -0.16 | Neutral | 0.451 | Benign | 0.209 | Benign | 4.13 | Benign | 0.56 | Tolerated | 0.0889 | 0.5349 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3232G>T | V1078F 2D  AIThe SynGAP1 missense variant V1078F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign effect for V1078F, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.986989 | Binding | 0.294 | 0.898 | 0.750 | -3.768 | Likely Benign | 0.570 | Likely Pathogenic | Likely Benign | 0.142 | Likely Benign | -0.97 | Neutral | 0.977 | Probably Damaging | 0.722 | Possibly Damaging | 3.87 | Benign | 0.02 | Affected | 0.0677 | 0.4561 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||||||||||||
| c.3233T>A | V1078D 2D  AIThe SynGAP1 missense variant V1078D is listed in ClinVar (ID 2993122.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Tools that predict a pathogenic effect are AlphaMissense‑Default, AlphaMissense‑Optimized, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the majority of predictions lean toward a benign impact, and this is consistent with the ClinVar “Uncertain” designation; there is no contradiction with the existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.986989 | Binding | 0.294 | 0.898 | 0.750 | Uncertain | 1 | -5.155 | Likely Benign | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.158 | Likely Benign | -1.45 | Neutral | 0.003 | Benign | 0.008 | Benign | 3.84 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1570 | 0.1173 | -3 | -2 | -7.7 | 15.96 | |||||||||||||||||||||||||||||||||||
| c.3233T>C | V1078A 2D  AIThe SynGAP1 missense variant V1078A is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign. Only two tools predict pathogenicity: SIFT and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of predictions indicate that V1078A is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.986989 | Binding | 0.294 | 0.898 | 0.750 | -2.794 | Likely Benign | 0.690 | Likely Pathogenic | Likely Benign | 0.089 | Likely Benign | -0.27 | Neutral | 0.011 | Benign | 0.006 | Benign | 3.94 | Benign | 0.02 | Affected | 0.2679 | 0.2546 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| c.3233T>G | V1078G 2D  AIThe SynGAP1 missense variant V1078G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign (3 benign vs 1 pathogenic). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence indicates a benign impact. This conclusion is not contradicted by ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.882776 | Disordered | 0.986989 | Binding | 0.294 | 0.898 | 0.750 | -3.270 | Likely Benign | 0.699 | Likely Pathogenic | Likely Benign | 0.168 | Likely Benign | -0.54 | Neutral | 0.157 | Benign | 0.292 | Benign | 3.85 | Benign | 0.00 | Affected | 0.2041 | 0.2693 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3298G>A | G1100S 2D AIThe SynGAP1 missense variant G1100S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; no Foldetta stability result is available. Overall, the majority of evidence points to a benign impact for G1100S, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.972009 | Binding | 0.360 | 0.865 | 0.875 | -2.898 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.114 | Likely Benign | -0.65 | Neutral | 0.943 | Possibly Damaging | 0.595 | Possibly Damaging | 2.10 | Pathogenic | 0.28 | Tolerated | 0.2501 | 0.5699 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3298G>C | G1100R 2D AIThe SynGAP1 missense variant G1100R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign), and Foldetta results are unavailable. Overall, the majority of available predictions lean toward pathogenicity, and this does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.882776 | Disordered | 0.972009 | Binding | 0.360 | 0.865 | 0.875 | -2.923 | Likely Benign | 0.603 | Likely Pathogenic | Likely Benign | 0.176 | Likely Benign | -2.05 | Neutral | 0.992 | Probably Damaging | 0.906 | Possibly Damaging | 1.92 | Pathogenic | 0.00 | Affected | 0.0986 | 0.5217 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3298G>T | G1100C 2D AIThe SynGAP1 missense variant G1100C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.972009 | Binding | 0.360 | 0.865 | 0.875 | -6.488 | Likely Benign | 0.150 | Likely Benign | Likely Benign | 0.174 | Likely Benign | -2.25 | Neutral | 0.999 | Probably Damaging | 0.950 | Probably Damaging | 1.91 | Pathogenic | 0.00 | Affected | 0.1354 | 0.4768 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.3299G>A | G1100D 2D AIThe SynGAP1 missense variant G1100D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.882776 | Disordered | 0.972009 | Binding | 0.360 | 0.865 | 0.875 | -5.235 | Likely Benign | 0.577 | Likely Pathogenic | Likely Benign | 0.141 | Likely Benign | -1.67 | Neutral | 0.049 | Benign | 0.030 | Benign | 1.93 | Pathogenic | 0.01 | Affected | 0.1924 | 0.3043 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3299G>C | G1100A 2D AIThe SynGAP1 missense variant G1100A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign based on current computational evidence, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.972009 | Binding | 0.360 | 0.865 | 0.875 | -2.862 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.146 | Likely Benign | -0.95 | Neutral | 0.943 | Possibly Damaging | 0.667 | Possibly Damaging | 2.01 | Pathogenic | 0.05 | Affected | 0.3442 | 0.5154 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3299G>T | G1100V 2D AIThe SynGAP1 missense variant G1100V is reported in gnomAD (variant ID 6‑33443851‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign); pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available. Overall, the balance of evidence favors a benign classification for G1100V, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.972009 | Binding | 0.360 | 0.865 | 0.875 | 6-33443851-G-T | 1 | 6.51e-7 | -2.362 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 0.198 | Likely Benign | -2.43 | Neutral | 0.992 | Probably Damaging | 0.906 | Possibly Damaging | 1.93 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.1297 | 0.4036 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||
| c.3349G>A | G1117S 2D AIThe SynGAP1 missense variant G1117S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.853192 | Binding | 0.323 | 0.914 | 0.750 | -3.890 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.211 | Likely Benign | -0.37 | Neutral | 0.032 | Benign | 0.026 | Benign | 5.08 | Benign | 0.17 | Tolerated | 0.2572 | 0.5111 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3349G>C | G1117R 2D AIThe SynGAP1 missense variant G1117R is not reported in ClinVar and is absent from gnomAD. Consensus among most in silico predictors is benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized all classify the change as tolerated or benign. No tool predicts pathogenicity. Two predictors (ESM1b and AlphaMissense‑Default) return uncertain results, but these do not alter the overall benign consensus. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta data are unavailable. Consequently, the variant is most likely benign, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.882776 | Disordered | 0.853192 | Binding | 0.323 | 0.914 | 0.750 | -7.132 | In-Between | 0.519 | Ambiguous | Likely Benign | 0.253 | Likely Benign | -0.68 | Neutral | 0.006 | Benign | 0.008 | Benign | 4.62 | Benign | 0.08 | Tolerated | 0.0937 | 0.4542 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3349G>T | G1117C 2D AIThe SynGAP1 missense variant G1117C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign 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 | 0.882776 | Disordered | 0.853192 | Binding | 0.323 | 0.914 | 0.750 | -9.045 | Likely Pathogenic | 0.112 | Likely Benign | Likely Benign | 0.359 | Likely Benign | -1.30 | Neutral | 0.994 | Probably Damaging | 0.840 | Possibly Damaging | 4.56 | Benign | 0.03 | Affected | 0.1347 | 0.4612 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.3350G>A | G1117D 2D AIThe SynGAP1 missense variant G1117D is catalogued in gnomAD (6‑33443902‑G‑A) but has no ClinVar entry. In silico predictors that agree on benign impact include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic effect, while ESM1b and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it contains two benign and two uncertain calls, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar classification (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.882776 | Disordered | 0.853192 | Binding | 0.323 | 0.914 | 0.750 | 6-33443902-G-A | 1 | 6.61e-7 | -7.594 | In-Between | 0.358 | Ambiguous | Likely Benign | 0.315 | Likely Benign | -0.38 | Neutral | 0.666 | Possibly Damaging | 0.355 | Benign | 4.57 | Benign | 0.24 | Tolerated | 4.32 | 2 | 0.1920 | 0.2635 | -1 | 1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||
| c.3350G>C | G1117A 2D AIThe SynGAP1 missense variant G1117A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.853192 | Binding | 0.323 | 0.914 | 0.750 | -6.514 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.183 | Likely Benign | -0.41 | Neutral | 0.152 | Benign | 0.071 | Benign | 4.61 | Benign | 0.23 | Tolerated | 0.3545 | 0.4944 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3350G>T | G1117V 2D AIThe SynGAP1 missense variant G1117V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while ESM1b is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments 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 | 0.882776 | Disordered | 0.853192 | Binding | 0.323 | 0.914 | 0.750 | -7.251 | In-Between | 0.083 | Likely Benign | Likely Benign | 0.284 | Likely Benign | -1.32 | Neutral | 0.011 | Benign | 0.014 | Benign | 4.57 | Benign | 0.04 | Affected | 0.1312 | 0.3680 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3838A>C | M1280L 2D AIThe SynGAP1 missense variant M1280L is not reported in ClinVar (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 M1280L, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.822030 | Binding | 0.510 | 0.726 | 0.875 | -1.391 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.204 | Likely Benign | -2.23 | Neutral | 0.052 | Benign | 0.017 | Benign | 2.40 | Pathogenic | 0.00 | Affected | 0.1113 | 0.3186 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3838A>G | M1280V 2D AIThe SynGAP1 missense variant M1280V is not reported in ClinVar (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 M1280V, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.822030 | Binding | 0.510 | 0.726 | 0.875 | -2.414 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.240 | Likely Benign | -2.24 | Neutral | 0.004 | Benign | 0.008 | Benign | 2.36 | Pathogenic | 0.00 | Affected | 0.2568 | 0.3137 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||||||||||||
| c.3838A>T | M1280L 2D AIThe SynGAP1 missense variant M1280L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign impact. The predictions do not contradict any ClinVar status, as no ClinVar claim exists for this variant. Thus, based on current computational predictions, the M1280L variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.822030 | Binding | 0.510 | 0.726 | 0.875 | -1.391 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.204 | Likely Benign | -2.23 | Neutral | 0.052 | Benign | 0.017 | Benign | 2.40 | Pathogenic | 0.00 | Affected | 0.1113 | 0.3186 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3839T>A | M1280K 2D AIThe SynGAP1 missense variant M1280K is not reported in ClinVar and has no entry in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Tools that predict a pathogenic effect are SIFT and FATHMM. 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 (majority vote) also indicates benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and consensus methods points to a benign impact for M1280K, 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 | 0.882776 | Disordered | 0.822030 | Binding | 0.510 | 0.726 | 0.875 | -2.963 | Likely Benign | 0.223 | Likely Benign | Likely Benign | 0.213 | Likely Benign | -1.42 | Neutral | 0.126 | Benign | 0.041 | Benign | 2.37 | Pathogenic | 0.00 | Affected | 0.1096 | 0.0488 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||||||
| c.3839T>C | M1280T 2D AIThe SynGAP1 missense variant M1280T is catalogued in gnomAD (6‑33447887‑T‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a benign or likely benign outcome. In contrast, SIFT and FATHMM predict a pathogenic impact. 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 supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic designation. 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 | 0.882776 | Disordered | 0.822030 | Binding | 0.510 | 0.726 | 0.875 | 6-33447887-T-C | 3 | 1.93e-6 | -2.305 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.158 | Likely Benign | -2.26 | Neutral | 0.369 | Benign | 0.120 | Benign | 2.34 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1814 | 0.2031 | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||||||||||||||||
| c.3839T>G | M1280R 2D AIThe SynGAP1 missense variant M1280R is not reported in ClinVar (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 M1280R, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.822030 | Binding | 0.510 | 0.726 | 0.875 | -2.347 | Likely Benign | 0.209 | Likely Benign | Likely Benign | 0.272 | Likely Benign | -1.97 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.44 | Pathogenic | 0.00 | Affected | 0.1339 | 0.0837 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||||||
| c.3840G>A | M1280I 2D AIThe SynGAP1 missense variant M1280I is not 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), AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. 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. | 0.882776 | Disordered | 0.822030 | Binding | 0.510 | 0.726 | 0.875 | -3.723 | Likely Benign | 0.251 | Likely Benign | Likely Benign | 0.166 | Likely Benign | -2.59 | Deleterious | 0.059 | Benign | 0.041 | Benign | 2.35 | Pathogenic | 0.00 | Affected | 0.0995 | 0.2468 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3840G>C | M1280I 2D AIThe SynGAP1 missense variant M1280I is not 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), AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. 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. | 0.882776 | Disordered | 0.822030 | Binding | 0.510 | 0.726 | 0.875 | -3.723 | Likely Benign | 0.251 | Likely Benign | Likely Benign | 0.166 | Likely Benign | -2.59 | Deleterious | 0.059 | Benign | 0.041 | Benign | 2.35 | Pathogenic | 0.00 | Affected | 0.0995 | 0.2468 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3840G>T | M1280I 2D AIThe SynGAP1 missense variant M1280I is not 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), AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. 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. | 0.882776 | Disordered | 0.822030 | Binding | 0.510 | 0.726 | 0.875 | -3.723 | Likely Benign | 0.251 | Likely Benign | Likely Benign | 0.166 | Likely Benign | -2.59 | Deleterious | 0.059 | Benign | 0.041 | Benign | 2.35 | Pathogenic | 0.00 | Affected | 0.0995 | 0.2468 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3940C>A | P1314T 2D AIThe SynGAP1 missense variant P1314T is present in gnomAD (ID 6‑33451814‑C‑A) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect. Benign predictions come from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; 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 impact, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, and this 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 | 0.882776 | Disordered | 0.971592 | Binding | 0.467 | 0.903 | 0.750 | 6-33451814-C-A | -4.083 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.066 | Likely Benign | 1.26 | Neutral | 0.061 | Benign | 0.045 | Benign | 4.32 | Benign | 0.97 | Tolerated | 3.77 | 5 | 0.1791 | 0.5626 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3940C>G | P1314A 2D AIThe SynGAP1 missense variant P1314A is catalogued in gnomAD (ID 6‑33451814‑C‑G) but has no ClinVar entry. Across the spectrum of in silico predictors, every tool listed—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—returns a benign or likely benign verdict. No pathogenic predictions appear in the dataset, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized scores benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Taken together, the evidence overwhelmingly supports a benign classification, and this conclusion does not conflict with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.971592 | Binding | 0.467 | 0.903 | 0.750 | 6-33451814-C-G | 1 | 6.22e-7 | -3.540 | Likely Benign | 0.061 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -0.37 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.23 | Benign | 0.93 | Tolerated | 3.77 | 5 | 0.3502 | 0.4441 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.3940C>T | P1314S 2D AIThe SynGAP1 missense variant P1314S has no ClinVar entry and is not reported in gnomAD. All evaluated in‑silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign effect, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method, 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 | 0.882776 | Disordered | 0.971592 | Binding | 0.467 | 0.903 | 0.750 | -3.838 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.046 | Likely Benign | 0.11 | Neutral | 0.005 | Benign | 0.003 | Benign | 4.22 | Benign | 0.72 | Tolerated | 0.3522 | 0.4751 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3941C>A | P1314Q 2D AIThe SynGAP1 missense variant P1314Q is listed in gnomAD (ID 6‑33451815‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign. No Foldetta stability data are available, so folding‑stability evidence is unavailable. Overall, the preponderance of computational evidence indicates that P1314Q 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 | 0.882776 | Disordered | 0.971592 | Binding | 0.467 | 0.903 | 0.750 | 6-33451815-C-A | -4.222 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -0.55 | Neutral | 0.618 | Possibly Damaging | 0.333 | Benign | 4.24 | Benign | 0.04 | Affected | 3.77 | 5 | 0.1612 | 0.4588 | -1 | 0 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||
| c.3941C>G | P1314R 2D AIThe SynGAP1 missense variant P1314R is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign likelihood. Foldetta results are not available, so they do not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.971592 | Binding | 0.467 | 0.903 | 0.750 | -4.234 | Likely Benign | 0.168 | Likely Benign | Likely Benign | 0.036 | Likely Benign | 0.01 | Neutral | 0.618 | Possibly Damaging | 0.206 | Benign | 4.25 | Benign | 0.09 | Tolerated | 0.1634 | 0.3405 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3941C>T | P1314L 2D AIThe SynGAP1 missense variant P1314L is listed in ClinVar as a benign alteration (ClinVar ID 646689.0) and is present in the gnomAD database (gnomAD ID 6‑33451815‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, which is consistent with the ClinVar classification. Thus, the variant is most likely benign and does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.971592 | Binding | 0.467 | 0.903 | 0.750 | Likely Benign | 1 | 6-33451815-C-T | 2 | 1.24e-6 | -4.040 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -0.20 | Neutral | 0.421 | Benign | 0.066 | Benign | 4.19 | Benign | 0.05 | Affected | 3.77 | 5 | 0.2310 | 0.5967 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||
| c.2221C>A | P741T 2D AIThe SynGAP1 missense variant P741T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.493550 | Uncertain | 0.354 | 0.859 | 0.875 | -4.626 | Likely Benign | 0.061 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -0.54 | Neutral | 0.010 | Benign | 0.022 | Benign | 2.86 | Benign | 0.05 | Affected | 0.1209 | 0.5080 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2221C>G | P741A 2D AIThe SynGAP1 missense variant P741A 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, 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 | 0.885302 | Disordered | 0.493550 | Uncertain | 0.354 | 0.859 | 0.875 | -3.995 | Likely Benign | 0.054 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -0.33 | Neutral | 0.425 | Benign | 0.136 | Benign | 3.01 | Benign | 0.98 | Tolerated | 0.2942 | 0.3883 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2221C>T | P741S 2D AIThe SynGAP1 missense variant P741S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33441686‑C‑T). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. Grouping by consensus, the benign‑predicting tools outnumber the pathogenic one. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” No Foldetta stability data are available, so it does not influence the conclusion. Overall, the computational evidence indicates that the variant is most likely benign, and this assessment does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.493550 | Uncertain | 0.354 | 0.859 | 0.875 | Uncertain | 2 | 6-33441686-C-T | 3 | 1.86e-6 | -3.700 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.27 | Neutral | 0.270 | Benign | 0.136 | Benign | 2.92 | Benign | 0.00 | Affected | 4.32 | 2 | 0.2888 | 0.4278 | 1 | -1 | 0.8 | -10.04 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.2222C>A | P741H 2D AIThe SynGAP1 missense variant P741H is not reported in ClinVar (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 | 0.885302 | Disordered | 0.493550 | Uncertain | 0.354 | 0.859 | 0.875 | -5.592 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.099 | Likely Benign | -0.99 | Neutral | 0.006 | Benign | 0.007 | Benign | 2.81 | Benign | 0.01 | Affected | 0.1372 | 0.3831 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2222C>G | P741R 2D AIThe SynGAP1 missense variant P741R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.493550 | Uncertain | 0.354 | 0.859 | 0.875 | -4.434 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.070 | Likely Benign | -1.19 | Neutral | 0.642 | Possibly Damaging | 0.393 | Benign | 2.85 | Benign | 0.02 | Affected | 0.1303 | 0.2712 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2222C>T | P741L 2D AIThe SynGAP1 missense variant P741L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.493550 | Uncertain | 0.354 | 0.859 | 0.875 | -4.850 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.109 | Likely Benign | -0.63 | Neutral | 0.001 | Benign | 0.003 | Benign | 2.84 | Benign | 0.03 | Affected | 0.1978 | 0.5780 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3295T>A | Y1099N 2D  AIThe SynGAP1 missense variant Y1099N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumDiv indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the consensus of the available predictions points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.974267 | Binding | 0.400 | 0.862 | 1.000 | -4.329 | Likely Benign | 0.269 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -1.01 | Neutral | 0.818 | Possibly Damaging | 0.360 | Benign | 2.83 | Benign | 0.16 | Tolerated | 0.2121 | 0.0935 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||||||||||||
| c.3295T>C | Y1099H 2D  AIThe SynGAP1 missense variant Y1099H is reported in gnomAD (variant ID 6-33443847‑T‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict it to be pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority‑vote) is likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.974267 | Binding | 0.400 | 0.862 | 1.000 | 6-33443847-T-C | 1 | 6.49e-7 | -3.620 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -0.50 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.76 | Benign | 0.18 | Tolerated | 3.77 | 5 | 0.2453 | 0.0735 | 2 | 0 | -1.9 | -26.03 | ||||||||||||||||||||||||||||||||||
| c.3295T>G | Y1099D 2D  AIThe SynGAP1 missense variant Y1099D is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all score the change as tolerated or benign, while only polyPhen‑2 HumDiv flags it as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is Likely Benign, and Foldetta results are unavailable. Taken together, the majority of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar assertion, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.974267 | Binding | 0.400 | 0.862 | 1.000 | -4.193 | Likely Benign | 0.429 | Ambiguous | Likely Benign | 0.130 | Likely Benign | -1.08 | Neutral | 0.818 | Possibly Damaging | 0.435 | Benign | 2.79 | Benign | 0.13 | Tolerated | 0.3819 | 0.0935 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||||||||||||
| c.3296A>C | Y1099S 2D  AIThe SynGAP1 missense variant Y1099S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this trend: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.974267 | Binding | 0.400 | 0.862 | 1.000 | -1.775 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.156 | Likely Benign | -0.23 | Neutral | 0.149 | Benign | 0.026 | Benign | 2.90 | Benign | 0.62 | Tolerated | 0.4564 | 0.2298 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||||
| c.3296A>G | Y1099C 2D  AIThe SynGAP1 missense variant Y1099C is reported in gnomAD (variant ID 6‑33443848‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.974267 | Binding | 0.400 | 0.862 | 1.000 | 6-33443848-A-G | 3 | 1.95e-6 | -5.670 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -1.13 | Neutral | 0.997 | Probably Damaging | 0.840 | Possibly Damaging | 2.73 | Benign | 0.14 | Tolerated | 3.77 | 5 | 0.3008 | 0.2382 | -2 | 0 | 3.8 | -60.04 | ||||||||||||||||||||||||||||||||||
| c.3296A>T | Y1099F 2D  AIThe SynGAP1 missense variant Y1099F is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.974267 | Binding | 0.400 | 0.862 | 1.000 | -3.651 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -0.85 | Neutral | 0.006 | Benign | 0.008 | Benign | 2.75 | Benign | 0.27 | Tolerated | 0.2453 | 0.2780 | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3316C>A | Q1106K 2D AIThe SynGAP1 missense variant Q1106K is catalogued in gnomAD (ID 6‑33443868‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized; pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. AlphaMissense‑Default is uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because the votes are split (two benign, one pathogenic, one uncertain). Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence favors a benign effect, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.885302 | Disordered | 0.952043 | Binding | 0.382 | 0.870 | 0.875 | 6-33443868-C-A | -3.368 | Likely Benign | 0.527 | Ambiguous | Likely Benign | 0.115 | Likely Benign | -2.49 | Neutral | 0.963 | Probably Damaging | 0.959 | Probably Damaging | 1.82 | Pathogenic | 0.16 | Tolerated | 3.77 | 5 | 0.1827 | 0.4800 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||
| c.3316C>G | Q1106E 2D AIThe SynGAP1 missense variant Q1106E is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, PolyPhen‑2 (HumDiv and HumVar) and FATHMM predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also likely benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for Q1106E, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.952043 | Binding | 0.382 | 0.870 | 0.875 | -5.074 | Likely Benign | 0.307 | Likely Benign | Likely Benign | 0.127 | Likely Benign | -1.60 | Neutral | 0.963 | Probably Damaging | 0.959 | Probably Damaging | 1.80 | Pathogenic | 0.15 | Tolerated | 0.1381 | 0.2663 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3317A>C | Q1106P 2D AIThe SynGAP1 missense variant Q1106P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the balance of evidence (5 benign vs 4 pathogenic predictions, with a benign high‑accuracy score and no contradictory ClinVar annotation) indicates that the variant is most likely benign. This conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.885302 | Disordered | 0.952043 | Binding | 0.382 | 0.870 | 0.875 | -3.807 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.162 | Likely Benign | -3.14 | Deleterious | 0.996 | Probably Damaging | 0.988 | Probably Damaging | 1.75 | Pathogenic | 0.31 | Tolerated | 0.2029 | 0.5781 | 0 | -1 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||||||||||||
| c.3317A>G | Q1106R 2D AIThe SynGAP1 missense variant Q1106R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. AlphaMissense‑Default is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it contains two benign, one pathogenic, and one uncertain call. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑confidence predictors (four benign vs. three pathogenic) lean toward a benign interpretation, and this assessment does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.885302 | Disordered | 0.952043 | Binding | 0.382 | 0.870 | 0.875 | -4.211 | Likely Benign | 0.475 | Ambiguous | Likely Benign | 0.133 | Likely Benign | -2.20 | Neutral | 0.985 | Probably Damaging | 0.973 | Probably Damaging | 1.80 | Pathogenic | 0.09 | Tolerated | 0.1412 | 0.2850 | 1 | 1 | -1.0 | 28.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3317A>T | Q1106L 2D AIThe SynGAP1 missense variant Q1106L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic impact. This assessment does not contradict ClinVar status, as the variant is currently unreported in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.885302 | Disordered | 0.952043 | Binding | 0.382 | 0.870 | 0.875 | -4.219 | Likely Benign | 0.171 | Likely Benign | Likely Benign | 0.169 | Likely Benign | -4.46 | Deleterious | 0.985 | Probably Damaging | 0.973 | Probably Damaging | 1.77 | Pathogenic | 0.05 | Affected | 0.0833 | 0.6282 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||||||||||||
| c.3318A>C | Q1106H 2D AIThe SynGAP1 missense variant Q1106H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.885302 | Disordered | 0.952043 | Binding | 0.382 | 0.870 | 0.875 | -4.893 | Likely Benign | 0.370 | Ambiguous | Likely Benign | 0.174 | Likely Benign | -3.03 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 1.75 | Pathogenic | 0.03 | Affected | 0.1453 | 0.4214 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||||
| c.3318A>T | Q1106H 2D AIThe SynGAP1 missense variant Q1106H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.885302 | Disordered | 0.952043 | Binding | 0.382 | 0.870 | 0.875 | -4.893 | Likely Benign | 0.370 | Ambiguous | Likely Benign | 0.174 | Likely Benign | -3.03 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 1.75 | Pathogenic | 0.03 | Affected | 0.1453 | 0.4214 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||||
| c.3400A>C | T1134P 2D AIThe SynGAP1 missense variant T1134P 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. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.813034 | Binding | 0.335 | 0.885 | 0.875 | -2.993 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.164 | Likely Benign | -0.57 | Neutral | 0.013 | Benign | 0.022 | Benign | 5.41 | Benign | 0.07 | Tolerated | 0.2001 | 0.5165 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3400A>G | T1134A 2D AIThe SynGAP1 missense variant T1134A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.813034 | Binding | 0.335 | 0.885 | 0.875 | -3.912 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.172 | Likely Benign | -0.71 | Neutral | 0.036 | Benign | 0.026 | Benign | 5.70 | Benign | 0.31 | Tolerated | 0.3756 | 0.4424 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3400A>T | T1134S 2D AIThe SynGAP1 missense variant T1134S is not reported in ClinVar and is absent from gnomAD, indicating no documented population frequency. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool predicts pathogenicity. The high‑accuracy consensus, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), also reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.813034 | Binding | 0.335 | 0.885 | 0.875 | -3.015 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.220 | Likely Benign | -0.42 | Neutral | 0.007 | Benign | 0.009 | Benign | 5.47 | Benign | 0.09 | Tolerated | 0.3189 | 0.4666 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3401C>A | T1134N 2D AIThe SynGAP1 missense variant T1134N 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 T1134N 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 | 0.885302 | Disordered | 0.813034 | Binding | 0.335 | 0.885 | 0.875 | -4.368 | Likely Benign | 0.176 | Likely Benign | Likely Benign | 0.193 | Likely Benign | -0.34 | Neutral | 0.001 | Benign | 0.001 | Benign | 5.42 | Benign | 0.04 | Affected | 0.1386 | 0.4870 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||||||||||||
| c.3401C>G | T1134S 2D AIThe SynGAP1 missense variant T1134S is not reported in ClinVar and is absent from gnomAD, indicating no documented population frequency. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool predicts pathogenicity. The high‑accuracy consensus, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), also reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.813034 | Binding | 0.335 | 0.885 | 0.875 | -3.015 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.228 | Likely Benign | -0.42 | Neutral | 0.007 | Benign | 0.009 | Benign | 5.47 | Benign | 0.09 | Tolerated | 0.3189 | 0.4666 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3401C>T | T1134I 2D AIThe SynGAP1 missense variant T1134I 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 reports a benign prediction. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.813034 | Binding | 0.335 | 0.885 | 0.875 | -4.072 | Likely Benign | 0.416 | Ambiguous | Likely Benign | 0.242 | Likely Benign | -1.93 | Neutral | 0.453 | Possibly Damaging | 0.162 | Benign | 5.52 | Benign | 0.44 | Tolerated | 0.1071 | 0.5447 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.3910C>A | P1304T 2D AIThe SynGAP1 missense variant P1304T is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the collective evidence strongly supports a benign classification, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.886417 | Binding | 0.475 | 0.866 | 0.875 | -4.454 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -0.42 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.86 | Benign | 0.14 | Tolerated | 0.1571 | 0.4914 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3910C>G | P1304A 2D AIThe SynGAP1 missense variant P1304A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.886417 | Binding | 0.475 | 0.866 | 0.875 | -4.072 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.069 | Likely Benign | 1.35 | Neutral | 0.001 | Benign | 0.002 | Benign | 3.09 | Benign | 1.00 | Tolerated | 0.2923 | 0.4117 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3910C>T | P1304S 2D AIThe SynGAP1 missense variant P1304S is reported in gnomAD (ID 6‑33451784‑C‑T) but has no ClinVar entry. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is provided). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.886417 | Binding | 0.475 | 0.866 | 0.875 | 6-33451784-C-T | 1 | 6.20e-7 | -4.103 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.039 | Likely Benign | 0.36 | Neutral | 0.059 | Benign | 0.041 | Benign | 3.03 | Benign | 0.58 | Tolerated | 3.77 | 5 | 0.2900 | 0.4442 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3911C>A | P1304Q 2D AIThe SynGAP1 missense variant P1304Q is not reported in ClinVar and has no entry in 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, is classified as Likely Benign. High‑accuracy predictions are consistent: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign 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 | 0.885302 | Disordered | 0.886417 | Binding | 0.475 | 0.866 | 0.875 | -4.890 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.119 | Likely Benign | -0.84 | Neutral | 0.586 | Possibly Damaging | 0.287 | Benign | 2.84 | Benign | 0.04 | Affected | 0.1512 | 0.4149 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3911C>G | P1304R 2D AIThe SynGAP1 missense variant P1304R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 HumDiv and SIFT predict pathogenicity, but these two tools represent a minority of the evidence. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of predictions supports a benign classification for P1304R, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.886417 | Binding | 0.475 | 0.866 | 0.875 | -4.518 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 0.108 | Likely Benign | -1.21 | Neutral | 0.586 | Possibly Damaging | 0.172 | Benign | 2.93 | Benign | 0.04 | Affected | 0.1717 | 0.3150 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3911C>T | P1304L 2D AIThe SynGAP1 missense variant P1304L is reported in gnomAD (ID 6‑33451785‑C‑T) and has no ClinVar entry. All evaluated in silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. The high‑accuracy consensus (SGM‑Consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome, while AlphaMissense‑Optimized independently scores it benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Based on the unanimous benign predictions and the absence of any ClinVar pathogenic classification, the variant is most likely benign and does not contradict existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.886417 | Binding | 0.475 | 0.866 | 0.875 | 6-33451785-C-T | 1 | 6.20e-7 | -4.080 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.137 | Likely Benign | -1.33 | Neutral | 0.126 | Benign | 0.066 | Benign | 2.83 | Benign | 0.06 | Tolerated | 0.2200 | 0.5478 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||
| c.3943T>A | W1315R 2D  AIThe SynGAP1 missense variant W1315R is not reported in ClinVar and has no entry in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the change as benign or likely benign. Only AlphaMissense‑Default predicts a pathogenic outcome, representing the sole discordant signal. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and high‑accuracy tools 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 | 0.885302 | Disordered | 0.973142 | Binding | 0.403 | 0.889 | 0.750 | 0.205 | Likely Benign | 0.660 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | 1.31 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.37 | Benign | 0.91 | Tolerated | 3.77 | 5 | 0.4317 | 0.0384 | 2 | -3 | -3.6 | -30.03 | |||||||||||||||||||||||||||||||||||||
| c.3943T>C | W1315R 2D AIThe SynGAP1 missense variant W1315R is listed in ClinVar (ID 1029092.0) with an “Uncertain” clinical significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as benign; Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.973142 | Binding | 0.403 | 0.889 | 0.750 | Uncertain | 1 | 0.205 | Likely Benign | 0.660 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | 1.31 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.37 | Benign | 0.91 | Tolerated | 3.77 | 5 | 0.4317 | 0.0384 | 2 | -3 | -3.6 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.3943T>G | W1315G 2D  AIThe SynGAP1 missense variant W1315G is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions strongly supports a benign classification, and this conclusion is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.973142 | Binding | 0.403 | 0.889 | 0.750 | 0.687 | Likely Benign | 0.193 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -1.36 | Neutral | 0.208 | Benign | 0.077 | Benign | 4.21 | Benign | 0.12 | Tolerated | 0.4126 | 0.1745 | -7 | -2 | 0.5 | -129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3944G>C | W1315S 2D  AIThe SynGAP1 missense variant W1315S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. 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 | 0.885302 | Disordered | 0.973142 | Binding | 0.403 | 0.889 | 0.750 | 0.896 | Likely Benign | 0.279 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -0.79 | Neutral | 0.115 | Benign | 0.057 | Benign | 4.26 | Benign | 0.13 | Tolerated | 0.3974 | 0.1211 | -2 | -3 | 0.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3944G>T | W1315L 2D  AIThe SynGAP1 missense variant W1315L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.973142 | Binding | 0.403 | 0.889 | 0.750 | 0.369 | Likely Benign | 0.304 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -0.65 | Neutral | 0.115 | Benign | 0.057 | Benign | 4.29 | Benign | 0.16 | Tolerated | 0.2256 | 0.3338 | -2 | -2 | 4.7 | -73.05 | |||||||||||||||||||||||||||||||||||||||
| c.3945G>C | W1315C 2D  AIThe SynGAP1 missense variant W1315C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar) and SIFT, together with 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 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 status, as the variant is currently unreported in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.973142 | Binding | 0.403 | 0.889 | 0.750 | -2.355 | Likely Benign | 0.671 | Likely Pathogenic | Likely Benign | 0.082 | Likely Benign | -1.54 | Neutral | 0.872 | Possibly Damaging | 0.468 | Possibly Damaging | 4.21 | Benign | 0.02 | Affected | 0.3427 | 0.1929 | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||||||||||||||||
| c.3945G>T | W1315C 2D AIThe SynGAP1 missense variant W1315C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for W1315C, 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 | 0.885302 | Disordered | 0.973142 | Binding | 0.403 | 0.889 | 0.750 | -2.355 | Likely Benign | 0.671 | Likely Pathogenic | Likely Benign | 0.082 | Likely Benign | -1.54 | Neutral | 0.872 | Possibly Damaging | 0.468 | Possibly Damaging | 4.21 | Benign | 0.02 | Affected | 0.3427 | 0.1929 | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||||||||||||||||
| c.2917G>A | G973R 2D AIThe SynGAP1 missense variant G973R is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.959498 | Binding | 0.390 | 0.897 | 0.625 | -3.950 | Likely Benign | 0.329 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -0.37 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.16 | Benign | 0.01 | Affected | 0.0930 | 0.4532 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2917G>C | G973R 2D AIThe SynGAP1 missense variant G973R is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic call comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta results are not available for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.959498 | Binding | 0.390 | 0.897 | 0.625 | -3.950 | Likely Benign | 0.329 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -0.37 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.16 | Benign | 0.01 | Affected | 0.0930 | 0.4532 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2917G>T | G973W 2D AIThe SynGAP1 missense variant G973W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized reports Benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for G973W, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.959498 | Binding | 0.390 | 0.897 | 0.625 | -6.896 | Likely Benign | 0.329 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -1.53 | Neutral | 0.983 | Probably Damaging | 0.813 | Possibly Damaging | 4.10 | Benign | 0.00 | Affected | 0.0846 | 0.4046 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.2918G>A | G973E 2D AIThe SynGAP1 missense variant G973E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.959498 | Binding | 0.390 | 0.897 | 0.625 | -3.712 | Likely Benign | 0.210 | Likely Benign | Likely Benign | 0.079 | Likely Benign | -0.72 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.19 | Benign | 0.01 | Affected | 0.1463 | 0.4258 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.2918G>C | G973A 2D AIThe SynGAP1 missense variant G973A is reported in gnomAD (ID 6‑33443470‑G‑C) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. The high‑accuracy consensus (SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and this assessment is consistent with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.959498 | Binding | 0.390 | 0.897 | 0.625 | 6-33443470-G-C | 1 | 6.20e-7 | -3.847 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.091 | Likely Benign | 0.14 | Neutral | 0.112 | Benign | 0.028 | Benign | 4.30 | Benign | 0.62 | Tolerated | 4.32 | 2 | 0.3405 | 0.5133 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2918G>T | G973V 2D AIThe SynGAP1 missense variant G973V is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it as pathogenic. Grouping by consensus, the benign‑predicting tools outnumber the single pathogenic prediction. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a benign classification. Foldetta results are unavailable, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.959498 | Binding | 0.390 | 0.897 | 0.625 | -4.688 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -0.76 | Neutral | 0.224 | Benign | 0.091 | Benign | 4.18 | Benign | 0.01 | Affected | 0.1392 | 0.3684 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3403A>C | K1135Q 2D AIThe SynGAP1 missense variant K1135Q has no ClinVar entry 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‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, 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 | 0.887230 | Disordered | 0.790969 | Binding | 0.303 | 0.889 | 0.875 | -4.622 | Likely Benign | 0.566 | Likely Pathogenic | Likely Benign | 0.171 | Likely Benign | -0.66 | Neutral | 0.099 | Benign | 0.150 | Benign | 5.43 | Benign | 0.07 | Tolerated | 0.5016 | 0.1356 | Weaken | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||||||||||
| c.3403A>G | K1135E 2D AIThe SynGAP1 missense variant K1135E is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33443955‑A‑G). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Only AlphaMissense‑Default predicts a pathogenic outcome, while AlphaMissense‑Optimized is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta) results are unavailable. Overall, the preponderance of evidence points to a benign impact for K1135E, and this assessment does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.790969 | Binding | 0.303 | 0.889 | 0.875 | 6-33443955-A-G | -6.499 | Likely Benign | 0.924 | Likely Pathogenic | Ambiguous | 0.239 | Likely Benign | -0.76 | Neutral | 0.224 | Benign | 0.237 | Benign | 5.45 | Benign | 0.12 | Tolerated | 4.32 | 2 | 0.4330 | 0.1476 | 1 | 0 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||||||||
| c.3404A>C | K1135T 2D AIThe SynGAP1 missense variant K1135T is listed in ClinVar (ID 1166087.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443956‑A‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.790969 | Binding | 0.303 | 0.889 | 0.875 | Conflicting | 2 | 6-33443956-A-C | 1 | 6.75e-7 | -4.778 | Likely Benign | 0.779 | Likely Pathogenic | Likely Benign | 0.210 | Likely Benign | -0.90 | Neutral | 0.411 | Benign | 0.321 | Benign | 5.46 | Benign | 0.10 | Tolerated | 4.32 | 2 | 0.2544 | 0.3521 | 0 | -1 | 3.2 | -27.07 | ||||||||||||||||||||||||||||||||
| c.3404A>G | K1135R 2D AIThe SynGAP1 missense variant K1135R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign impact for K1135R, 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 | 0.887230 | Disordered | 0.790969 | Binding | 0.303 | 0.889 | 0.875 | -2.286 | Likely Benign | 0.122 | Likely Benign | Likely Benign | 0.209 | Likely Benign | -0.82 | Neutral | 0.586 | Possibly Damaging | 0.321 | Benign | 5.44 | Benign | 0.15 | Tolerated | 0.5095 | 0.1674 | Weaken | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||||||||||
| c.3404A>T | K1135M 2D AIThe SynGAP1 K1135M 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 outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is not available for this variant. Overall, the balance of evidence leans toward a benign interpretation, 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 | 0.887230 | Disordered | 0.790969 | Binding | 0.303 | 0.889 | 0.875 | -5.953 | Likely Benign | 0.931 | Likely Pathogenic | Ambiguous | 0.423 | Likely Benign | -1.65 | Neutral | 0.938 | Possibly Damaging | 0.819 | Possibly Damaging | 5.42 | Benign | 0.02 | Affected | 0.1669 | 0.4164 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.3405G>C | K1135N 2D AIThe SynGAP1 missense variant K1135N is listed in ClinVar (ID 633521.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. In contrast, AlphaMissense‑Default and AlphaMissense‑Optimized both predict a pathogenic outcome. High‑accuracy assessments further show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) remains Likely Benign. No Foldetta (FoldX‑MD/Rosetta stability) result is available for this variant. Overall, the majority of predictions support a benign classification, which does not contradict the current ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.790969 | Binding | 0.303 | 0.889 | 0.875 | Uncertain | 1 | -5.715 | Likely Benign | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.166 | Likely Benign | -0.97 | Neutral | 0.411 | Benign | 0.321 | Benign | 5.43 | Benign | 0.07 | Tolerated | 4.32 | 2 | 0.4152 | 0.1793 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||
| c.3405G>T | K1135N 2D AIThe SynGAP1 missense variant K1135N is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33443957‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are AlphaMissense‑Default and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains likely benign; Foldetta results are unavailable. Overall, the majority of predictions (seven benign vs. two pathogenic) support a benign interpretation. This consensus does not contradict ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.790969 | Binding | 0.303 | 0.889 | 0.875 | 6-33443957-G-T | -5.715 | Likely Benign | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.166 | Likely Benign | -0.97 | Neutral | 0.411 | Benign | 0.321 | Benign | 5.43 | Benign | 0.07 | Tolerated | 4.32 | 2 | 0.4152 | 0.1793 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||
| c.3952C>A | L1318M 2D AIThe SynGAP1 missense variant L1318M is listed in gnomAD (ID 6‑33451826‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 HumDiv and SIFT predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.968271 | Binding | 0.399 | 0.865 | 0.750 | 6-33451826-C-A | -4.625 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -0.62 | Neutral | 0.939 | Possibly Damaging | 0.396 | Benign | 4.01 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1083 | 0.4027 | 2 | 4 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||
| c.3952C>G | L1318V 2D AIThe SynGAP1 missense variant L1318V is catalogued in gnomAD (ID 6‑33451826‑C‑G) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized returns a benign prediction, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the computational evidence overwhelmingly supports a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, and this assessment does not contradict the ClinVar record, which contains no pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.968271 | Binding | 0.399 | 0.865 | 0.750 | 6-33451826-C-G | 1 | 6.31e-7 | -3.938 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -0.58 | Neutral | 0.113 | Benign | 0.028 | Benign | 4.08 | Benign | 0.75 | Tolerated | 3.77 | 5 | 0.1861 | 0.3027 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.3953T>A | L1318Q 2D AIThe SynGAP1 missense variant L1318Q is reported in gnomAD (variant ID 6‑33451827‑T‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates benign. No Foldetta stability analysis is available, so it does not influence the conclusion. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.968271 | Binding | 0.399 | 0.865 | 0.750 | 6-33451827-T-A | 1 | 6.32e-7 | -3.445 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -2.06 | Neutral | 0.834 | Possibly Damaging | 0.307 | Benign | 4.04 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1410 | 0.0903 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||
| c.3953T>C | L1318P 2D AIThe SynGAP1 missense variant L1318P is listed in gnomAD (ID 6‑33451827‑T‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, while pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict any ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.968271 | Binding | 0.399 | 0.865 | 0.750 | 6-33451827-T-C | -2.307 | Likely Benign | 0.116 | Likely Benign | Likely Benign | 0.126 | Likely Benign | -2.90 | Deleterious | 0.813 | Possibly Damaging | 0.212 | Benign | 3.98 | Benign | 0.00 | Affected | 3.77 | 5 | 0.3424 | 0.1411 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||
| c.3953T>G | L1318R 2D AIThe SynGAP1 missense variant L1318R is reported in gnomAD (variant ID 6-33451827‑T‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic impact. The SGM‑Consensus, 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 (majority vote) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a benign effect, and this conclusion is not contradicted by any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.968271 | Binding | 0.399 | 0.865 | 0.750 | 6-33451827-T-G | -3.381 | Likely Benign | 0.187 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -1.58 | Neutral | 0.588 | Possibly Damaging | 0.212 | Benign | 4.01 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1429 | 0.1303 | -2 | -3 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||
| c.3964G>A | A1322T 2D AIThe SynGAP1 missense variant A1322T is catalogued in gnomAD (ID 6‑33451838‑G‑A) but has no ClinVar entry. All available in silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic outcome. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method, has no reported result for this variant. Overall, the evidence strongly supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.921040 | Binding | 0.466 | 0.825 | 0.875 | 6-33451838-G-A | -4.940 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.079 | Likely Benign | 0.51 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.20 | Benign | 0.27 | Tolerated | 3.77 | 5 | 0.1972 | 0.7582 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||
| c.3964G>C | A1322P 2D AIThe SynGAP1 missense variant A1322P is reported in ClinVar (ID 1169945.0) as benign and is present in gnomAD (variant ID 6‑33451838‑G‑C). Across the available in‑silico predictors, all tools uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign predictions. No tool in the dataset indicates a pathogenic effect. High‑accuracy assessments corroborate this consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. The Foldetta protein‑folding stability analysis is not available for this variant. Overall, the computational evidence strongly supports a benign classification, which is consistent with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.921040 | Binding | 0.466 | 0.825 | 0.875 | Benign | 1 | 6-33451838-G-C | -1.153 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.090 | Likely Benign | 0.03 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.15 | Benign | 0.23 | Tolerated | 3.77 | 5 | 0.2255 | 0.6094 | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||||||
| c.3964G>T | A1322S 2D AIThe SynGAP1 missense variant A1322S is catalogued in gnomAD (ID 6‑33451838‑G‑T) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the variant as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the evidence strongly supports a benign classification, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.921040 | Binding | 0.466 | 0.825 | 0.875 | 6-33451838-G-T | -4.570 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.086 | Likely Benign | 1.38 | Neutral | 0.003 | Benign | 0.001 | Benign | 4.48 | Benign | 0.57 | Tolerated | 3.77 | 5 | 0.2954 | 0.6084 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.3965C>A | A1322D 2D AIThe SynGAP1 missense variant A1322D is catalogued in gnomAD (ID 6‑33451839‑C‑A) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool listed—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classifies the substitution as benign. No pathogenic predictions are reported. Grouping by consensus, all available tools fall into the benign category, with no tools indicating pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no result for this variant, so its status is unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.921040 | Binding | 0.466 | 0.825 | 0.875 | 6-33451839-C-A | -5.744 | Likely Benign | 0.284 | Likely Benign | Likely Benign | 0.092 | Likely Benign | 0.70 | Neutral | 0.013 | Benign | 0.004 | Benign | 4.17 | Benign | 0.45 | Tolerated | 3.77 | 5 | 0.2246 | 0.3134 | -2 | 0 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||
| c.3965C>G | A1322G 2D AIThe SynGAP1 missense variant A1322G is catalogued in gnomAD (ID 6‑33451839‑C‑G) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized indicates a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign status. Foldetta results are not available for this variant. Consequently, the variant is most likely benign, and this prediction does not contradict any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.921040 | Binding | 0.466 | 0.825 | 0.875 | 6-33451839-C-G | -4.159 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.053 | Likely Benign | 0.42 | Neutral | 0.005 | Benign | 0.002 | Benign | 4.16 | Benign | 0.62 | Tolerated | 3.77 | 5 | 0.2160 | 0.4741 | 0 | 1 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.3965C>T | A1322V 2D AIThe SynGAP1 missense variant A1322V is catalogued in gnomAD (ID 6‑33451839‑C‑T) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized returns a benign prediction, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta results are not available for this variant. Taken together, the computational evidence overwhelmingly supports a benign effect, and this conclusion does not conflict with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.921040 | Binding | 0.466 | 0.825 | 0.875 | 6-33451839-C-T | -5.376 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.52 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.17 | Benign | 0.15 | Tolerated | 3.77 | 5 | 0.1507 | 0.6747 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||
| c.3982C>G | R1328G 2D AIThe SynGAP1 missense variant R1328G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.911775 | Binding | 0.360 | 0.762 | 0.875 | -3.470 | Likely Benign | 0.513 | Ambiguous | Likely Benign | 0.076 | Likely Benign | -2.19 | Neutral | 0.784 | Possibly Damaging | 0.145 | Benign | 4.07 | Benign | 0.01 | Affected | 0.3736 | 0.2562 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3982C>T | R1328W 2D AIThe SynGAP1 missense variant R1328W is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33451856‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default predict a pathogenic outcome. ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign, while Foldetta results are unavailable. Taken together, the majority of high‑confidence predictions favor a benign impact, and there is no conflict with ClinVar status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.887230 | Disordered | 0.911775 | Binding | 0.360 | 0.762 | 0.875 | 6-33451856-C-T | 4 | 2.56e-6 | -7.022 | In-Between | 0.779 | Likely Pathogenic | Likely Benign | 0.125 | Likely Benign | -2.40 | Neutral | 0.997 | Probably Damaging | 0.756 | Possibly Damaging | 4.04 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1349 | 0.2906 | -3 | 2 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.3983G>A | R1328Q 2D AIThe SynGAP1 missense variant R1328Q is listed in ClinVar (ID 1805359.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451857‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this is not in conflict with the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.911775 | Binding | 0.360 | 0.762 | 0.875 | Uncertain | 3 | 6-33451857-G-A | 35 | 1.49e-4 | -2.921 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -1.02 | Neutral | 0.799 | Possibly Damaging | 0.098 | Benign | 4.12 | Benign | 0.03 | Affected | 3.77 | 5 | 0.3503 | 0.1775 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.3983G>C | R1328P 2D AIThe SynGAP1 missense variant R1328P (ClinVar ID 1258976.0) is classified as Benign in ClinVar and is observed in gnomAD (6‑33451857‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta results are unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also indicates a likely benign outcome; no Foldetta stability data are reported. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar designation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.911775 | Binding | 0.360 | 0.762 | 0.875 | Benign | 1 | 6-33451857-G-C | -1.220 | Likely Benign | 0.466 | Ambiguous | Likely Benign | 0.060 | Likely Benign | -2.01 | Neutral | 0.927 | Possibly Damaging | 0.452 | Possibly Damaging | 4.06 | Benign | 0.01 | Affected | 3.77 | 5 | 0.2205 | 0.3361 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||
| c.3983G>T | R1328L 2D AIThe SynGAP1 missense variant R1328L is listed in gnomAD (ID 6‑33451857‑G‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.911775 | Binding | 0.360 | 0.762 | 0.875 | 6-33451857-G-T | -3.233 | Likely Benign | 0.452 | Ambiguous | Likely Benign | 0.038 | Likely Benign | -1.94 | Neutral | 0.784 | Possibly Damaging | 0.145 | Benign | 4.08 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1978 | 0.3555 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||||
| c.2209C>A | Q737K 2D AIThe SynGAP1 missense variant Q737K 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, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign 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. Taken together, the majority of evidence points to a benign effect for Q737K, and this conclusion is not in conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.425743 | Uncertain | 0.323 | 0.803 | 0.875 | -5.841 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -1.16 | Neutral | 0.906 | Possibly Damaging | 0.551 | Possibly Damaging | 2.77 | Benign | 0.07 | Tolerated | 0.2081 | 0.4009 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2209C>G | Q737E 2D AIThe SynGAP1 missense variant Q737E 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 | 0.889439 | Disordered | 0.425743 | Uncertain | 0.323 | 0.803 | 0.875 | -5.288 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.046 | Likely Benign | -1.05 | Neutral | 0.906 | Possibly Damaging | 0.629 | Possibly Damaging | 2.76 | Benign | 0.04 | Affected | 0.1635 | 0.2355 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2210A>C | Q737P 2D AIThe SynGAP1 missense variant Q737P is listed in ClinVar (ID 2580571.0) with an uncertain significance designation and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only SIFT indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta stability analysis is unavailable. Taken together, the preponderance of evidence supports a benign classification for Q737P, 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 | 0.889439 | Disordered | 0.425743 | Uncertain | 0.323 | 0.803 | 0.875 | Uncertain | 1 | -2.407 | Likely Benign | 0.054 | Likely Benign | Likely Benign | 0.154 | Likely Benign | -1.22 | Neutral | 0.005 | Benign | 0.013 | Benign | 2.78 | Benign | 0.04 | Affected | 4.07 | 3 | 0.2366 | 0.4981 | -1 | 0 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||
| c.2210A>G | Q737R 2D AIThe SynGAP1 missense variant Q737R 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 points to a benign impact for Q737R, 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 | 0.889439 | Disordered | 0.425743 | Uncertain | 0.323 | 0.803 | 0.875 | -4.524 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -1.02 | Neutral | 0.986 | Probably Damaging | 0.793 | Possibly Damaging | 2.74 | Benign | 0.06 | Tolerated | 0.1688 | 0.1852 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.2210A>T | Q737L 2D AIThe SynGAP1 missense variant Q737L is not reported 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 the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.425743 | Uncertain | 0.323 | 0.803 | 0.875 | -2.789 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -2.44 | Neutral | 0.959 | Probably Damaging | 0.721 | Possibly Damaging | 2.80 | Benign | 1.00 | Tolerated | 0.0958 | 0.5494 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2211G>C | Q737H 2D AIThe SynGAP1 missense variant Q737H is not reported 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 computational evidence points to a benign effect for Q737H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.425743 | Uncertain | 0.323 | 0.803 | 0.875 | -4.517 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.139 | Likely Benign | -1.55 | Neutral | 0.996 | Probably Damaging | 0.930 | Probably Damaging | 2.72 | Benign | 0.04 | Affected | 0.1683 | 0.3707 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2211G>T | Q737H 2D AIThe SynGAP1 missense variant Q737H is not reported 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 Q737H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.425743 | Uncertain | 0.323 | 0.803 | 0.875 | -4.517 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.132 | Likely Benign | -1.55 | Neutral | 0.996 | Probably Damaging | 0.930 | Probably Damaging | 2.72 | Benign | 0.04 | Affected | 0.1683 | 0.3707 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2818G>A | G940S 2D AIThe SynGAP1 missense variant G940S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443370‑G‑A). All available in silico predictors agree on a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” High‑accuracy tools reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no reported result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign classification, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.920635 | Binding | 0.383 | 0.902 | 0.625 | Uncertain | 1 | 6-33443370-G-A | 1 | 6.20e-7 | -5.451 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.135 | Likely Benign | 0.45 | Neutral | 0.409 | Benign | 0.253 | Benign | 2.77 | Benign | 0.44 | Tolerated | 3.77 | 5 | 0.2590 | 0.4907 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||
| c.2818G>C | G940R 2D AIThe SynGAP1 missense variant G940R is listed in ClinVar (ID 1923639.0) as Benign and is present in gnomAD (6‑33443370‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and Foldetta (FoldX‑MD/Rosetta stability assessment) has no available result for this variant. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta data is unavailable. Overall, the majority of evidence points to a benign impact, which is consistent with the ClinVar classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.920635 | Binding | 0.383 | 0.902 | 0.625 | Benign | 1 | 6-33443370-G-C | 5 | 3.10e-6 | -6.169 | Likely Benign | 0.480 | Ambiguous | Likely Benign | 0.060 | Likely Benign | 0.02 | Neutral | 0.922 | Possibly Damaging | 0.543 | Possibly Damaging | 2.73 | Benign | 0.15 | Tolerated | 3.77 | 5 | 0.0922 | 0.4024 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||
| c.2818G>T | G940C 2D AIThe SynGAP1 missense variant G940C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this conclusion, so the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.920635 | Binding | 0.383 | 0.902 | 0.625 | -8.158 | Likely Pathogenic | 0.097 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -0.40 | Neutral | 0.996 | Probably Damaging | 0.905 | Possibly Damaging | 2.70 | Benign | 0.11 | Tolerated | 0.1307 | 0.4354 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.2819G>A | G940D 2D AIThe SynGAP1 missense variant G940D is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443371‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Two tools, AlphaMissense‑Default and ESM1b, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it receives two benign and two uncertain votes, and Foldetta’s protein‑folding stability analysis is unavailable. Overall, the balance of evidence favors a benign classification, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.889439 | Disordered | 0.920635 | Binding | 0.383 | 0.902 | 0.625 | 6-33443371-G-A | 6 | 3.72e-6 | -7.311 | In-Between | 0.397 | Ambiguous | Likely Benign | 0.076 | Likely Benign | -0.68 | Neutral | 0.770 | Possibly Damaging | 0.583 | Possibly Damaging | 2.72 | Benign | 0.17 | Tolerated | 3.77 | 5 | 0.1837 | 0.2252 | -1 | 1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||
| c.2819G>C | G940A 2D AIThe SynGAP1 missense variant G940A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is that the variant is most likely benign, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.920635 | Binding | 0.383 | 0.902 | 0.625 | -5.356 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.163 | Likely Benign | 0.64 | Neutral | 0.004 | Benign | 0.012 | Benign | 2.85 | Benign | 0.89 | Tolerated | 0.3627 | 0.4831 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2819G>T | G940V 2D AIThe SynGAP1 missense variant G940V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the consensus of available predictions points to a benign impact, and this is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.920635 | Binding | 0.383 | 0.902 | 0.625 | -6.252 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.110 | Likely Benign | 0.36 | Neutral | 0.626 | Possibly Damaging | 0.419 | Benign | 2.92 | Benign | 0.31 | Tolerated | 0.1222 | 0.3822 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3049T>A | F1017I 2D AIThe SynGAP1 missense variant F1017I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of conventional tools (5 pathogenic vs 4 benign) lean toward pathogenicity, but the single high‑accuracy benign prediction introduces uncertainty. The variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | -3.244 | Likely Benign | 0.584 | Likely Pathogenic | Likely Benign | 0.113 | Likely Benign | -2.55 | Deleterious | 0.951 | Possibly Damaging | 0.710 | Possibly Damaging | 2.50 | Benign | 0.05 | Affected | 0.2050 | 0.1969 | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.3049T>C | F1017L 2D AIThe SynGAP1 missense variant F1017L is listed in ClinVar (ID 3719654.0) as benign and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM‑Consensus score (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus (majority vote) is benign. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence points to a benign impact, aligning with the ClinVar classification and showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | Benign | 1 | -2.048 | Likely Benign | 0.934 | Likely Pathogenic | Ambiguous | 0.157 | Likely Benign | -2.38 | Neutral | 0.798 | Possibly Damaging | 0.373 | Benign | 2.65 | Benign | 0.72 | Tolerated | 3.77 | 5 | 0.2198 | 0.3027 | 0 | 2 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||
| c.3049T>G | F1017V 2D AIThe SynGAP1 missense variant F1017V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for F1017V, and this conclusion does not contradict any ClinVar annotation because the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | -2.517 | Likely Benign | 0.497 | Ambiguous | Likely Benign | 0.161 | Likely Benign | -2.97 | Deleterious | 0.905 | Possibly Damaging | 0.637 | Possibly Damaging | 2.51 | Benign | 0.03 | Affected | 0.1964 | 0.2137 | -1 | -1 | 1.4 | -48.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3050T>A | F1017Y 2D AIThe SynGAP1 missense variant F1017Y is reported in gnomAD (6‑33443602‑T‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic outcome are SIFT and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | 6-33443602-T-A | -3.583 | Likely Benign | 0.186 | Likely Benign | Likely Benign | 0.042 | Likely Benign | -0.75 | Neutral | 0.012 | Benign | 0.044 | Benign | 2.47 | Pathogenic | 0.05 | Affected | 3.77 | 5 | 0.1432 | 0.1801 | 3 | 7 | -4.1 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.3050T>C | F1017S 2D AIThe SynGAP1 missense variant F1017S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains Likely Pathogenic; Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | -1.804 | Likely Benign | 0.782 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | -3.16 | Deleterious | 0.986 | Probably Damaging | 0.848 | Possibly Damaging | 2.46 | Pathogenic | 0.00 | Affected | 0.4491 | 0.0000 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||||||||||||
| c.3050T>G | F1017C 2D AIThe SynGAP1 missense variant F1017C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Pathogenic, and the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | -5.769 | Likely Benign | 0.706 | Likely Pathogenic | Likely Benign | 0.133 | Likely Benign | -3.71 | Deleterious | 0.999 | Probably Damaging | 0.944 | Probably Damaging | 2.42 | Pathogenic | 0.00 | Affected | 0.2488 | 0.1137 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||||||||||||
| c.3051C>A | F1017L 2D AIThe SynGAP1 missense variant F1017L is catalogued in gnomAD (ID 6‑33443603‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM; pathogenic predictions come from polyPhen‑2 HumDiv and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and therefore reports a likely benign outcome. AlphaMissense‑Optimized yields an uncertain result, and no Foldetta stability data are available. Overall, the preponderance of evidence points to a benign effect. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | 6-33443603-C-A | -2.048 | Likely Benign | 0.934 | Likely Pathogenic | Ambiguous | 0.140 | Likely Benign | -2.38 | Neutral | 0.798 | Possibly Damaging | 0.373 | Benign | 2.65 | Benign | 0.72 | Tolerated | 3.77 | 5 | 0.2198 | 0.3027 | 0 | 2 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||
| c.3051C>G | F1017L 2D AIThe SynGAP1 missense variant F1017L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM, while polyPhen‑2 HumDiv and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign based on current predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.954171 | Binding | 0.322 | 0.801 | 0.625 | -2.048 | Likely Benign | 0.934 | Likely Pathogenic | Ambiguous | 0.140 | Likely Benign | -2.38 | Neutral | 0.798 | Possibly Damaging | 0.373 | Benign | 2.65 | Benign | 0.72 | Tolerated | 3.77 | 5 | 0.2198 | 0.3027 | 0 | 2 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||
| c.3343A>C | I1115L 2D  AIThe SynGAP1 missense variant I1115L is listed in ClinVar (ID 4178654) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443895‑A‑C). 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 effect, so the pathogenic‑prediction group is empty. High‑accuracy assessments reinforce this benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign 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 | 0.889439 | Disordered | 0.892339 | Binding | 0.308 | 0.912 | 0.750 | Uncertain | 1 | 6-33443895-A-C | 1 | 7.56e-7 | -2.308 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.120 | Likely Benign | -0.46 | Neutral | 0.004 | Benign | 0.007 | Benign | 2.82 | Benign | 1.00 | Tolerated | 4.32 | 2 | 0.1154 | 0.4575 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||||
| c.3343A>G | I1115V 2D  AIThe SynGAP1 missense variant I1115V is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.892339 | Binding | 0.308 | 0.912 | 0.750 | -2.512 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.104 | Likely Benign | 0.06 | Neutral | 0.002 | Benign | 0.007 | Benign | 2.76 | Benign | 0.68 | Tolerated | 0.1561 | 0.3871 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3343A>T | I1115F 2D  AIThe SynGAP1 missense variant I1115F is reported in gnomAD (ID 6‑33443895‑A‑T) and has no ClinVar entry. All available in silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are not available. Based on the unanimous benign predictions and the lack of a ClinVar pathogenic classification, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.892339 | Binding | 0.308 | 0.912 | 0.750 | 6-33443895-A-T | -3.426 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.98 | Neutral | 0.230 | Benign | 0.098 | Benign | 2.71 | Benign | 0.19 | Tolerated | 4.32 | 2 | 0.0769 | 0.4338 | 0 | 1 | -1.7 | 34.02 | ||||||||||||||||||||||||||||||||||||
| c.3344T>A | I1115N 2D  AIThe SynGAP1 missense variant I1115N 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 | 0.889439 | Disordered | 0.892339 | Binding | 0.308 | 0.912 | 0.750 | -4.018 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 0.095 | Likely Benign | -0.60 | Neutral | 0.009 | Benign | 0.011 | Benign | 2.77 | Benign | 0.08 | Tolerated | 0.1299 | 0.1270 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3344T>C | I1115T 2D  AIThe SynGAP1 missense variant I1115T is listed in ClinVar (ID 130530) as Benign and is present in gnomAD (variant ID 6‑33443896‑T‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts Benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence strongly favors a benign impact, consistent with the ClinVar designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.892339 | Binding | 0.308 | 0.912 | 0.750 | Benign | 10 | 6-33443896-T-C | 20536 | 1.36e-2 | -2.670 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.100 | Likely Benign | -0.04 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.76 | Benign | 0.23 | Tolerated | 4.32 | 2 | 0.1397 | 0.2252 | 0 | -1 | -5.2 | -12.05 | ||||||||||||||||||||||||||||||||
| c.3344T>G | I1115S 2D  AIThe SynGAP1 missense variant I1115S is catalogued in gnomAD (ID 6‑33443896‑T‑G) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the 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 unavailable. Overall, the consensus of all available predictions is benign, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.892339 | Binding | 0.308 | 0.912 | 0.750 | 6-33443896-T-G | -0.579 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.128 | Likely Benign | 0.67 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.88 | Benign | 0.14 | Tolerated | 4.32 | 2 | 0.2986 | 0.1453 | -2 | -1 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||||||||
| c.3345T>G | I1115M 2D  AIThe SynGAP1 missense variant I1115M is reported in gnomAD (variant ID 6‑33443897‑T‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags it as pathogenic, creating a single discordant call. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus 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 classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.892339 | Binding | 0.308 | 0.912 | 0.750 | 6-33443897-T-G | 4 | 2.77e-6 | -3.708 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.106 | Likely Benign | -0.38 | Neutral | 0.512 | Possibly Damaging | 0.200 | Benign | 2.71 | Benign | 0.23 | Tolerated | 4.32 | 2 | 0.1030 | 0.4162 | 1 | 2 | -2.6 | 18.03 | ||||||||||||||||||||||||||||||||||
| c.3346G>A | G1116R 2D AIThe SynGAP1 missense variant G1116R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the majority of computational evidence points to a benign effect for G1116R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.873279 | Binding | 0.320 | 0.909 | 0.750 | -6.379 | Likely Benign | 0.495 | Ambiguous | Likely Benign | 0.368 | Likely Benign | -0.60 | Neutral | 0.922 | Possibly Damaging | 0.657 | Possibly Damaging | 4.18 | Benign | 0.04 | Affected | 0.0925 | 0.4342 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3346G>C | G1116R 2D AIThe SynGAP1 missense variant G1116R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the majority of computational evidence points to a benign effect for G1116R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.873279 | Binding | 0.320 | 0.909 | 0.750 | -6.379 | Likely Benign | 0.495 | Ambiguous | Likely Benign | 0.368 | Likely Benign | -0.60 | Neutral | 0.922 | Possibly Damaging | 0.657 | Possibly Damaging | 4.18 | Benign | 0.04 | Affected | 0.0925 | 0.4342 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3346G>T | G1116W 2D AIThe SynGAP1 missense variant G1116W is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443898‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b all predict a pathogenic outcome. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta’s protein‑folding stability result is unavailable. Taken together, the majority of reliable predictors and the consensus high‑accuracy tools indicate a benign effect. This conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.889439 | Disordered | 0.873279 | Binding | 0.320 | 0.909 | 0.750 | 6-33443898-G-T | -9.448 | Likely Pathogenic | 0.356 | Ambiguous | Likely Benign | 0.405 | Likely Benign | -1.27 | Neutral | 0.996 | Probably Damaging | 0.946 | Probably Damaging | 4.04 | Benign | 0.01 | Affected | 4.32 | 2 | 0.0776 | 0.4046 | -2 | -7 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||
| c.3347G>A | G1116E 2D AIThe SynGAP1 missense variant G1116E is reported in gnomAD (variant ID 6-33443899‑G‑A) but has no ClinVar entry. Functional prediction tools uniformly favor a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while AlphaMissense‑Default remains uncertain. No tool predicts pathogenicity. The high‑accuracy consensus (SGM‑Consensus) also indicates a likely benign outcome, and AlphaMissense‑Optimized corroborates this. Foldetta, a protein‑folding stability predictor, was not available for this variant. Overall, the collective evidence strongly supports a benign impact, and this conclusion is not contradicted by any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.873279 | Binding | 0.320 | 0.909 | 0.750 | 6-33443899-G-A | -6.375 | Likely Benign | 0.375 | Ambiguous | Likely Benign | 0.345 | Likely Benign | -0.33 | Neutral | 0.043 | Benign | 0.022 | Benign | 4.06 | Benign | 0.07 | Tolerated | 4.32 | 2 | 0.1467 | 0.4069 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||
| c.3347G>C | G1116A 2D AIThe SynGAP1 missense variant G1116A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.873279 | Binding | 0.320 | 0.909 | 0.750 | -5.753 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.288 | Likely Benign | -0.24 | Neutral | 0.010 | Benign | 0.022 | Benign | 4.08 | Benign | 0.24 | Tolerated | 0.3417 | 0.4944 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3347G>T | G1116V 2D AIThe SynGAP1 missense variant G1116V is reported in gnomAD (variant ID 6‑33443899‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, creating a single discordant signal. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates 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 | 0.889439 | Disordered | 0.873279 | Binding | 0.320 | 0.909 | 0.750 | 6-33443899-G-T | -6.426 | Likely Benign | 0.102 | Likely Benign | Likely Benign | 0.393 | Likely Benign | -0.79 | Neutral | 0.626 | Possibly Damaging | 0.375 | Benign | 4.06 | Benign | 0.06 | Tolerated | 4.32 | 2 | 0.1268 | 0.3494 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||
| c.2914C>A | P972T 2D AIThe SynGAP1 missense variant P972T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.954150 | Binding | 0.472 | 0.904 | 0.625 | -5.144 | Likely Benign | 0.057 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -1.01 | Neutral | 0.078 | Benign | 0.042 | Benign | 4.29 | Benign | 0.03 | Affected | 0.1802 | 0.5726 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2914C>G | P972A 2D AIThe SynGAP1 missense variant P972A is listed in ClinVar with an uncertain significance (ClinVar ID 3172763.0) and is present in the gnomAD database (gnomAD ID 6‑33443466‑C‑G). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the computational evidence strongly suggests the variant is most likely benign, and this conclusion does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.954150 | Binding | 0.472 | 0.904 | 0.625 | Uncertain | 1 | 6-33443466-C-G | 1 | 6.20e-7 | -0.167 | Likely Benign | 0.045 | Likely Benign | Likely Benign | 0.046 | Likely Benign | -0.89 | Neutral | 0.016 | Benign | 0.011 | Benign | 4.29 | Benign | 0.07 | Tolerated | 4.32 | 2 | 0.3212 | 0.4753 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||
| c.2914C>T | P972S 2D AIThe SynGAP1 missense variant P972S (ClinVar ID 3361353.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33443466‑C‑T). Consensus among most in silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as benign. Only SIFT classifies it as pathogenic, representing the sole discordant prediction. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” No Foldetta stability analysis is available for this residue. Overall, the preponderance of computational evidence points to a benign effect, which is consistent with the ClinVar designation of uncertainty rather than pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.954150 | Binding | 0.472 | 0.904 | 0.625 | Uncertain | 1 | 6-33443466-C-T | 4 | 2.48e-6 | -4.008 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -0.38 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.28 | Benign | 0.05 | Affected | 4.32 | 2 | 0.3168 | 0.4822 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||
| c.2915C>A | P972H 2D AIThe SynGAP1 missense variant P972H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools (polyPhen‑2 HumDiv and SIFT) predict pathogenicity, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods points to a benign classification, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.954150 | Binding | 0.472 | 0.904 | 0.625 | -4.791 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -1.62 | Neutral | 0.589 | Possibly Damaging | 0.229 | Benign | 4.19 | Benign | 0.02 | Affected | 0.1930 | 0.4798 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2915C>G | P972R 2D AIThe SynGAP1 missense variant P972R is reported in gnomAD (ID 6‑33443467‑C‑G) but has no ClinVar entry. All evaluated in silico predictors classify it as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Based on the unanimous benign predictions and lack of ClinVar pathogenic annotation, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.954150 | Binding | 0.472 | 0.904 | 0.625 | 6-33443467-C-G | -4.483 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -1.44 | Neutral | 0.290 | Benign | 0.114 | Benign | 4.23 | Benign | 0.12 | Tolerated | 4.32 | 2 | 0.1379 | 0.3931 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||
| c.2915C>T | P972L 2D AIThe SynGAP1 missense variant P972L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.954150 | Binding | 0.472 | 0.904 | 0.625 | -4.399 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.020 | Likely Benign | -1.73 | Neutral | 0.036 | Benign | 0.026 | Benign | 4.24 | Benign | 0.02 | Affected | 0.2107 | 0.5447 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3265G>A | G1089R 2D AIThe SynGAP1 missense variant G1089R is catalogued in gnomAD (ID 6‑33443817‑G‑A) but has no ClinVar entry. Functional prediction tools split in a 6‑to‑3 ratio: benign calls come from REVEL, polyPhen‑2 HumVar, and ESM1b, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. AlphaMissense‑Optimized yields an Uncertain result, and no Foldetta stability assessment is available. Overall, the majority of high‑confidence predictors lean toward pathogenicity, and this assessment does not conflict with ClinVar status, which is currently unreported. Thus, the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.891961 | Disordered | 0.976771 | Binding | 0.366 | 0.890 | 1.000 | 6-33443817-G-A | 1 | 6.35e-7 | -4.757 | Likely Benign | 0.897 | Likely Pathogenic | Ambiguous | 0.222 | Likely Benign | -3.13 | Deleterious | 0.896 | Possibly Damaging | 0.325 | Benign | 2.42 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.0934 | 0.4415 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||
| c.3265G>C | G1089R 2D AIThe SynGAP1 missense variant G1089R is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 HumVar, and ESM1b, while pathogenic calls are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, FATHMM, and AlphaMissense‑Default. Grouping by consensus, seven tools predict pathogenicity and three predict benign, giving a net pathogenic signal. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized is uncertain, but the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic. Foldetta stability analysis is unavailable. Overall, the evidence points to the variant being most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.891961 | Disordered | 0.976771 | Binding | 0.366 | 0.890 | 1.000 | -4.757 | Likely Benign | 0.897 | Likely Pathogenic | Ambiguous | 0.228 | Likely Benign | -3.13 | Deleterious | 0.896 | Possibly Damaging | 0.325 | Benign | 2.42 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.0934 | 0.4415 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.3265G>T | G1089W 2D AIThe SynGAP1 missense variant G1089W is not reported in ClinVar and has no allele in gnomAD. Functional prediction tools show a split: benign calls come from REVEL and ESM1b, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the consensus SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments give an uncertain result from AlphaMissense‑Optimized, a Likely Pathogenic verdict from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and no available Foldetta stability data. Overall, the majority of evidence points to a deleterious effect, so the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.891961 | Disordered | 0.976771 | Binding | 0.366 | 0.890 | 1.000 | -6.561 | Likely Benign | 0.863 | Likely Pathogenic | Ambiguous | 0.236 | Likely Benign | -3.45 | Deleterious | 1.000 | Probably Damaging | 0.988 | Probably Damaging | 2.37 | Pathogenic | 0.00 | Affected | 0.0840 | 0.4610 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3266G>A | G1089E 2D AIThe SynGAP1 missense variant G1089E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas a majority (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a 2‑vs‑2 split, and Foldetta results are unavailable. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.891961 | Disordered | 0.976771 | Binding | 0.366 | 0.890 | 1.000 | -3.233 | Likely Benign | 0.926 | Likely Pathogenic | Ambiguous | 0.170 | Likely Benign | -2.85 | Deleterious | 0.992 | Probably Damaging | 0.834 | Possibly Damaging | 2.59 | Benign | 0.01 | Affected | 0.1460 | 0.4387 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3266G>C | G1089A 2D AIThe SynGAP1 missense variant G1089A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation—there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.976771 | Binding | 0.366 | 0.890 | 1.000 | -2.864 | Likely Benign | 0.224 | Likely Benign | Likely Benign | 0.142 | Likely Benign | -1.73 | Neutral | 0.186 | Benign | 0.055 | Benign | 2.45 | Pathogenic | 0.02 | Affected | 0.3475 | 0.5331 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3266G>T | G1089V 2D AIThe SynGAP1 missense variant G1089V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact for G1089V. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.891961 | Disordered | 0.976771 | Binding | 0.366 | 0.890 | 1.000 | -4.809 | Likely Benign | 0.527 | Ambiguous | Likely Benign | 0.182 | Likely Benign | -2.81 | Deleterious | 0.984 | Probably Damaging | 0.722 | Possibly Damaging | 2.40 | Pathogenic | 0.00 | Affected | 0.1326 | 0.4413 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||||
| 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.3970C>A | P1324T 2D AIThe SynGAP1 missense variant P1324T is listed in gnomAD (ID 6‑33451844‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the available predictions points to a benign effect, and this conclusion does not contradict any ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.899181 | Binding | 0.432 | 0.793 | 0.875 | 6-33451844-C-A | -5.289 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.072 | Likely Benign | 0.95 | Neutral | 0.588 | Possibly Damaging | 0.175 | Benign | 4.43 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1863 | 0.4761 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3970C>G | P1324A 2D AIThe SynGAP1 missense variant P1324A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.899181 | Binding | 0.432 | 0.793 | 0.875 | -4.416 | Likely Benign | 0.056 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -0.57 | Neutral | 0.011 | Benign | 0.017 | Benign | 4.30 | Benign | 0.00 | Affected | 0.3489 | 0.3776 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3970C>T | P1324S 2D AIThe SynGAP1 missense variant P1324S is listed in ClinVar as Benign (ClinVar ID 1137951.0) and is present in gnomAD (ID 6‑33451844‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) also benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, which is consistent with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.899181 | Binding | 0.432 | 0.793 | 0.875 | Likely Benign | 1 | 6-33451844-C-T | 5 | 3.26e-6 | -5.451 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.049 | Likely Benign | 0.35 | Neutral | 0.225 | Benign | 0.092 | Benign | 4.33 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3505 | 0.4450 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||
| c.3971C>A | P1324Q 2D AIThe SynGAP1 missense variant P1324Q is reported in gnomAD (ID 6‑33451845‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign status. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the consensus of the majority of tools, including the high‑accuracy predictors, points to a benign effect. This prediction is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.899181 | Binding | 0.432 | 0.793 | 0.875 | 6-33451845-C-A | -5.577 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.028 | Likely Benign | -0.69 | Neutral | 0.027 | Benign | 0.010 | Benign | 4.27 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1744 | 0.4736 | -1 | 0 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||
| c.3971C>G | P1324R 2D AIThe SynGAP1 missense variant P1324R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.899181 | Binding | 0.432 | 0.793 | 0.875 | -5.718 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -0.80 | Neutral | 0.414 | Benign | 0.133 | Benign | 4.28 | Benign | 0.00 | Affected | 0.1723 | 0.3613 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3971C>T | P1324L 2D AIThe SynGAP1 missense variant P1324L is reported in gnomAD (ID 6‑33451845‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.899181 | Binding | 0.432 | 0.793 | 0.875 | 6-33451845-C-T | -5.549 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -1.17 | Neutral | 0.414 | Benign | 0.175 | Benign | 4.26 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2507 | 0.5864 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||
| c.4003G>A | G1335S 2D AIThe SynGAP1 missense variant G1335S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33451877‑G‑A). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence indicates that G1335S is most likely pathogenic, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.891961 | Disordered | 0.967705 | Binding | 0.323 | 0.724 | 0.750 | Conflicting | 2 | 6-33451877-G-A | 3 | 2.37e-6 | -4.495 | Likely Benign | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.362 | Likely Benign | -3.79 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.04 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2452 | 0.5895 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||
| c.4003G>C | G1335R 2D AIThe SynGAP1 missense variant G1335R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: benign predictions come from REVEL and ESM1b, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. Foldetta results are not available. Overall, the preponderance of evidence supports a pathogenic classification for G1335R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.891961 | Disordered | 0.967705 | Binding | 0.323 | 0.724 | 0.750 | -4.921 | Likely Benign | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.394 | Likely Benign | -5.06 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.02 | Pathogenic | 0.00 | Affected | 0.1071 | 0.5024 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.4003G>T | G1335C 2D AIThe SynGAP1 missense variant G1335C is listed in gnomAD (variant ID 6-33451877‑G‑T) but has no ClinVar entry. Functional prediction tools split into two 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 AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote) also indicates Likely Pathogenic. Foldetta results are not available for this variant. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.891961 | Disordered | 0.967705 | Binding | 0.323 | 0.724 | 0.750 | 6-33451877-G-T | 1 | 7.91e-7 | -6.878 | Likely Benign | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.426 | Likely Benign | -5.51 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.01 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1376 | 0.4513 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||
| c.4004G>A | G1335D 2D AIThe SynGAP1 missense variant G1335D is reported in ClinVar as “not listed” and is present in gnomAD (variant ID 6‑33451878‑G‑A). Functional prediction tools that agree on a benign effect are REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote) also indicates Likely Pathogenic. Foldetta results are not available for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and the SGM‑Consensus suggests that G1335D is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.891961 | Disordered | 0.967705 | Binding | 0.323 | 0.724 | 0.750 | 6-33451878-G-A | -5.687 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.404 | Likely Benign | -4.42 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.02 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2120 | 0.3702 | -1 | 1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||
| c.4004G>C | G1335A 2D AIThe SynGAP1 missense variant G1335A is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely pathogenic. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic effect for G1335A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.891961 | Disordered | 0.967705 | Binding | 0.323 | 0.724 | 0.750 | -4.942 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.357 | Likely Benign | -3.69 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.05 | Pathogenic | 0.00 | Affected | 0.3383 | 0.4953 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.4004G>T | G1335V 2D AIThe SynGAP1 missense variant G1335V is not reported in ClinVar and is absent from 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 AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus 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 evidence points to a pathogenic impact, and this assessment does not conflict with the ClinVar status, which currently has no entry for G1335V. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.891961 | Disordered | 0.967705 | Binding | 0.323 | 0.724 | 0.750 | -4.982 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.394 | Likely Benign | -5.65 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.02 | Pathogenic | 0.00 | Affected | 0.1124 | 0.4195 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| 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.2815C>A | P939T 2D AIThe SynGAP1 missense variant P939T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy predictions show AlphaMissense‑Optimized as benign, while the SGM Consensus remains inconclusive and Foldetta is unavailable. Overall, more tools (five) predict pathogenicity than benign (four), suggesting the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as the variant has not yet been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.935841 | Binding | 0.397 | 0.897 | 0.625 | -5.739 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.139 | Likely Benign | -3.34 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.22 | Pathogenic | 0.00 | Affected | 0.1788 | 0.5310 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||||||
| c.2815C>G | P939A 2D AIThe SynGAP1 missense variant P939A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign versus two pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools therefore provide a benign prediction from AlphaMissense‑Optimized, an inconclusive SGM Consensus, and no Foldetta data. Overall, the majority of individual predictors (five pathogenic versus four benign) lean toward a pathogenic interpretation, and this does not contradict the lack of ClinVar annotation. **Thus, the variant is most likely pathogenic based on the current computational predictions.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.935841 | Binding | 0.397 | 0.897 | 0.625 | -4.614 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -3.57 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.40 | Pathogenic | 0.00 | Affected | 0.3565 | 0.4336 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2815C>T | P939S 2D AIThe SynGAP1 missense variant P939S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools specifically show AlphaMissense‑Optimized as benign, while SGM Consensus and Foldetta remain unavailable. Overall, the majority of predictions (5 pathogenic vs. 4 benign) indicate that P939S is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.935841 | Binding | 0.397 | 0.897 | 0.625 | -4.331 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -3.44 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.24 | Pathogenic | 0.00 | Affected | 0.3372 | 0.4517 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2816C>A | P939Q 2D AIThe SynGAP1 missense variant P939Q is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs. two pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus remains inconclusive and Foldetta is unavailable. Overall, five of the nine evaluated tools predict pathogenicity versus four predicting benignity, giving a slight tilt toward a pathogenic interpretation. This prediction does not contradict ClinVar status, as no ClinVar entry exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.935841 | Binding | 0.397 | 0.897 | 0.625 | -4.950 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.156 | Likely Benign | -3.45 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.18 | Pathogenic | 0.00 | Affected | 0.1551 | 0.4342 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||||||
| c.2816C>G | P939R 2D AIThe SynGAP1 missense variant P939R is reported in gnomAD (ID 6‑33443368‑C‑G) but has no ClinVar entry. Functional prediction tools show mixed results: benign calls come from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Grouping by consensus, the benign‑predicted tools outnumbered the pathogenic ones by one, but the overall tally favors pathogenicity (5 pathogenic vs 4 benign). High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is benign, but the SGM Consensus (a 2‑vs‑2 majority among AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields no clear verdict, and Foldetta data are unavailable. Consequently, the variant is most likely pathogenic according to the available predictions, and this assessment does not contradict any ClinVar status because none is reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.935841 | Binding | 0.397 | 0.897 | 0.625 | 6-33443368-C-G | 1 | 6.20e-7 | -4.863 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.199 | Likely Benign | -3.79 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.18 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1360 | 0.3336 | -2 | 0 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.2816C>T | P939L 2D AIThe SynGAP1 missense variant P939L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy predictions show AlphaMissense‑Optimized as benign, while SGM Consensus and Foldetta are unavailable. Overall, five tools predict pathogenicity versus four predicting benign, so the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.935841 | Binding | 0.397 | 0.897 | 0.625 | -4.191 | Likely Benign | 0.138 | Likely Benign | Likely Benign | 0.159 | Likely Benign | -3.69 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.18 | Pathogenic | 0.00 | Affected | 0.2113 | 0.5142 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3076G>A | D1026N 2D AIThe SynGAP1 D1026N variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and therefore reports a likely benign outcome. AlphaMissense‑Optimized also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | -4.166 | Likely Benign | 0.608 | Likely Pathogenic | Likely Benign | 0.117 | Likely Benign | -2.07 | Neutral | 0.411 | Benign | 0.239 | Benign | 2.55 | Benign | 0.01 | Affected | 0.1240 | 0.5060 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3076G>C | D1026H 2D AIThe SynGAP1 missense variant D1026H is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443628‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑to‑2 split. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (five pathogenic vs. three benign) lean toward a pathogenic impact. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | 6-33443628-G-C | 1 | 6.20e-7 | -4.412 | Likely Benign | 0.900 | Likely Pathogenic | Ambiguous | 0.105 | Likely Benign | -2.03 | Neutral | 0.832 | Possibly Damaging | 0.600 | Possibly Damaging | 2.48 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1470 | 0.5345 | -1 | 1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||
| c.3076G>T | D1026Y 2D AIThe SynGAP1 missense variant D1026Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default all classify the variant as damaging. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Based on the preponderance of pathogenic predictions and the SGM‑Consensus outcome, the variant is most likely pathogenic; this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | -6.999 | Likely Benign | 0.892 | Likely Pathogenic | Ambiguous | 0.200 | Likely Benign | -3.08 | Deleterious | 0.938 | Possibly Damaging | 0.596 | Possibly Damaging | 2.47 | Pathogenic | 0.00 | Affected | 0.0676 | 0.4936 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| c.3077A>C | D1026A 2D AIThe SynGAP1 D1026A variant is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM, while those that predict a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a tie, and Foldetta results are not available. Overall, the majority of standard tools favor a benign interpretation, and no ClinVar entry contradicts this assessment. Thus, the variant is most likely benign based on current predictions, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | -4.211 | Likely Benign | 0.849 | Likely Pathogenic | Ambiguous | 0.070 | Likely Benign | -2.69 | Deleterious | 0.112 | Benign | 0.061 | Benign | 2.53 | Benign | 0.02 | Affected | 0.3392 | 0.5279 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.3077A>G | D1026G 2D AIThe SynGAP1 missense variant D1026G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two benign, two pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | -4.125 | Likely Benign | 0.691 | Likely Pathogenic | Likely Benign | 0.098 | Likely Benign | -2.84 | Deleterious | 0.001 | Benign | 0.005 | Benign | 2.67 | Benign | 0.01 | Affected | 0.3377 | 0.5042 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3077A>T | D1026V 2D AIThe SynGAP1 missense variant D1026V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Tools that predict a pathogenic effect are PROVEAN, SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and therefore also indicates a likely pathogenic outcome. AlphaMissense‑Optimized is uncertain, and no Foldetta stability result is available, so it does not contribute evidence. Overall, the majority of reliable predictors classify the variant as pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | -5.871 | Likely Benign | 0.900 | Likely Pathogenic | Ambiguous | 0.144 | Likely Benign | -3.13 | Deleterious | 0.004 | Benign | 0.004 | Benign | 2.48 | Pathogenic | 0.00 | Affected | 0.0957 | 0.5236 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.3078C>A | D1026E 2D AIThe SynGAP1 missense variant D1026E is not reported in ClinVar and is absent from gnomAD. All available in silico predictors classify the change as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence strongly supports a benign classification, and this is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | -3.431 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.37 | Neutral | 0.001 | Benign | 0.005 | Benign | 2.73 | Benign | 0.56 | Tolerated | 0.1449 | 0.4783 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3078C>G | D1026E 2D AIThe SynGAP1 missense variant D1026E is not reported in ClinVar and is absent from gnomAD. All available in silico predictors classify the change as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence strongly supports a benign classification, and this is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | -3.431 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.37 | Neutral | 0.001 | Benign | 0.005 | Benign | 2.73 | Benign | 0.56 | Tolerated | 0.1449 | 0.4783 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3334G>A | E1112K 2D AIThe SynGAP1 missense variant E1112K is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign. Only two tools predict pathogenicity: SIFT and AlphaMissense‑Default. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the conclusion. Overall, the majority of predictions, including the high‑accuracy tools, suggest the variant is most likely benign, and this is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.909381 | Binding | 0.335 | 0.902 | 0.875 | -3.772 | Likely Benign | 0.684 | Likely Pathogenic | Likely Benign | 0.210 | Likely Benign | 0.15 | Neutral | 0.245 | Benign | 0.096 | Benign | 2.82 | Benign | 0.02 | Affected | 0.3002 | 0.7704 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3334G>C | E1112Q 2D AIThe SynGAP1 missense variant E1112Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from multiple in silico predictors and high‑accuracy tools points to a benign impact for E1112Q, and this conclusion does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.909381 | Binding | 0.335 | 0.902 | 0.875 | -1.975 | Likely Benign | 0.364 | Ambiguous | Likely Benign | 0.102 | Likely Benign | -0.48 | Neutral | 0.611 | Possibly Damaging | 0.305 | Benign | 2.71 | Benign | 0.42 | Tolerated | 0.2031 | 0.7430 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3335A>C | E1112A 2D AIThe SynGAP1 missense variant E1112A is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.909381 | Binding | 0.335 | 0.902 | 0.875 | -3.227 | Likely Benign | 0.373 | Ambiguous | Likely Benign | 0.096 | Likely Benign | -1.86 | Neutral | 0.393 | Benign | 0.131 | Benign | 2.71 | Benign | 0.02 | Affected | 0.3929 | 0.7528 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3335A>G | E1112G 2D AIThe SynGAP1 missense variant E1112G is reported in gnomAD (ID 6‑33443887‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN and SIFT. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yielding a “Likely Benign” classification. AlphaMissense‑Optimized independently predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the preponderance of evidence from both general and high‑accuracy tools indicates the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.909381 | Binding | 0.335 | 0.902 | 0.875 | 6-33443887-A-G | 1 | 6.73e-7 | -3.459 | Likely Benign | 0.277 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -2.58 | Deleterious | 0.058 | Benign | 0.015 | Benign | 2.70 | Benign | 0.01 | Affected | 4.32 | 2 | 0.2795 | 0.6220 | -2 | 0 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||
| c.3335A>T | E1112V 2D AIThe SynGAP1 missense variant E1112V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) also as benign; Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact for E1112V, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.909381 | Binding | 0.335 | 0.902 | 0.875 | -3.971 | Likely Benign | 0.579 | Likely Pathogenic | Likely Benign | 0.139 | Likely Benign | -2.28 | Neutral | 0.440 | Benign | 0.140 | Benign | 2.70 | Benign | 0.00 | Affected | 0.1481 | 0.7567 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.3336G>C | E1112D 2D AIThe SynGAP1 missense variant E1112D is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.909381 | Binding | 0.335 | 0.902 | 0.875 | -4.286 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -1.24 | Neutral | 0.005 | Benign | 0.005 | Benign | 2.69 | Benign | 0.06 | Tolerated | 4.32 | 2 | 0.2343 | 0.5553 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||
| c.3336G>T | E1112D 2D AIThe SynGAP1 missense variant E1112D is catalogued in gnomAD (variant ID 6-33443888‑G‑T) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool examined—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classifies the substitution as benign. No pathogenic predictions are reported. Grouping by consensus, all listed tools fall into the benign category, with no tools indicating pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Based on the unanimous benign predictions and the absence of any ClinVar pathogenic classification, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.909381 | Binding | 0.335 | 0.902 | 0.875 | 6-33443888-G-T | -4.286 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -1.24 | Neutral | 0.005 | Benign | 0.005 | Benign | 2.69 | Benign | 0.06 | Tolerated | 4.32 | 2 | 0.2343 | 0.5553 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.3361A>C | S1121R 2D AIThe SynGAP1 missense variant S1121R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign, reflecting the majority of benign predictions. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact for S1121R, and this conclusion is consistent with the lack of ClinVar reporting. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.810024 | Binding | 0.365 | 0.935 | 0.875 | -6.945 | Likely Benign | 0.597 | Likely Pathogenic | Likely Benign | 0.142 | Likely Benign | -0.34 | Neutral | 0.016 | Benign | 0.015 | Benign | 5.45 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1346 | 0.3431 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.3361A>G | S1121G 2D AIThe SynGAP1 missense variant S1121G is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443913‑A‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also benign. Foldetta results are not available. Overall, the preponderance of evidence indicates that the variant is most likely benign, which does not contradict the current ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.810024 | Binding | 0.365 | 0.935 | 0.875 | Uncertain | 1 | 6-33443913-A-G | 1 | 7.00e-7 | -1.220 | Likely Benign | 0.054 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.53 | Neutral | 0.003 | Benign | 0.004 | Benign | 6.63 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2724 | 0.4657 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||
| c.3361A>T | S1121C 2D AIThe SynGAP1 missense variant S1121C is listed in gnomAD (ID 6‑33443913‑A‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect 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 the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.810024 | Binding | 0.365 | 0.935 | 0.875 | 6-33443913-A-T | -7.431 | In-Between | 0.094 | Likely Benign | Likely Benign | 0.354 | Likely Benign | -0.99 | Neutral | 0.994 | Probably Damaging | 0.840 | Possibly Damaging | 5.43 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1705 | 0.5691 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||
| c.3362G>A | S1121N 2D AIThe SynGAP1 missense variant S1121N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable. Overall, the consensus of the majority of predictors and the high‑accuracy tools points to a benign classification, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.810024 | Binding | 0.365 | 0.935 | 0.875 | -6.564 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.221 | Likely Benign | -0.12 | Neutral | 0.802 | Possibly Damaging | 0.266 | Benign | 5.50 | Benign | 0.00 | Affected | 0.1980 | 0.4211 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| c.3362G>C | S1121T 2D AIThe SynGAP1 missense variant S1121T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign 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 (none is provided). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.810024 | Binding | 0.365 | 0.935 | 0.875 | -6.442 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -0.23 | Neutral | 0.011 | Benign | 0.026 | Benign | 5.45 | Benign | 0.00 | Affected | 0.2108 | 0.5582 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3362G>T | S1121I 2D AIThe SynGAP1 missense variant S1121I 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 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. 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 | 0.894241 | Disordered | 0.810024 | Binding | 0.365 | 0.935 | 0.875 | -6.215 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 0.455 | Likely Benign | -0.96 | Neutral | 0.875 | Possibly Damaging | 0.559 | Possibly Damaging | 5.44 | Benign | 0.00 | Affected | 0.1504 | 0.4776 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.3363C>A | S1121R 2D AIThe SynGAP1 missense variant S1121R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.810024 | Binding | 0.365 | 0.935 | 0.875 | -6.945 | Likely Benign | 0.597 | Likely Pathogenic | Likely Benign | 0.100 | Likely Benign | -0.34 | Neutral | 0.016 | Benign | 0.015 | Benign | 5.45 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1346 | 0.3431 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.3363C>G | S1121R 2D AIThe SynGAP1 missense variant S1121R is catalogued in gnomAD (ID 6‑33443915‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all report benign. Only SIFT and AlphaMissense‑Default predict pathogenicity, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.810024 | Binding | 0.365 | 0.935 | 0.875 | 6-33443915-C-G | -6.945 | Likely Benign | 0.597 | Likely Pathogenic | Likely Benign | 0.101 | Likely Benign | -0.34 | Neutral | 0.016 | Benign | 0.015 | Benign | 5.45 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1346 | 0.3431 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| c.3376G>A | G1126S 2D AIThe SynGAP1 missense variant G1126S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also predicts Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign impact for G1126S, 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 | 0.894241 | Disordered | 0.837209 | Binding | 0.345 | 0.918 | 0.875 | -5.004 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.268 | Likely Benign | -0.28 | Neutral | 0.611 | Possibly Damaging | 0.171 | Benign | 4.78 | Benign | 0.74 | Tolerated | 0.2509 | 0.5300 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3376G>C | G1126R 2D AIThe SynGAP1 missense variant G1126R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Two tools—ESM1b and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is uncertain due to a 2‑to‑2 split between benign and uncertain calls; Foldetta’s protein‑folding stability analysis is unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict any ClinVar annotation because no ClinVar record exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.837209 | Binding | 0.345 | 0.918 | 0.875 | -7.760 | In-Between | 0.522 | Ambiguous | Likely Benign | 0.345 | Likely Benign | -0.56 | Neutral | 0.971 | Probably Damaging | 0.597 | Possibly Damaging | 4.77 | Benign | 0.01 | Affected | 0.0946 | 0.4532 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3376G>T | G1126C 2D AIThe SynGAP1 missense variant G1126C is listed in ClinVar (ID 469157.0) with an “Uncertain” status and is present in gnomAD (6‑33443928‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are SIFT and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.837209 | Binding | 0.345 | 0.918 | 0.875 | Uncertain | 1 | 6-33443928-G-T | 11 | 7.35e-6 | -9.389 | Likely Pathogenic | 0.113 | Likely Benign | Likely Benign | 0.449 | Likely Benign | -1.40 | Neutral | 0.005 | Benign | 0.005 | Benign | 4.74 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1326 | 0.4427 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||
| c.3377G>A | G1126D 2D AISynGAP1 missense variant G1126D is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The AlphaMissense‑Default result is uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.894241 | Disordered | 0.837209 | Binding | 0.345 | 0.918 | 0.875 | Uncertain | 1 | -8.888 | Likely Pathogenic | 0.432 | Ambiguous | Likely Benign | 0.376 | Likely Benign | -0.65 | Neutral | 0.906 | Possibly Damaging | 0.473 | Possibly Damaging | 4.82 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1725 | 0.2224 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||
| c.3377G>C | G1126A 2D AIThe SynGAP1 missense variant G1126A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.837209 | Binding | 0.345 | 0.918 | 0.875 | -6.402 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.228 | Likely Benign | -0.63 | Neutral | 0.124 | Benign | 0.061 | Benign | 4.83 | Benign | 0.56 | Tolerated | 0.3505 | 0.5333 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3377G>T | G1126V 2D AIThe SynGAP1 missense variant G1126V is listed in ClinVar with an uncertain significance and is present in the gnomAD database. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score all classify the change as benign. Only the SIFT algorithm predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized reports a benign effect, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign, while Foldetta’s protein‑folding stability analysis is unavailable. Overall, the preponderance of evidence points to a benign variant, 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 | 0.894241 | Disordered | 0.837209 | Binding | 0.345 | 0.918 | 0.875 | Uncertain | 1 | 6-33443929-G-T | -6.536 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.357 | Likely Benign | -1.20 | Neutral | 0.009 | Benign | 0.008 | Benign | 4.76 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1366 | 0.3884 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||
| c.3268A>C | N1090H 2D AIThe SynGAP1 missense variant N1090H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | -3.744 | Likely Benign | 0.447 | Ambiguous | Likely Benign | 0.094 | Likely Benign | -1.42 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.67 | Benign | 0.10 | Tolerated | 0.1604 | 0.7550 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3268A>G | N1090D 2D AIThe SynGAP1 missense variant N1090D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and no Foldetta stability data is available. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | -3.354 | Likely Benign | 0.827 | Likely Pathogenic | Ambiguous | 0.066 | Likely Benign | -1.39 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.70 | Benign | 0.47 | Tolerated | 0.1994 | 0.4375 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3268A>T | N1090Y 2D AIThe SynGAP1 missense variant N1090Y is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign, reflecting the majority of benign calls. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign effect for the variant, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | -4.744 | Likely Benign | 0.651 | Likely Pathogenic | Likely Benign | 0.139 | Likely Benign | -2.26 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.66 | Benign | 0.05 | Affected | 0.0661 | 0.5998 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||||||||||||
| c.3269A>C | N1090T 2D AIThe SynGAP1 missense variant N1090T is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of high‑accuracy predictors (AlphaMissense‑Optimized and the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also support a benign classification. In contrast, polyPhen‑2 (both HumDiv and HumVar tracks) predict a pathogenic impact, but these are the only tools in disagreement. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. Overall, the preponderance of evidence points to a benign effect for the variant, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | -3.478 | Likely Benign | 0.542 | Ambiguous | Likely Benign | 0.129 | Likely Benign | -0.78 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.77 | Benign | 0.58 | Tolerated | 0.1451 | 0.7930 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||||||||||
| c.3269A>G | N1090S 2D AIThe SynGAP1 missense variant N1090S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | -2.451 | Likely Benign | 0.228 | Likely Benign | Likely Benign | 0.135 | Likely Benign | -0.49 | Neutral | 0.997 | Probably Damaging | 0.983 | Probably Damaging | 2.97 | Benign | 0.38 | Tolerated | 0.3980 | 0.7620 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||||||||||
| c.3269A>T | N1090I 2D AIThe SynGAP1 missense variant N1090I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the balance of evidence from both general and high‑accuracy predictors points to a benign classification, and this conclusion does not contradict the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | -4.356 | Likely Benign | 0.765 | Likely Pathogenic | Likely Benign | 0.173 | Likely Benign | -2.14 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.67 | Benign | 0.02 | Affected | 0.0781 | 0.6279 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3270T>A | N1090K 2D AIThe SynGAP1 missense variant N1090K is reported in ClinVar as “None” and is present in gnomAD (ID 6‑33443822‑T‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains likely benign; a Foldetta stability analysis is unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) and the consensus result lean toward a benign interpretation. This conclusion does not contradict ClinVar, which currently has no pathogenic classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | 6-33443822-T-A | 2 | 1.28e-6 | -3.423 | Likely Benign | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.053 | Likely Benign | -1.52 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.73 | Benign | 0.18 | Tolerated | 3.77 | 5 | 0.2147 | 0.6121 | 0 | 1 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||
| c.3270T>G | N1090K 2D AIThe SynGAP1 missense variant N1090K has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. The overall balance of evidence leans toward a benign interpretation, and this is consistent with the lack of a ClinVar classification. Thus, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | -3.423 | Likely Benign | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.053 | Likely Benign | -1.52 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.73 | Benign | 0.18 | Tolerated | 3.77 | 5 | 0.2147 | 0.6121 | 0 | 1 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||
| c.3364G>A | G1122S 2D AIThe SynGAP1 missense variant G1122S is listed in ClinVar (ID 643187) as Benign and is present in gnomAD (6‑33443916‑G‑A). 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 report benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized indicates Benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports Likely Benign. The Foldetta stability analysis is unavailable for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, aligning with the ClinVar classification and showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.814918 | Binding | 0.357 | 0.932 | 0.875 | Benign/Likely benign | 3 | 6-33443916-G-A | 27 | 1.79e-5 | -4.880 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.189 | Likely Benign | -0.08 | Neutral | 0.022 | Benign | 0.006 | Benign | 4.89 | Benign | 0.92 | Tolerated | 3.77 | 5 | 0.2537 | 0.5111 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||
| c.3364G>C | G1122R 2D AIThe SynGAP1 missense variant G1122R is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, SIFT, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence (six benign versus three pathogenic predictions, plus a benign consensus) indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.896620 | Disordered | 0.814918 | Binding | 0.357 | 0.932 | 0.875 | -9.063 | Likely Pathogenic | 0.507 | Ambiguous | Likely Benign | 0.319 | Likely Benign | -0.05 | Neutral | 0.639 | Possibly Damaging | 0.351 | Benign | 4.64 | Benign | 0.05 | Affected | 0.0976 | 0.4342 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3364G>T | G1122C 2D AIThe SynGAP1 missense variant G1122C is listed in ClinVar with no submitted interpretation and is present in gnomAD (variant ID 6‑33443916‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b 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 high‑confidence tools—supports a benign classification, and this conclusion does not contradict the ClinVar status, which currently has no pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.814918 | Binding | 0.357 | 0.932 | 0.875 | 6-33443916-G-T | -8.895 | Likely Pathogenic | 0.110 | Likely Benign | Likely Benign | 0.375 | Likely Benign | -1.30 | Neutral | 0.975 | Probably Damaging | 0.733 | Possibly Damaging | 4.48 | Benign | 0.08 | Tolerated | 3.77 | 5 | 0.1343 | 0.4227 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||
| c.3365G>A | G1122D 2D AIThe SynGAP1 missense variant G1122D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only ESM1b predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also favors benign (2 benign vs. 1 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that G1122D is most likely benign, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.896620 | Disordered | 0.814918 | Binding | 0.357 | 0.932 | 0.875 | -9.991 | Likely Pathogenic | 0.430 | Ambiguous | Likely Benign | 0.332 | Likely Benign | -0.49 | Neutral | 0.411 | Benign | 0.091 | Benign | 4.49 | Benign | 0.10 | Tolerated | 0.1746 | 0.2035 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3365G>C | G1122A 2D AIThe SynGAP1 missense variant G1122A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and there is no conflict with ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.814918 | Binding | 0.357 | 0.932 | 0.875 | -6.692 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.168 | Likely Benign | -0.52 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.52 | Benign | 0.62 | Tolerated | 0.3487 | 0.4944 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3365G>T | G1122V 2D AIThe SynGAP1 missense variant G1122V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) reports likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign, and this assessment 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 | 0.896620 | Disordered | 0.814918 | Binding | 0.357 | 0.932 | 0.875 | -6.398 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.271 | Likely Benign | -1.18 | Neutral | 0.059 | Benign | 0.025 | Benign | 4.49 | Benign | 0.10 | Tolerated | 0.1381 | 0.3694 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3382G>A | G1128R 2D AIThe SynGAP1 missense variant G1128R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.865136 | Binding | 0.309 | 0.911 | 0.875 | -5.009 | Likely Benign | 0.692 | Likely Pathogenic | Likely Benign | 0.396 | Likely Benign | -0.79 | Neutral | 0.846 | Possibly Damaging | 0.346 | Benign | 4.38 | Benign | 0.12 | Tolerated | 0.0950 | 0.4725 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3382G>C | G1128R 2D AIThe SynGAP1 missense variant G1128R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.865136 | Binding | 0.309 | 0.911 | 0.875 | -5.009 | Likely Benign | 0.692 | Likely Pathogenic | Likely Benign | 0.397 | Likely Benign | -0.79 | Neutral | 0.846 | Possibly Damaging | 0.346 | Benign | 4.38 | Benign | 0.12 | Tolerated | 0.0950 | 0.4725 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3382G>T | G1128W 2D AIThe SynGAP1 missense variant G1128W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields an inconclusive result (two benign, two uncertain), and Foldetta data are unavailable. Overall, the balance of evidence favors a benign classification. This conclusion does not contradict ClinVar status, as the variant has no existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.896620 | Disordered | 0.865136 | Binding | 0.309 | 0.911 | 0.875 | -7.341 | In-Between | 0.402 | Ambiguous | Likely Benign | 0.464 | Likely Benign | -1.36 | Neutral | 0.011 | Benign | 0.008 | Benign | 4.36 | Benign | 0.02 | Affected | 0.0796 | 0.4540 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||||||
| c.3383G>A | G1128E 2D AIThe SynGAP1 missense variant G1128E is present in gnomAD (6‑33443935‑G‑A) and has no ClinVar entry. In silico predictors that agree on a benign effect include REVEL, PROVEAN, PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as likely benign. High‑accuracy tools reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is a high‑accuracy majority vote. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its stability impact remains unknown. Overall, the computational evidence overwhelmingly supports a benign classification, and this is consistent with the absence of a pathogenic ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.865136 | Binding | 0.309 | 0.911 | 0.875 | 6-33443935-G-A | 1 | 6.70e-7 | -5.580 | Likely Benign | 0.452 | Ambiguous | Likely Benign | 0.235 | Likely Benign | -0.24 | Neutral | 0.002 | Benign | 0.008 | Benign | 4.43 | Benign | 1.00 | Tolerated | 4.32 | 4 | 0.1610 | 0.4497 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| c.3383G>C | G1128A 2D AIThe SynGAP1 missense variant G1128A 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 results are unavailable. Based on the collective predictions, 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 | 0.896620 | Disordered | 0.865136 | Binding | 0.309 | 0.911 | 0.875 | -5.015 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.209 | Likely Benign | -0.26 | Neutral | 0.009 | Benign | 0.008 | Benign | 4.47 | Benign | 0.46 | Tolerated | 0.3588 | 0.5252 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3383G>T | G1128V 2D AIThe SynGAP1 missense variant G1128V is reported in gnomAD (variant ID 6‑33443935‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags it as pathogenic, creating a single discordant call. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates 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 | 0.896620 | Disordered | 0.865136 | Binding | 0.309 | 0.911 | 0.875 | 6-33443935-G-T | -5.111 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.399 | Likely Benign | -0.69 | Neutral | 0.611 | Possibly Damaging | 0.185 | Benign | 4.39 | Benign | 0.09 | Tolerated | 4.32 | 4 | 0.1358 | 0.3922 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||
| c.3979C>A | P1327T 2D AIThe SynGAP1 missense variant P1327T is reported in gnomAD (ID 6‑33451853‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are not available. Taken together, the majority of evidence points to a benign impact. There is no ClinVar classification to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | 6-33451853-C-A | -5.263 | Likely Benign | 0.150 | Likely Benign | Likely Benign | 0.144 | Likely Benign | 1.20 | Neutral | 0.994 | Probably Damaging | 0.908 | Possibly Damaging | 4.51 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.1386 | 0.4779 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3979C>G | P1327A 2D AIThe SynGAP1 missense variant P1327A is reported in gnomAD (ID 6‑33451853‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict the variant to be pathogenic. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a pathogenic ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | 6-33451853-C-G | 2 | 1.28e-6 | -4.661 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -0.37 | Neutral | 0.980 | Probably Damaging | 0.811 | Possibly Damaging | 4.24 | Benign | 0.42 | Tolerated | 3.77 | 5 | 0.3152 | 0.3645 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.3979C>T | P1327S 2D AIThe SynGAP1 missense variant P1327S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33451853‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | Uncertain | 1 | 6-33451853-C-T | -4.744 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.092 | Likely Benign | 0.28 | Neutral | 0.980 | Probably Damaging | 0.857 | Possibly Damaging | 4.25 | Benign | 0.71 | Tolerated | 3.77 | 5 | 0.3098 | 0.4025 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3980C>A | P1327H 2D AIThe SynGAP1 missense variant P1327H is reported in gnomAD (ID 6‑33451854‑C‑A) and has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus is Likely Benign, and Foldetta results are unavailable. Based on the preponderance of evidence from both general and high‑accuracy predictors, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | 6-33451854-C-A | -5.496 | Likely Benign | 0.263 | Likely Benign | Likely Benign | 0.144 | Likely Benign | -0.49 | Neutral | 0.998 | Probably Damaging | 0.953 | Probably Damaging | 4.09 | Benign | 0.04 | Affected | 3.77 | 5 | 0.1559 | 0.3932 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||
| c.3980C>G | P1327R 2D AIThe SynGAP1 missense variant P1327R is reported in gnomAD (variant ID 6‑33451854‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict the variant to be pathogenic. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a likely benign outcome. No Foldetta stability analysis is available, so it does not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | 6-33451854-C-G | -4.724 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.137 | Likely Benign | -0.95 | Neutral | 0.994 | Probably Damaging | 0.937 | Probably Damaging | 4.12 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.1442 | 0.2798 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||
| c.3980C>T | P1327L 2D AIThe SynGAP1 missense variant P1327L is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33451854‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a benign outcome. Foldetta results are not available for this variant. Overall, the majority of computational evidence supports a benign classification, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | Uncertain | 1 | 6-33451854-C-T | 2 | 1.28e-6 | -5.264 | Likely Benign | 0.242 | Likely Benign | Likely Benign | 0.142 | Likely Benign | -1.24 | Neutral | 0.994 | Probably Damaging | 0.908 | Possibly Damaging | 4.12 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.2123 | 0.5538 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||
| c.3061C>A | Q1021K 2D AIThe SynGAP1 missense variant Q1021K is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a mixed signal: benign predictions come from REVEL, PROVEAN, ESM1b, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments are limited: AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. Given the predominance of benign calls in the consensus and the lack of a ClinVar pathogenic annotation, the variant is most likely benign, with no conflict with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | -4.276 | Likely Benign | 0.786 | Likely Pathogenic | Ambiguous | 0.175 | Likely Benign | -1.79 | Neutral | 0.963 | Probably Damaging | 0.973 | Probably Damaging | 2.66 | Benign | 0.03 | Affected | 0.1551 | 0.4139 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3061C>G | Q1021E 2D AIThe SynGAP1 missense variant Q1021E is evaluated by multiple in silico tools. Benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions are reported by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The AlphaMissense‑Default tool gives an uncertain result. The consensus prediction from the SGM framework, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus also indicates a likely benign effect. No Foldetta stability analysis is available for this residue. ClinVar contains no entry for this variant, and it is absent from gnomAD, so there is no external evidence to contradict the computational assessment. Based on the collective predictions, the variant is most likely benign, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | -4.852 | Likely Benign | 0.545 | Ambiguous | Likely Benign | 0.137 | Likely Benign | -1.21 | Neutral | 0.963 | Probably Damaging | 0.973 | Probably Damaging | 2.65 | Benign | 0.03 | Affected | 0.1317 | 0.2069 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3062A>C | Q1021P 2D AIThe SynGAP1 missense variant Q1021P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q1021P, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | -3.522 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.235 | Likely Benign | -2.11 | Neutral | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.56 | Benign | 0.02 | Affected | 0.2022 | 0.4789 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3062A>G | Q1021R 2D AIThe SynGAP1 missense variant Q1021R is catalogued in gnomAD (ID 6‑33443614‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves as “Likely Benign” (three benign votes versus one pathogenic). High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | 6-33443614-A-G | 1 | 6.20e-7 | -4.467 | Likely Benign | 0.770 | Likely Pathogenic | Likely Benign | 0.174 | Likely Benign | -1.80 | Neutral | 0.985 | Probably Damaging | 0.982 | Probably Damaging | 2.61 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1257 | 0.2405 | 1 | 1 | -1.0 | 28.06 | ||||||||||||||||||||||||||||||||||
| c.3062A>T | Q1021L 2D AIThe SynGAP1 missense variant Q1021L is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (5 pathogenic vs. 4 benign) indicate that the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as the variant has no existing ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | -5.780 | Likely Benign | 0.678 | Likely Pathogenic | Likely Benign | 0.226 | Likely Benign | -3.36 | Deleterious | 0.985 | Probably Damaging | 0.982 | Probably Damaging | 2.58 | Benign | 0.01 | Affected | 0.0688 | 0.5039 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||||||||||||
| c.3063G>C | Q1021H 2D AIThe SynGAP1 missense variant Q1021H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, as no ClinVar status is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | -4.694 | Likely Benign | 0.664 | Likely Pathogenic | Likely Benign | 0.184 | Likely Benign | -1.72 | Neutral | 0.996 | Probably Damaging | 0.995 | Probably Damaging | 2.61 | Benign | 0.01 | Affected | 0.1211 | 0.3601 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3063G>T | Q1021H 2D AIThe SynGAP1 missense variant Q1021H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.979641 | Binding | 0.326 | 0.763 | 0.500 | -4.694 | Likely Benign | 0.664 | Likely Pathogenic | Likely Benign | 0.184 | Likely Benign | -1.72 | Neutral | 0.996 | Probably Damaging | 0.995 | Probably Damaging | 2.61 | Benign | 0.01 | Affected | 0.1211 | 0.3601 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3082C>A | L1028M 2D AIThe SynGAP1 missense variant L1028M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for the variant, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.995137 | Binding | 0.364 | 0.730 | 0.500 | -4.591 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -0.07 | Neutral | 0.986 | Probably Damaging | 0.825 | Possibly Damaging | 2.70 | Benign | 0.18 | Tolerated | 0.0776 | 0.3124 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3082C>G | L1028V 2D AIThe SynGAP1 missense variant L1028V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. Foldetta results are not available, so they do not influence the assessment. Overall, the majority of computational evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.995137 | Binding | 0.364 | 0.730 | 0.500 | -3.992 | Likely Benign | 0.217 | Likely Benign | Likely Benign | 0.042 | Likely Benign | -0.68 | Neutral | 0.737 | Possibly Damaging | 0.376 | Benign | 2.74 | Benign | 0.26 | Tolerated | 0.1328 | 0.2715 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3083T>A | L1028Q 2D AIThe SynGAP1 missense variant L1028Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.995137 | Binding | 0.364 | 0.730 | 0.500 | -2.718 | Likely Benign | 0.612 | Likely Pathogenic | Likely Benign | 0.179 | Likely Benign | -0.19 | Neutral | 0.986 | Probably Damaging | 0.825 | Possibly Damaging | 2.80 | Benign | 0.38 | Tolerated | 0.1110 | 0.1403 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3083T>C | L1028P 2D AIThe SynGAP1 missense variant L1028P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Taken together, the majority of evidence points to a benign impact for this variant, and there is no ClinVar annotation to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.995137 | Binding | 0.364 | 0.730 | 0.500 | -3.080 | Likely Benign | 0.594 | Likely Pathogenic | Likely Benign | 0.215 | Likely Benign | -0.42 | Neutral | 0.004 | Benign | 0.010 | Benign | 2.70 | Benign | 0.25 | Tolerated | 0.2846 | 0.1763 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3083T>G | L1028R 2D AIThe SynGAP1 missense variant L1028R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.995137 | Binding | 0.364 | 0.730 | 0.500 | -2.204 | Likely Benign | 0.793 | Likely Pathogenic | Ambiguous | 0.167 | Likely Benign | -0.24 | Neutral | 0.960 | Probably Damaging | 0.761 | Possibly Damaging | 2.75 | Benign | 0.84 | Tolerated | 0.1328 | 0.1603 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3379G>A | G1127R 2D AIThe SynGAP1 missense variant G1127R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443931‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.852422 | Binding | 0.344 | 0.915 | 0.875 | Uncertain | 1 | 6-33443931-G-A | 2 | 1.34e-6 | -5.949 | Likely Benign | 0.629 | Likely Pathogenic | Likely Benign | 0.341 | Likely Benign | -0.87 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.86 | Benign | 0.12 | Tolerated | 4.32 | 4 | 0.0929 | 0.4532 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||
| c.3379G>C | G1127R 2D AIThe SynGAP1 missense variant G1127R is listed in ClinVar (ID 2967461.0) with an “Uncertain” clinical significance and is present in gnomAD (6‑33443931‑G‑C). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that G1127R is most likely benign, which does not contradict the ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.852422 | Binding | 0.344 | 0.915 | 0.875 | Conflicting | 2 | 6-33443931-G-C | 16 | 1.07e-5 | -5.949 | Likely Benign | 0.629 | Likely Pathogenic | Likely Benign | 0.341 | Likely Benign | -0.87 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.86 | Benign | 0.12 | Tolerated | 4.32 | 4 | 0.0929 | 0.4532 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||
| c.3379G>T | G1127W 2D AIThe SynGAP1 missense variant G1127W is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443931‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b all predict a pathogenic outcome; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta’s protein‑folding stability result is unavailable. Overall, the balance of evidence, particularly from the high‑accuracy tools, indicates that the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.899122 | Disordered | 0.852422 | Binding | 0.344 | 0.915 | 0.875 | 6-33443931-G-T | 3 | 2.01e-6 | -9.850 | Likely Pathogenic | 0.418 | Ambiguous | Likely Benign | 0.394 | Likely Benign | -1.36 | Neutral | 0.983 | Probably Damaging | 0.665 | Possibly Damaging | 4.79 | Benign | 0.03 | Affected | 4.32 | 4 | 0.0782 | 0.4032 | -2 | -7 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||
| c.3380G>A | G1127E 2D AIThe SynGAP1 missense variant G1127E is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the remaining tools (ESM1b and AlphaMissense‑Default) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a tie between benign and uncertain calls. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the evidence strongly points to a benign effect, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.899122 | Disordered | 0.852422 | Binding | 0.344 | 0.915 | 0.875 | -7.359 | In-Between | 0.422 | Ambiguous | Likely Benign | 0.314 | Likely Benign | -0.56 | Neutral | 0.224 | Benign | 0.091 | Benign | 4.88 | Benign | 0.15 | Tolerated | 0.1395 | 0.4244 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3380G>C | G1127A 2D AIThe SynGAP1 missense variant G1127A is listed in ClinVar (ID 426748.0) with an uncertain significance status and is present in gnomAD (variant ID 6‑33443932‑G‑C). 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. 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 combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the evidence strongly supports a benign classification, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.852422 | Binding | 0.344 | 0.915 | 0.875 | Conflicting | 4 | 6-33443932-G-C | 4 | 2.68e-6 | -5.949 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.164 | Likely Benign | -0.43 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.83 | Benign | 1.00 | Tolerated | 4.32 | 4 | 0.3420 | 0.4933 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||
| c.3380G>T | G1127V 2D AIThe SynGAP1 missense variant G1127V is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443932‑G‑T). All available in silico predictors classify the change as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic prediction. Grouping by agreement, the benign‑predicting tools comprise the entire set, while no pathogenic predictions exist. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are unavailable. Overall, the variant is most likely benign, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.852422 | Binding | 0.344 | 0.915 | 0.875 | Uncertain | 1 | 6-33443932-G-T | 1 | 6.69e-7 | -6.097 | Likely Benign | 0.094 | Likely Benign | Likely Benign | 0.230 | Likely Benign | -1.01 | Neutral | 0.004 | Benign | 0.005 | Benign | 4.81 | Benign | 0.17 | Tolerated | 4.32 | 4 | 0.1281 | 0.3669 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||
| c.3946A>C | N1316H 2D AIThe SynGAP1 missense variant N1316H is reported in gnomAD (ID 6‑33451820‑A‑C) 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, derived from a majority vote of 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 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 to the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.971970 | Binding | 0.380 | 0.885 | 0.750 | 6-33451820-A-C | -4.151 | Likely Benign | 0.247 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -1.87 | Neutral | 0.939 | Possibly Damaging | 0.496 | Possibly Damaging | 3.95 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1535 | 0.6636 | 1 | 2 | 0.3 | 23.04 | ||||||||||||||||||||||||||||||||||||
| c.3946A>G | N1316D 2D AIThe SynGAP1 missense variant N1316D is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33451820‑A‑G). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also leans toward benign, with two benign and one pathogenic prediction among the four considered. 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 the ClinVar status, which currently has no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.899122 | Disordered | 0.971970 | Binding | 0.380 | 0.885 | 0.750 | 6-33451820-A-G | -2.717 | Likely Benign | 0.364 | Ambiguous | Likely Benign | 0.057 | Likely Benign | -2.80 | Deleterious | 0.225 | Benign | 0.084 | Benign | 3.96 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2095 | 0.3745 | 1 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||
| c.3946A>T | N1316Y 2D AIThe SynGAP1 missense variant N1316Y is reported in gnomAD (variant ID 6‑33451820‑A‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, polyPhen2_HumVar, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions come from polyPhen2_HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also 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 status (none is available). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.971970 | Binding | 0.380 | 0.885 | 0.750 | 6-33451820-A-T | -5.579 | Likely Benign | 0.392 | Ambiguous | Likely Benign | 0.101 | Likely Benign | -2.48 | Neutral | 0.939 | Possibly Damaging | 0.396 | Benign | 3.90 | Benign | 0.00 | Affected | 3.77 | 5 | 0.0671 | 0.5365 | -2 | -2 | 2.2 | 49.07 | ||||||||||||||||||||||||||||||||||||
| c.3947A>C | N1316T 2D AIThe SynGAP1 missense variant N1316T is reported in gnomAD (ID 6‑33451821‑A‑C) but has no ClinVar entry. 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. When predictions are grouped by consensus, the benign‑predicating tools outnumber the pathogenic ones. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.971970 | Binding | 0.380 | 0.885 | 0.750 | 6-33451821-A-C | -3.080 | Likely Benign | 0.315 | Likely Benign | Likely Benign | 0.107 | Likely Benign | -3.18 | Deleterious | 0.127 | Benign | 0.045 | Benign | 3.96 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1450 | 0.6621 | 0 | 0 | 2.8 | -13.00 | ||||||||||||||||||||||||||||||||||||
| c.3947A>G | N1316S 2D AIThe SynGAP1 missense variant N1316S is reported in gnomAD (ID 6‑33451821‑A‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the majority of 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 | 0.899122 | Disordered | 0.971970 | Binding | 0.380 | 0.885 | 0.750 | 6-33451821-A-G | 1 | 6.25e-7 | -2.906 | Likely Benign | 0.169 | Likely Benign | Likely Benign | 0.084 | Likely Benign | -2.69 | Deleterious | 0.004 | Benign | 0.003 | Benign | 4.03 | Benign | 0.00 | Affected | 3.77 | 5 | 0.3937 | 0.6307 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||||||||||
| c.3947A>T | N1316I 2D AIThe SynGAP1 missense variant N1316I is not 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict 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. | 0.899122 | Disordered | 0.971970 | Binding | 0.380 | 0.885 | 0.750 | -4.829 | Likely Benign | 0.635 | Likely Pathogenic | Likely Benign | 0.147 | Likely Benign | -2.86 | Deleterious | 0.009 | Benign | 0.004 | Benign | 3.91 | Benign | 0.00 | Affected | 0.0719 | 0.5354 | -2 | -3 | 8.0 | -0.94 | ||||||||||||||||||||||||||||||||||||||||
| c.3948T>A | N1316K 2D AIThe SynGAP1 missense variant N1316K is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33451822‑T‑A). 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; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none). Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.899122 | Disordered | 0.971970 | Binding | 0.380 | 0.885 | 0.750 | 6-33451822-T-A | -3.815 | Likely Benign | 0.699 | Likely Pathogenic | Likely Benign | 0.044 | Likely Benign | -3.27 | Deleterious | 0.414 | Benign | 0.063 | Benign | 4.00 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2065 | 0.5500 | 0 | 1 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||
| c.3948T>G | N1316K 2D AIThe SynGAP1 missense variant N1316K is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33451822‑T‑G). 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; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign + 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 is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.899122 | Disordered | 0.971970 | Binding | 0.380 | 0.885 | 0.750 | 6-33451822-T-G | -3.815 | Likely Benign | 0.699 | Likely Pathogenic | Likely Benign | 0.044 | Likely Benign | -3.27 | Deleterious | 0.414 | Benign | 0.063 | Benign | 4.00 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2065 | 0.5500 | 0 | 1 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||
| c.3958C>A | P1320T 2D AIThe SynGAP1 missense variant P1320T is reported in gnomAD (variant ID 6‑33451832‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: the majority (REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a benign effect, while a minority (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT) predict pathogenicity. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a benign impact. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.946297 | Binding | 0.510 | 0.833 | 0.750 | 6-33451832-C-A | 1 | 6.42e-7 | -5.355 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -0.86 | Neutral | 0.994 | Probably Damaging | 0.981 | Probably Damaging | 4.21 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1787 | 0.6392 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||
| c.3958C>G | P1320A 2D AIThe SynGAP1 missense variant P1320A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for P1320A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.946297 | Binding | 0.510 | 0.833 | 0.750 | -4.099 | Likely Benign | 0.055 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -0.92 | Neutral | 0.980 | Probably Damaging | 0.956 | Probably Damaging | 4.25 | Benign | 0.00 | Affected | 0.3517 | 0.5583 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3958C>T | P1320S 2D AIThe SynGAP1 missense variant P1320S is listed in ClinVar (ID 469160.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451832‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this is not in conflict with the ClinVar “Uncertain” status. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.946297 | Binding | 0.510 | 0.833 | 0.750 | Uncertain | 1 | 6-33451832-C-T | 2 | 1.28e-6 | -4.928 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.69 | Neutral | 0.980 | Probably Damaging | 0.968 | Probably Damaging | 4.25 | Benign | 0.00 | Affected | 3.77 | 5 | 0.3390 | 0.5814 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||
| c.3959C>A | P1320H 2D AIThe SynGAP1 missense variant P1320H is listed in gnomAD (ID 6‑33451833‑C‑A) and has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.946297 | Binding | 0.510 | 0.833 | 0.750 | 6-33451833-C-A | 2 | 1.29e-6 | -6.296 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.114 | Likely Benign | -1.05 | Neutral | 0.998 | Probably Damaging | 0.990 | Probably Damaging | 4.17 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1955 | 0.5461 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||
| c.3959C>G | P1320R 2D AIThe SynGAP1 missense variant P1320R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.946297 | Binding | 0.510 | 0.833 | 0.750 | -5.204 | Likely Benign | 0.160 | Likely Benign | Likely Benign | 0.142 | Likely Benign | -1.39 | Neutral | 0.994 | Probably Damaging | 0.987 | Probably Damaging | 4.25 | Benign | 0.00 | Affected | 0.1558 | 0.4052 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3959C>T | P1320L 2D AIThe SynGAP1 missense variant P1320L is reported in gnomAD (variant ID 6‑33451833‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta’s protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign effect for P1320L, and this conclusion is not contradicted by any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.946297 | Binding | 0.510 | 0.833 | 0.750 | 6-33451833-C-T | -5.187 | Likely Benign | 0.094 | Likely Benign | Likely Benign | 0.115 | Likely Benign | -1.22 | Neutral | 0.994 | Probably Damaging | 0.981 | Probably Damaging | 4.18 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2622 | 0.6744 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||
| c.2359C>A | P787T 2D AISynGAP1 missense variant P787T is listed in ClinVar as benign (ClinVar ID 862728.0) and is present in gnomAD (6‑33442911‑C‑A). Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions are made by AlphaMissense‑Default, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and the SGM‑Consensus score. The high‑accuracy AlphaMissense‑Optimized result is benign, whereas the SGM‑Consensus, derived from a 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 majority of evidence points to a pathogenic effect, which contradicts the ClinVar benign classification. Thus, the variant is most likely pathogenic, contradicting the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.901269 | Disordered | 0.613211 | Binding | 0.377 | 0.899 | 0.750 | Likely Benign | 1 | 6-33442911-C-A | 17 | 1.05e-5 | -4.813 | Likely Benign | 0.603 | Likely Pathogenic | Likely Benign | 0.258 | Likely Benign | -4.40 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.46 | Pathogenic | 0.01 | Affected | 3.64 | 6 | 0.1577 | 0.5629 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||
| c.2359C>G | P787A 2D AIThe SynGAP1 P787A missense variant 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 a majority (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM) predict a pathogenic impact. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta results are unavailable. Overall, the balance of evidence—five pathogenic versus three benign predictions, with the SGM Consensus supporting pathogenicity—suggests that the variant is most likely pathogenic. 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. | SH3-binding motif | 0.901269 | Disordered | 0.613211 | Binding | 0.377 | 0.899 | 0.750 | -4.542 | Likely Benign | 0.451 | Ambiguous | Likely Benign | 0.242 | Likely Benign | -4.23 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.48 | Pathogenic | 0.02 | Affected | 0.3425 | 0.4444 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2359C>T | P787S 2D AIThe SynGAP1 P787S variant is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33442911‑C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic majority. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.901269 | Disordered | 0.613211 | Binding | 0.377 | 0.899 | 0.750 | Uncertain | 1 | 6-33442911-C-T | 3 | 1.86e-6 | -4.203 | Likely Benign | 0.564 | Ambiguous | Likely Benign | 0.221 | Likely Benign | -3.81 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.48 | Pathogenic | 0.02 | Affected | 3.64 | 6 | 0.3420 | 0.4675 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||
| c.2360C>A | P787H 2D AIThe SynGAP1 missense variant P787H has no ClinVar entry and is not listed in gnomAD. Prediction tools that classify the variant as benign include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default—predict it to be pathogenic. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic” (3 pathogenic votes versus 1 benign). High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains pathogenic; Foldetta results are unavailable. Overall, the majority of predictions lean toward pathogenicity, but this is contradicted by the benign call from AlphaMissense‑Optimized. Because ClinVar has no reported status, there is no conflict with existing clinical annotations. Thus, the variant is most likely pathogenic based on the prevailing computational evidence, though one high‑accuracy tool suggests a benign effect. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.901269 | Disordered | 0.613211 | Binding | 0.377 | 0.899 | 0.750 | -5.819 | Likely Benign | 0.691 | Likely Pathogenic | Likely Benign | 0.308 | Likely Benign | -4.96 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.44 | Pathogenic | 0.01 | Affected | 0.1790 | 0.4061 | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||||
| c.2360C>G | P787R 2D AIThe SynGAP1 missense variant P787R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of conventional tools lean toward pathogenicity, whereas the single high‑accuracy tool indicates benign and the consensus is unresolved. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.901269 | Disordered | 0.613211 | Binding | 0.377 | 0.899 | 0.750 | -5.013 | Likely Benign | 0.784 | Likely Pathogenic | Likely Benign | 0.268 | Likely Benign | -4.41 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.50 | Benign | 0.03 | Affected | 0.1373 | 0.2741 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2360C>T | P787L 2D AIThe SynGAP1 missense variant P787L is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that classify the variant as benign include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default—predict it to be pathogenic. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains pathogenic; Foldetta results are unavailable. Overall, the majority of predictions (seven pathogenic vs. three benign) lean toward pathogenicity, and this conclusion is not contradicted by any ClinVar annotation. Thus, the variant is most likely pathogenic based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.901269 | Disordered | 0.613211 | Binding | 0.377 | 0.899 | 0.750 | -3.924 | Likely Benign | 0.747 | Likely Pathogenic | Likely Benign | 0.256 | Likely Benign | -5.89 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.45 | Pathogenic | 0.01 | Affected | 0.2254 | 0.6034 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||||
| c.3313C>G | R1105G 2D AIThe SynGAP1 missense variant R1105G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Consensus from standard in silico predictors shows a split: benign calls come from REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessment gives a benign prediction from AlphaMissense‑Optimized, a pathogenic consensus from the SGM method (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and no result from Foldetta, so its stability impact is unavailable. Overall, the majority of tools lean toward a benign effect, but the high‑accuracy consensus is conflicted. Thus, the variant is most likely benign based on the bulk of predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.901269 | Disordered | 0.954396 | Binding | 0.330 | 0.863 | 0.875 | -4.900 | Likely Benign | 0.438 | Ambiguous | Likely Benign | 0.146 | Likely Benign | -3.48 | Deleterious | 0.677 | Possibly Damaging | 0.168 | Benign | 2.45 | Pathogenic | 0.09 | Tolerated | 0.3293 | 0.4269 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3313C>T | R1105W 2D AIThe SynGAP1 missense variant R1105W is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443865‑C‑T). Prediction tools show mixed results: benign calls come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The AlphaMissense‑Default tool remains uncertain. A consensus analysis (SGM) that aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic majority. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, whereas the SGM Consensus predicts pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for R1105W, which does not conflict with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.901269 | Disordered | 0.954396 | Binding | 0.330 | 0.863 | 0.875 | Uncertain | 1 | 6-33443865-C-T | 6 | 3.93e-6 | -6.911 | Likely Benign | 0.488 | Ambiguous | Likely Benign | 0.133 | Likely Benign | -4.34 | Deleterious | 0.999 | Probably Damaging | 0.696 | Possibly Damaging | 2.42 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.1154 | 0.4117 | -3 | 2 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||
| c.3314G>A | R1105Q 2D AIThe SynGAP1 missense variant R1105Q is listed in ClinVar (ID 1803693.0) with an uncertain significance status and is present in gnomAD (variant ID 6‑33443866‑G‑A). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated outcomes. Only polyPhen‑2 HumDiv predicts a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments further support this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates the variant is most likely benign, which is consistent with its ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.901269 | Disordered | 0.954396 | Binding | 0.330 | 0.863 | 0.875 | Uncertain | 2 | 6-33443866-G-A | 3 | 1.96e-6 | -3.666 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -1.21 | Neutral | 0.958 | Probably Damaging | 0.194 | Benign | 2.50 | Benign | 0.16 | Tolerated | 3.77 | 5 | 0.2942 | 0.3174 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.3314G>C | R1105P 2D AIThe SynGAP1 missense variant R1105P is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leans pathogenic. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of predictions (six benign vs. two pathogenic) suggest a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current predictive evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.901269 | Disordered | 0.954396 | Binding | 0.330 | 0.863 | 0.875 | -3.325 | Likely Benign | 0.425 | Ambiguous | Likely Benign | 0.149 | Likely Benign | -3.22 | Deleterious | 0.007 | Benign | 0.006 | Benign | 2.44 | Pathogenic | 0.08 | Tolerated | 0.2031 | 0.5101 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3314G>T | R1105L 2D AIThe SynGAP1 missense variant R1105L is not reported in ClinVar and is present in gnomAD (ID 6‑33443866‑G‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, and FATHMM. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized classifies the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this residue, so its stability impact is unavailable. Overall, the balance of evidence leans toward a benign effect, with no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.901269 | Disordered | 0.954396 | Binding | 0.330 | 0.863 | 0.875 | 6-33443866-G-T | -4.031 | Likely Benign | 0.459 | Ambiguous | Likely Benign | 0.125 | Likely Benign | -3.51 | Deleterious | 0.677 | Possibly Damaging | 0.168 | Benign | 2.46 | Pathogenic | 0.19 | Tolerated | 3.77 | 5 | 0.1734 | 0.5373 | -2 | -3 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||
| c.3967C>A | P1323T 2D AIThe SynGAP1 missense variant P1323T is reported in gnomAD (ID 6‑33451841‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as tolerated or benign. Only two algorithms—polyPhen‑2 HumDiv and SIFT—suggest a damaging impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not conflict with any ClinVar classification, as none is present. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.901269 | Disordered | 0.907659 | Binding | 0.489 | 0.814 | 0.875 | 6-33451841-C-A | -6.296 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.064 | Likely Benign | -0.37 | Neutral | 0.588 | Possibly Damaging | 0.227 | Benign | 3.95 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1988 | 0.5161 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3967C>G | P1323A 2D AIThe SynGAP1 missense variant P1323A is catalogued in gnomAD (ID 6‑33451841‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated outcomes, while the single pathogenic signal comes from SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign classification. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is likely benign; Foldetta results are not available. Overall, the consensus of available predictions points to a benign impact for P1323A, and this conclusion is not contradicted by ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.901269 | Disordered | 0.907659 | Binding | 0.489 | 0.814 | 0.875 | 6-33451841-C-G | -4.802 | Likely Benign | 0.053 | Likely Benign | Likely Benign | 0.040 | Likely Benign | -0.73 | Neutral | 0.011 | Benign | 0.017 | Benign | 3.92 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3743 | 0.3976 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||
| c.3967C>T | P1323S 2D AIThe SynGAP1 missense variant P1323S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.901269 | Disordered | 0.907659 | Binding | 0.489 | 0.814 | 0.875 | -6.007 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -0.52 | Neutral | 0.588 | Possibly Damaging | 0.122 | Benign | 3.88 | Benign | 0.00 | Affected | 0.3758 | 0.4371 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3968C>A | P1323Q 2D AIThe SynGAP1 missense variant P1323Q is reported in gnomAD (ID 6‑33451842‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 HumDiv and SIFT predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that P1323Q is most likely benign, and this conclusion is not contradicted by any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.901269 | Disordered | 0.907659 | Binding | 0.489 | 0.814 | 0.875 | 6-33451842-C-A | -6.134 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.033 | Likely Benign | -0.85 | Neutral | 0.712 | Possibly Damaging | 0.328 | Benign | 3.82 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1791 | 0.4657 | -1 | 0 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||
| c.3968C>G | P1323R 2D AIThe SynGAP1 missense variant P1323R is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that P1323R is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.901269 | Disordered | 0.907659 | Binding | 0.489 | 0.814 | 0.875 | -5.785 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -0.67 | Neutral | 0.002 | Benign | 0.003 | Benign | 3.82 | Benign | 0.00 | Affected | 0.1725 | 0.3015 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3968C>T | P1323L 2D AIThe SynGAP1 missense variant P1323L is reported in gnomAD (variant ID 6‑33451842‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority‑vote) is benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.901269 | Disordered | 0.907659 | Binding | 0.489 | 0.814 | 0.875 | 6-33451842-C-T | 3 | 1.95e-6 | -6.005 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -1.04 | Neutral | 0.414 | Benign | 0.175 | Benign | 3.82 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2650 | 0.6052 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| c.3229A>C | T1077P 2D AIThe SynGAP1 missense variant T1077P is reported in ClinVar as “Not submitted” and is not present in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and no Foldetta stability assessment is available. High‑accuracy evidence shows AlphaMissense‑Optimized classifying the variant as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicating a likely benign outcome, and Foldetta results are unavailable. Overall, the majority of predictions and the high‑accuracy consensus point to a benign impact. This conclusion is not contradicted by ClinVar status, which has no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.988141 | Binding | 0.329 | 0.892 | 0.750 | -2.436 | Likely Benign | 0.345 | Ambiguous | Likely Benign | 0.164 | Likely Benign | -0.91 | Neutral | 0.970 | Probably Damaging | 0.787 | Possibly Damaging | 4.16 | Benign | 0.04 | Affected | 0.1876 | 0.4788 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3229A>G | T1077A 2D AIThe SynGAP1 missense variant T1077A is catalogued in gnomAD (ID 6‑33443781‑A‑G) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized returns a benign prediction, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.988141 | Binding | 0.329 | 0.892 | 0.750 | 6-33443781-A-G | -3.303 | Likely Benign | 0.280 | Likely Benign | Likely Benign | 0.153 | Likely Benign | -0.60 | Neutral | 0.288 | Benign | 0.194 | Benign | 4.25 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.3373 | 0.4393 | 0 | 1 | 2.5 | -30.03 | ||||||||||||||||||||||||||||||||||||
| c.3229A>T | T1077S 2D AIThe SynGAP1 missense variant T1077S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.988141 | Binding | 0.329 | 0.892 | 0.750 | -2.929 | Likely Benign | 0.201 | Likely Benign | Likely Benign | 0.114 | Likely Benign | -0.45 | Neutral | 0.068 | Benign | 0.025 | Benign | 4.32 | Benign | 0.06 | Tolerated | 0.2788 | 0.4635 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3230C>A | T1077K 2D AIThe SynGAP1 missense variant T1077K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are not available. Overall, the majority of evidence—including the SGM‑Consensus—suggests a benign impact, and this conclusion does not contradict the absence of a ClinVar entry. Thus, based on current predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.988141 | Binding | 0.329 | 0.892 | 0.750 | -4.196 | Likely Benign | 0.928 | Likely Pathogenic | Ambiguous | 0.110 | Likely Benign | -1.44 | Neutral | 0.818 | Possibly Damaging | 0.460 | Possibly Damaging | 4.21 | Benign | 0.03 | Affected | 0.1176 | 0.3968 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||||
| c.3230C>G | T1077R 2D AIThe SynGAP1 missense variant T1077R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), which collectively classify the variant as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and no Foldetta stability assessment is available. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.988141 | Binding | 0.329 | 0.892 | 0.750 | -4.109 | Likely Benign | 0.890 | Likely Pathogenic | Ambiguous | 0.121 | Likely Benign | -1.01 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 4.18 | Benign | 0.03 | Affected | 0.1028 | 0.3491 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||||||||||||
| c.3230C>T | T1077I 2D AIThe SynGAP1 missense variant T1077I is listed in gnomAD (ID 6‑33443782‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions (REVEL, PROVEAN, SIFT, ESM1b, FATHMM) and pathogenic predictions (PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, AlphaMissense‑Default). The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to a likely benign verdict (3 benign vs. 1 pathogenic). High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized returns an uncertain result, while Foldetta (combining FoldX‑MD and Rosetta outputs) is not available for this residue. Taken together, the majority of evidence points toward a benign effect. This conclusion is consistent with the absence of a ClinVar pathogenic classification, and there is no contradiction with existing database annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.988141 | Binding | 0.329 | 0.892 | 0.750 | 6-33443782-C-T | 1 | 6.25e-7 | -4.710 | Likely Benign | 0.919 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | -1.11 | Neutral | 0.970 | Probably Damaging | 0.787 | Possibly Damaging | 4.19 | Benign | 0.33 | Tolerated | 3.77 | 5 | 0.1135 | 0.5870 | -1 | 0 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||||||
| c.3385C>A | L1129M 2D AIThe SynGAP1 missense variant L1129M 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, and 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 for L1129M, and this conclusion does not conflict with ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.876543 | Binding | 0.339 | 0.909 | 0.875 | -4.233 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.295 | Likely Benign | -0.59 | Neutral | 0.918 | Possibly Damaging | 0.697 | Possibly Damaging | 5.43 | Benign | 0.00 | Affected | 0.1100 | 0.4236 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3385C>G | L1129V 2D AIThe SynGAP1 missense variant L1129V 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. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.876543 | Binding | 0.339 | 0.909 | 0.875 | -3.595 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.262 | Likely Benign | -0.87 | Neutral | 0.393 | Benign | 0.187 | Benign | 5.46 | Benign | 0.00 | Affected | 0.1814 | 0.3804 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3386T>A | L1129Q 2D AIThe SynGAP1 missense variant L1129Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.876543 | Binding | 0.339 | 0.909 | 0.875 | -3.684 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.453 | Likely Benign | -1.63 | Neutral | 0.846 | Possibly Damaging | 0.525 | Possibly Damaging | 5.49 | Benign | 0.00 | Affected | 0.1278 | 0.1436 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3386T>C | L1129P 2D AIThe SynGAP1 missense variant L1129P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence—including high‑accuracy tools—points to a benign effect, and this conclusion does not contradict the current ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.876543 | Binding | 0.339 | 0.909 | 0.875 | Uncertain | 2 | -2.991 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.432 | Likely Benign | 0.27 | Neutral | 0.971 | Probably Damaging | 0.773 | Possibly Damaging | 5.44 | Benign | 0.00 | Affected | 4.32 | 4 | 0.3017 | 0.2231 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||
| c.3386T>G | L1129R 2D AIThe SynGAP1 missense variant L1129R 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 a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.876543 | Binding | 0.339 | 0.909 | 0.875 | -2.613 | Likely Benign | 0.442 | Ambiguous | Likely Benign | 0.376 | Likely Benign | -1.68 | Neutral | 0.005 | Benign | 0.007 | Benign | 5.48 | Benign | 0.00 | Affected | 0.1334 | 0.1636 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3388A>C | K1130Q 2D AIThe SynGAP1 missense variant K1130Q is reported in gnomAD (ID 6‑33443940‑A‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (derived from the 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 preponderance of evidence from both general and high‑accuracy predictors points to a benign impact, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.863782 | Binding | 0.350 | 0.904 | 0.750 | 6-33443940-A-C | -3.548 | Likely Benign | 0.529 | Ambiguous | Likely Benign | 0.337 | Likely Benign | -1.25 | Neutral | 0.818 | Possibly Damaging | 0.355 | Benign | 5.44 | Benign | 0.00 | Affected | 4.32 | 4 | 0.4964 | 0.1756 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||||||||
| c.3388A>G | K1130E 2D AIThe SynGAP1 missense variant K1130E is not reported in ClinVar (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. Those 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) yields a Likely Benign classification, while AlphaMissense‑Optimized remains Uncertain. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of tools and the SGM consensus support a benign impact, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.863782 | Binding | 0.350 | 0.904 | 0.750 | -4.998 | Likely Benign | 0.946 | Likely Pathogenic | Ambiguous | 0.422 | Likely Benign | -1.23 | Neutral | 0.649 | Possibly Damaging | 0.266 | Benign | 5.45 | Benign | 0.00 | Affected | 0.4251 | 0.1876 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3389A>C | K1130T 2D AIThe SynGAP1 missense variant K1130T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) which classifies it as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized result is Uncertain, and the Foldetta protein‑folding stability assessment is unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is 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 | 0.903857 | Disordered | 0.863782 | Binding | 0.350 | 0.904 | 0.750 | -3.550 | Likely Benign | 0.829 | Likely Pathogenic | Ambiguous | 0.397 | Likely Benign | -1.38 | Neutral | 0.481 | Possibly Damaging | 0.157 | Benign | 5.47 | Benign | 0.00 | Affected | 0.2572 | 0.4349 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||||||
| c.3389A>G | K1130R 2D AIThe SynGAP1 missense variant K1130R is reported in gnomAD (variant ID 6‑33443941‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority‑vote) is benign; Foldetta results are 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 | 0.903857 | Disordered | 0.863782 | Binding | 0.350 | 0.904 | 0.750 | 6-33443941-A-G | -2.163 | Likely Benign | 0.155 | Likely Benign | Likely Benign | 0.187 | Likely Benign | -0.94 | Neutral | 0.014 | Benign | 0.008 | Benign | 5.44 | Benign | 0.00 | Affected | 4.32 | 4 | 0.5096 | 0.2074 | Weaken | 2 | 3 | -0.6 | 28.01 | |||||||||||||||||||||||||||||||||||
| c.3389A>T | K1130M 2D AIThe SynGAP1 K1130M 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 the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which collectively suggest a likely benign outcome. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no available prediction for this variant. Overall, the balance of evidence leans toward a benign classification, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for K1130M. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.863782 | Binding | 0.350 | 0.904 | 0.750 | -4.844 | Likely Benign | 0.858 | Likely Pathogenic | Ambiguous | 0.476 | Likely Benign | -1.62 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 5.42 | Benign | 0.00 | Affected | 0.1703 | 0.4407 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.3390G>C | K1130N 2D AIThe SynGAP1 missense variant K1130N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) which classifies it as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no available prediction for this variant. Overall, the majority of evidence points to a benign impact. The variant’s predicted benign status does not contradict ClinVar, as no ClinVar entry exists. Thus, based on current computational predictions, the K1130N variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.863782 | Binding | 0.350 | 0.904 | 0.750 | -4.822 | Likely Benign | 0.946 | Likely Pathogenic | Ambiguous | 0.336 | Likely Benign | -1.02 | Neutral | 0.818 | Possibly Damaging | 0.287 | Benign | 5.43 | Benign | 0.00 | Affected | 0.4119 | 0.2393 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3390G>T | K1130N 2D AIThe SynGAP1 missense variant K1130N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) which classifies it as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no available prediction for this variant. Overall, the majority of evidence points to a benign impact. The variant’s predicted benign status does not contradict ClinVar, as no ClinVar entry exists. Thus, based on current computational predictions, the K1130N variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.863782 | Binding | 0.350 | 0.904 | 0.750 | -4.822 | Likely Benign | 0.946 | Likely Pathogenic | Ambiguous | 0.336 | Likely Benign | -1.02 | Neutral | 0.818 | Possibly Damaging | 0.287 | Benign | 5.43 | Benign | 0.00 | Affected | 0.4119 | 0.2393 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3406C>A | Q1136K 2D AIThe SynGAP1 missense variant Q1136K is listed in gnomAD (ID 6‑33443958‑C‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.775584 | Binding | 0.321 | 0.884 | 0.875 | 6-33443958-C-A | -5.698 | Likely Benign | 0.397 | Ambiguous | Likely Benign | 0.236 | Likely Benign | -1.43 | Neutral | 0.625 | Possibly Damaging | 0.258 | Benign | 5.55 | Benign | 0.17 | Tolerated | 4.32 | 2 | 0.1891 | 0.4841 | 1 | 1 | -0.4 | 0.04 | ||||||||||||||||||||||||||||||||||||
| c.3406C>G | Q1136E 2D AIThe SynGAP1 missense variant Q1136E is catalogued in gnomAD (ID 6‑33443958‑C‑G) and has no ClinVar entry. All evaluated in silico predictors uniformly classify the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic or likely pathogenic outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method, did not provide a result for this variant. Overall, the computational evidence strongly supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.775584 | Binding | 0.321 | 0.884 | 0.875 | 6-33443958-C-G | 4 | 2.71e-6 | -6.677 | Likely Benign | 0.277 | Likely Benign | Likely Benign | 0.209 | Likely Benign | -1.13 | Neutral | 0.022 | Benign | 0.026 | Benign | 5.46 | Benign | 0.11 | Tolerated | 4.32 | 2 | 0.1487 | 0.2886 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||
| c.3407A>C | Q1136P 2D AIThe SynGAP1 missense variant Q1136P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q1136P, and 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 | 0.775584 | Binding | 0.321 | 0.884 | 0.875 | -5.067 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.364 | Likely Benign | -1.06 | Neutral | 0.961 | Probably Damaging | 0.745 | Possibly Damaging | 5.42 | Benign | 0.03 | Affected | 0.2188 | 0.5344 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3407A>G | Q1136R 2D AIThe SynGAP1 missense variant Q1136R 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 high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also leans benign; Foldetta data are not available. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a benign classification, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.775584 | Binding | 0.321 | 0.884 | 0.875 | -5.526 | Likely Benign | 0.478 | Ambiguous | Likely Benign | 0.173 | Likely Benign | -1.42 | Neutral | 0.801 | Possibly Damaging | 0.506 | Possibly Damaging | 6.28 | Benign | 0.09 | Tolerated | 0.1527 | 0.3073 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.3407A>T | Q1136L 2D AIThe SynGAP1 missense variant Q1136L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign effect. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is benign, and this 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 | 0.903857 | Disordered | 0.775584 | Binding | 0.321 | 0.884 | 0.875 | -6.020 | Likely Benign | 0.203 | Likely Benign | Likely Benign | 0.242 | Likely Benign | -2.42 | Neutral | 0.005 | Benign | 0.026 | Benign | 5.44 | Benign | 0.23 | Tolerated | 0.0861 | 0.6395 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3408G>C | Q1136H 2D AIThe SynGAP1 missense variant Q1136H is not reported 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 likely benign. Foldetta results are not available, so they do not influence the assessment. Overall, the majority of evidence points to a benign effect for Q1136H, and 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 | 0.775584 | Binding | 0.321 | 0.884 | 0.875 | -5.658 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.347 | Likely Benign | -1.98 | Neutral | 0.989 | Probably Damaging | 0.879 | Possibly Damaging | 5.42 | Benign | 0.03 | Affected | 4.32 | 2 | 0.1482 | 0.4637 | 0 | 3 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||
| c.3408G>T | Q1136H 2D AIThe SynGAP1 missense variant Q1136H is reported in gnomAD (variant ID 6-33443960‑G‑T) 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, 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. No Foldetta stability analysis is available, so it does not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.775584 | Binding | 0.321 | 0.884 | 0.875 | 6-33443960-G-T | -5.658 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.347 | Likely Benign | -1.98 | Neutral | 0.989 | Probably Damaging | 0.879 | Possibly Damaging | 5.42 | Benign | 0.03 | Affected | 4.32 | 2 | 0.1482 | 0.4637 | 0 | 3 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||
| 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.2812G>A | G938R 2D AIThe SynGAP1 missense variant G938R is listed in ClinVar (ID 1019898.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence (seven benign versus three pathogenic predictions) supports a benign classification. This consensus does not contradict the ClinVar “Uncertain” designation, which remains unresolved. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.949795 | Binding | 0.318 | 0.883 | 0.625 | Uncertain | 1 | -5.271 | Likely Benign | 0.732 | Likely Pathogenic | Likely Benign | 0.141 | Likely Benign | -1.11 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.74 | Benign | 0.36 | Tolerated | 3.77 | 5 | 0.0924 | 0.3614 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.2812G>C | G938R 2D AIThe SynGAP1 missense variant G938R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Benign” call. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.949795 | Binding | 0.318 | 0.883 | 0.625 | -5.271 | Likely Benign | 0.732 | Likely Pathogenic | Likely Benign | 0.141 | Likely Benign | -1.11 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.74 | Benign | 0.36 | Tolerated | 3.77 | 5 | 0.0924 | 0.3614 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.2812G>T | G938W 2D AIThe SynGAP1 missense variant G938W is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs. four benign) indicate that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar annotation exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.905695 | Disordered | 0.949795 | Binding | 0.318 | 0.883 | 0.625 | -8.763 | Likely Pathogenic | 0.604 | Likely Pathogenic | Likely Benign | 0.194 | Likely Benign | -1.71 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.70 | Benign | 0.04 | Affected | 0.0762 | 0.4008 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||||||
| c.2813G>A | G938E 2D AIThe SynGAP1 missense variant G938E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The variant’s predicted benign status does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.949795 | Binding | 0.318 | 0.883 | 0.625 | -5.394 | Likely Benign | 0.577 | Likely Pathogenic | Likely Benign | 0.112 | Likely Benign | -1.40 | Neutral | 0.997 | Probably Damaging | 0.979 | Probably Damaging | 2.75 | Benign | 0.28 | Tolerated | 0.1370 | 0.3720 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.2813G>C | G938A 2D AIThe SynGAP1 missense variant G938A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta’s protein‑folding stability analysis is not available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.949795 | Binding | 0.318 | 0.883 | 0.625 | -5.068 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.095 | Likely Benign | -0.41 | Neutral | 0.979 | Probably Damaging | 0.821 | Possibly Damaging | 2.80 | Benign | 0.82 | Tolerated | 0.3462 | 0.4948 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2813G>T | G938V 2D AIThe SynGAP1 missense variant G938V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that G938V is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.949795 | Binding | 0.318 | 0.883 | 0.625 | -6.112 | Likely Benign | 0.153 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -0.81 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.83 | Benign | 0.31 | Tolerated | 0.1230 | 0.3811 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3337G>A | G1113S 2D AIThe SynGAP1 missense variant G1113S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | -3.601 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -0.51 | Neutral | 0.905 | Possibly Damaging | 0.538 | Possibly Damaging | 2.58 | Benign | 0.35 | Tolerated | 0.2499 | 0.5309 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3337G>C | G1113R 2D AIThe SynGAP1 missense variant G1113R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign based on current predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | -4.765 | Likely Benign | 0.618 | Likely Pathogenic | Likely Benign | 0.063 | Likely Benign | -1.54 | Neutral | 0.986 | Probably Damaging | 0.848 | Possibly Damaging | 2.65 | Benign | 0.64 | Tolerated | 0.0939 | 0.4426 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3337G>T | G1113C 2D AIThe SynGAP1 missense variant G1113C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. ESM1b is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | -7.917 | In-Between | 0.128 | Likely Benign | Likely Benign | 0.130 | Likely Benign | -1.64 | Neutral | 0.999 | Probably Damaging | 0.917 | Probably Damaging | 2.50 | Benign | 0.06 | Tolerated | 0.1325 | 0.4956 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.3338G>A | G1113D 2D AIThe SynGAP1 missense variant G1113D is listed in ClinVar with an uncertain significance (ClinVar ID 2766136.0) and is present in gnomAD (variant ID 6‑33443890‑G‑A). Functional prediction tools that agree on a benign outcome include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—all of which classify the substitution as benign. AlphaMissense‑Optimized also predicts a benign effect, whereas AlphaMissense‑Default remains uncertain. No tool predicts a pathogenic effect. The high‑accuracy consensus methods reinforce this benign assessment: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” and AlphaMissense‑Optimized also indicates benign. Foldetta, a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the collective evidence strongly supports a benign impact, and this conclusion does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | Uncertain | 1 | 6-33443890-G-A | -4.638 | Likely Benign | 0.354 | Ambiguous | Likely Benign | 0.061 | Likely Benign | -0.72 | Neutral | 0.029 | Benign | 0.017 | Benign | 2.58 | Benign | 0.34 | Tolerated | 4.32 | 2 | 0.1872 | 0.2452 | -1 | 1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||
| c.3338G>C | G1113A 2D AIThe SynGAP1 missense variant G1113A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of tools, including the high‑accuracy predictors, indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | -4.714 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -1.15 | Neutral | 0.798 | Possibly Damaging | 0.433 | Benign | 2.58 | Benign | 0.50 | Tolerated | 0.3444 | 0.5342 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3338G>T | G1113V 2D AIThe SynGAP1 missense variant G1113V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | -5.708 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -1.98 | Neutral | 0.827 | Possibly Damaging | 0.456 | Possibly Damaging | 2.53 | Benign | 0.11 | Tolerated | 0.1333 | 0.4224 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3340A>C | S1114R 2D AIThe SynGAP1 missense variant S1114R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a likely benign outcome. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence supports a benign classification, and this conclusion does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | -5.718 | Likely Benign | 0.696 | Likely Pathogenic | Likely Benign | 0.037 | Likely Benign | -1.52 | Neutral | 0.157 | Benign | 0.153 | Benign | 2.68 | Benign | 0.03 | Affected | 0.0999 | 0.3649 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3340A>G | S1114G 2D AIThe SynGAP1 missense variant S1114G is reported in gnomAD (ID 6‑33443892‑A‑G) but has no ClinVar entry. All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | 6-33443892-A-G | -3.894 | Likely Benign | 0.064 | Likely Benign | Likely Benign | 0.080 | Likely Benign | -1.33 | Neutral | 0.000 | Benign | 0.000 | Benign | 2.75 | Benign | 0.08 | Tolerated | 4.32 | 2 | 0.2414 | 0.4914 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||||
| c.3340A>T | S1114C 2D AIThe SynGAP1 missense variant S1114C is reported in gnomAD (ID 6‑33443892‑A‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | 6-33443892-A-T | -8.600 | Likely Pathogenic | 0.091 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -1.77 | Neutral | 0.938 | Possibly Damaging | 0.552 | Possibly Damaging | 2.63 | Benign | 0.01 | Affected | 4.32 | 2 | 0.1101 | 0.5675 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||
| c.3341G>A | S1114N 2D AIThe SynGAP1 missense variant S1114N is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool predicts pathogenicity. The high‑accuracy consensus, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), also reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | -6.089 | Likely Benign | 0.106 | Likely Benign | Likely Benign | 0.047 | Likely Benign | -0.51 | Neutral | 0.071 | Benign | 0.058 | Benign | 2.71 | Benign | 0.06 | Tolerated | 0.1416 | 0.4610 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| c.3341G>C | S1114T 2D AIThe SynGAP1 missense variant S1114T is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | -5.919 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -0.87 | Neutral | 0.071 | Benign | 0.078 | Benign | 2.69 | Benign | 0.10 | Tolerated | 0.1424 | 0.6095 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3341G>T | S1114I 2D AIThe SynGAP1 missense variant S1114I is reported in gnomAD (ID 6‑33443893‑G‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | 6-33443893-G-T | -6.718 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.023 | Likely Benign | -1.86 | Neutral | 0.570 | Possibly Damaging | 0.292 | Benign | 2.65 | Benign | 0.02 | Affected | 4.32 | 2 | 0.1159 | 0.5276 | -2 | -1 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||
| c.3342C>A | S1114R 2D AIThe SynGAP1 missense variant S1114R is not reported in ClinVar and has no entry in gnomAD. Prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. Only two tools predict pathogenicity: SIFT and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of predictions, including the high‑accuracy tools, suggest the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | -5.718 | Likely Benign | 0.696 | Likely Pathogenic | Likely Benign | 0.035 | Likely Benign | -1.52 | Neutral | 0.157 | Benign | 0.153 | Benign | 2.68 | Benign | 0.03 | Affected | 0.0999 | 0.3649 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3342C>G | S1114R 2D AIThe SynGAP1 missense variant S1114R is not reported in ClinVar and has no entry in gnomAD. Prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. Only two tools predict pathogenicity: SIFT and AlphaMissense‑Default. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of predictions, including the high‑accuracy tools, suggest the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | -5.718 | Likely Benign | 0.696 | Likely Pathogenic | Likely Benign | 0.035 | Likely Benign | -1.52 | Neutral | 0.157 | Benign | 0.153 | Benign | 2.68 | Benign | 0.03 | Affected | 0.0999 | 0.3649 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.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.3949G>A | G1317S 2D AIThe SynGAP1 missense variant G1317S is listed in ClinVar with an uncertain significance and is present in the gnomAD database. 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 score (Likely Benign). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized returns a benign prediction, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the computational evidence overwhelmingly 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 | 0.908098 | Disordered | 0.971158 | Binding | 0.385 | 0.879 | 0.750 | Conflicting | 3 | 6-33451823-G-A | 1 | 6.26e-7 | -3.522 | Likely Benign | 0.145 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -2.45 | Neutral | 0.127 | Benign | 0.045 | Benign | 4.08 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2546 | 0.4935 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||
| c.3949G>C | G1317R 2D AIThe SynGAP1 missense variant G1317R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability prediction is available for this variant. Overall, the computational evidence overwhelmingly suggests that G1317R is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.971158 | Binding | 0.385 | 0.879 | 0.750 | -3.646 | Likely Benign | 0.619 | Likely Pathogenic | Likely Benign | 0.176 | Likely Benign | -2.17 | Neutral | 0.834 | Possibly Damaging | 0.307 | Benign | 4.04 | Benign | 0.00 | Affected | 0.1018 | 0.3791 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3949G>T | G1317C 2D AIThe SynGAP1 missense variant G1317C is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33451823‑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, and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, while Foldetta results are unavailable. Overall, the majority of reliable predictions favor a benign impact, and this is consistent with the lack of ClinVar evidence. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.908098 | Disordered | 0.971158 | Binding | 0.385 | 0.879 | 0.750 | 6-33451823-G-T | -5.850 | Likely Benign | 0.342 | Ambiguous | Likely Benign | 0.162 | Likely Benign | -3.83 | Deleterious | 0.939 | Possibly Damaging | 0.570 | Possibly Damaging | 3.99 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1345 | 0.3753 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||
| c.3950G>A | G1317D 2D AIThe SynGAP1 missense variant G1317D is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33451824‑G‑A). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign prediction (2 benign vs. 1 pathogenic, with one uncertain). Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.908098 | Disordered | 0.971158 | Binding | 0.385 | 0.879 | 0.750 | 6-33451824-G-A | -4.860 | Likely Benign | 0.520 | Ambiguous | Likely Benign | 0.081 | Likely Benign | -3.54 | Deleterious | 0.588 | Possibly Damaging | 0.212 | Benign | 4.03 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2115 | 0.2859 | -1 | 1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||
| c.3950G>C | G1317A 2D AIThe SynGAP1 missense variant G1317A is not 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, 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 | 0.908098 | Disordered | 0.971158 | Binding | 0.385 | 0.879 | 0.750 | -3.761 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -2.62 | Deleterious | 0.001 | Benign | 0.002 | Benign | 4.08 | Benign | 0.00 | Affected | 0.3582 | 0.4284 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3950G>T | G1317V 2D AIThe SynGAP1 missense variant G1317V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, PROVEAN and SIFT predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.971158 | Binding | 0.385 | 0.879 | 0.750 | -4.604 | Likely Benign | 0.286 | Likely Benign | Likely Benign | 0.050 | Likely Benign | -2.99 | Deleterious | 0.004 | Benign | 0.004 | Benign | 4.05 | Benign | 0.00 | Affected | 0.1132 | 0.3635 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3097T>A | S1033T 2D AIThe SynGAP1 missense variant S1033T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.993473 | Binding | 0.294 | 0.737 | 0.625 | -3.702 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.029 | Likely Benign | -0.05 | Neutral | 0.568 | Possibly Damaging | 0.171 | Benign | 2.73 | Benign | 0.58 | Tolerated | 0.1379 | 0.6089 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3097T>C | S1033P 2D AIThe SynGAP1 missense variant S1033P is not reported in ClinVar and is absent from gnomAD, indicating no documented population frequency. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are not available, so they do not influence the overall assessment. Based on the consensus of all available predictions, the variant is most likely benign, and this conclusion is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.993473 | Binding | 0.294 | 0.737 | 0.625 | -2.046 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.068 | Likely Benign | 0.05 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.68 | Benign | 0.27 | Tolerated | 0.1889 | 0.5486 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3097T>G | S1033A 2D AIThe SynGAP1 missense variant S1033A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Overall, the consensus of all available predictions indicates that the variant is most likely benign, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.993473 | Binding | 0.294 | 0.737 | 0.625 | -3.107 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.06 | Neutral | 0.220 | Benign | 0.085 | Benign | 2.81 | Benign | 1.00 | Tolerated | 0.4387 | 0.5282 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3098C>A | S1033Y 2D AIThe SynGAP1 missense variant S1033Y is reported in gnomAD (ID 6‑33443650‑C‑A) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.993473 | Binding | 0.294 | 0.737 | 0.625 | 6-33443650-C-A | 1 | 6.19e-7 | -4.857 | Likely Benign | 0.564 | Ambiguous | Likely Benign | 0.034 | Likely Benign | -1.01 | Neutral | 0.021 | Benign | 0.008 | Benign | 2.69 | Benign | 0.04 | Affected | 3.77 | 5 | 0.0708 | 0.5262 | -2 | -3 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||
| c.3098C>G | S1033C 2D AIThe SynGAP1 missense variant S1033C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for S1033C, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.993473 | Binding | 0.294 | 0.737 | 0.625 | -6.263 | Likely Benign | 0.198 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.39 | Neutral | 0.992 | Probably Damaging | 0.750 | Possibly Damaging | 2.68 | Benign | 0.12 | Tolerated | 0.1031 | 0.5704 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.3098C>T | S1033F 2D AIThe SynGAP1 missense variant S1033F is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus is Likely Benign, and Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.993473 | Binding | 0.294 | 0.737 | 0.625 | -5.013 | Likely Benign | 0.555 | Ambiguous | Likely Benign | 0.022 | Likely Benign | -1.02 | Neutral | 0.440 | Benign | 0.185 | Benign | 2.70 | Benign | 0.05 | Affected | 0.0699 | 0.5546 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.3262A>C | S1088R 2D AIThe SynGAP1 missense variant S1088R is not reported in ClinVar and has no gnomAD entry. Prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, and FATHMM, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves as Likely Benign, reflecting the majority of benign calls. High‑accuracy assessments further support this: AlphaMissense‑Optimized labels the variant as Pathogenic, but the SGM‑Consensus (majority vote) remains Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence leans toward a benign effect; this conclusion does not conflict with ClinVar, which contains no entry for S1088R. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | -4.588 | Likely Benign | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.209 | Likely Benign | -1.96 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1190 | 0.4502 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.3262A>G | S1088G 2D AIThe SynGAP1 missense variant S1088G is listed in ClinVar (ID 2742833.0) with an “Uncertain” clinical significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as Likely Benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this is consistent with the ClinVar “Uncertain” status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | Uncertain | 1 | -5.034 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.163 | Likely Benign | -1.83 | Neutral | 0.979 | Probably Damaging | 0.973 | Probably Damaging | 2.63 | Benign | 0.03 | Affected | 3.77 | 5 | 0.2541 | 0.5170 | 0 | 1 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.3262A>T | S1088C 2D AIThe SynGAP1 missense variant S1088C is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and SIFT. Two tools, AlphaMissense‑Default and ESM1b, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it contains two benign and two uncertain calls, and Foldetta data are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | -7.532 | In-Between | 0.547 | Ambiguous | Likely Benign | 0.212 | Likely Benign | -2.33 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.59 | Benign | 0.01 | Affected | 0.1571 | 0.6166 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.3263G>A | S1088N 2D AIThe SynGAP1 missense variant S1088N has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, while the SGM‑Consensus (derived from the four high‑accuracy tools) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence leans toward a benign impact, and this assessment does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | -5.227 | Likely Benign | 0.791 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | -1.25 | Neutral | 0.991 | Probably Damaging | 0.982 | Probably Damaging | 2.69 | Benign | 0.02 | Affected | 0.1940 | 0.5197 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| c.3263G>C | S1088T 2D AIThe SynGAP1 missense variant S1088T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | -4.569 | Likely Benign | 0.295 | Likely Benign | Likely Benign | 0.175 | Likely Benign | -1.32 | Neutral | 0.979 | Probably Damaging | 0.973 | Probably Damaging | 2.71 | Benign | 0.04 | Affected | 0.2048 | 0.6514 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3263G>T | S1088I 2D AIThe SynGAP1 missense variant S1088I is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33443815‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. AlphaMissense‑Optimized is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the balance of evidence, the variant is most likely benign; this assessment does not contradict ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | 6-33443815-G-T | -4.893 | Likely Benign | 0.891 | Likely Pathogenic | Ambiguous | 0.288 | Likely Benign | -2.05 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.62 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1322 | 0.5712 | -2 | -1 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||
| c.3264C>A | S1088R 2D AIThe SynGAP1 missense variant S1088R is not reported in ClinVar and is present in gnomAD (ID 6‑33443816‑C‑A). Prediction tools that classify the variant as benign include REVEL, PROVEAN, ESM1b, and FATHMM, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized predict it to be pathogenic. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains benign; Foldetta results are unavailable. Overall, the balance of evidence—five pathogenic versus four benign predictions—suggests the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for S1088R. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | 6-33443816-C-A | -4.588 | Likely Benign | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.181 | Likely Benign | -1.96 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1190 | 0.4502 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| c.3264C>G | S1088R 2D AIThe SynGAP1 missense variant S1088R has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic impact are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, whereas the SGM‑Consensus remains Benign; Foldetta results are unavailable. Overall, the balance of evidence slightly favors a pathogenic interpretation, with no conflict with ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | -4.588 | Likely Benign | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.181 | Likely Benign | -1.96 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1190 | 0.4502 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.3331A>C | K1111Q 2D AIThe SynGAP1 missense variant K1111Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only polyPhen‑2 HumDiv predicts it as pathogenic. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely benign. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates likely benign; Foldetta results are not available. Overall, the consensus of available predictions indicates that K1111Q is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.921455 | Binding | 0.300 | 0.902 | 0.875 | -3.687 | Likely Benign | 0.261 | Likely Benign | Likely Benign | 0.036 | Likely Benign | -0.80 | Neutral | 0.666 | Possibly Damaging | 0.267 | Benign | 2.66 | Benign | 0.31 | Tolerated | 0.4577 | 0.1714 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3331A>G | K1111E 2D AIThe SynGAP1 missense variant K1111E is not reported in ClinVar and has no entry in gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all score it as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also classifies it as likely benign. Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy tools further support a benign interpretation: AlphaMissense‑Optimized returns a benign prediction, while the SGM‑Consensus (majority vote) remains benign; a Foldetta stability assessment is unavailable. Taken together, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.921455 | Binding | 0.300 | 0.902 | 0.875 | -3.666 | Likely Benign | 0.565 | Likely Pathogenic | Likely Benign | 0.089 | Likely Benign | -0.86 | Neutral | 0.451 | Benign | 0.193 | Benign | 2.69 | Benign | 0.23 | Tolerated | 0.3846 | 0.1833 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3332A>C | K1111T 2D AIThe SynGAP1 missense variant K1111T is reported in gnomAD (ID 6‑33443884‑A‑C) but has no ClinVar entry. Consensus from multiple in silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all classify it as benign, and AlphaMissense‑Optimized also predicts benign. No tool predicts pathogenicity; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign,” and Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this conclusion is not contradicted by ClinVar status, which currently has no classification for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.921455 | Binding | 0.300 | 0.902 | 0.875 | 6-33443884-A-C | 2 | 1.32e-6 | -4.037 | Likely Benign | 0.519 | Ambiguous | Likely Benign | 0.080 | Likely Benign | -0.90 | Neutral | 0.292 | Benign | 0.110 | Benign | 2.64 | Benign | 0.28 | Tolerated | 4.32 | 2 | 0.2250 | 0.4425 | -1 | 0 | 3.2 | -27.07 | ||||||||||||||||||||||||||||||||||
| c.3332A>G | K1111R 2D AIThe SynGAP1 missense variant K1111R is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.921455 | Binding | 0.300 | 0.902 | 0.875 | -2.495 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.059 | Likely Benign | -0.30 | Neutral | 0.006 | Benign | 0.006 | Benign | 2.74 | Benign | 0.71 | Tolerated | 0.4664 | 0.2031 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||||||||||||
| c.3332A>T | K1111M 2D AIThe SynGAP1 missense variant K1111M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Taken together, the majority of evidence points to a benign impact for K1111M. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.921455 | Binding | 0.300 | 0.902 | 0.875 | -5.579 | Likely Benign | 0.759 | Likely Pathogenic | Likely Benign | 0.071 | Likely Benign | -1.75 | Neutral | 0.072 | Benign | 0.029 | Benign | 2.59 | Benign | 0.12 | Tolerated | 0.1388 | 0.4701 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.3333G>C | K1111N 2D AIThe SynGAP1 missense variant K1111N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and AlphaMissense‑Optimized is uncertain. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.921455 | Binding | 0.300 | 0.902 | 0.875 | -4.503 | Likely Benign | 0.833 | Likely Pathogenic | Ambiguous | 0.048 | Likely Benign | -0.77 | Neutral | 0.666 | Possibly Damaging | 0.211 | Benign | 2.64 | Benign | 0.15 | Tolerated | 0.3667 | 0.2350 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3333G>T | K1111N 2D AIThe SynGAP1 missense variant K1111N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and AlphaMissense‑Optimized is uncertain. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.921455 | Binding | 0.300 | 0.902 | 0.875 | -4.503 | Likely Benign | 0.833 | Likely Pathogenic | Ambiguous | 0.048 | Likely Benign | -0.77 | Neutral | 0.666 | Possibly Damaging | 0.211 | Benign | 2.64 | Benign | 0.15 | Tolerated | 0.3667 | 0.2350 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.4027C>A | H1343N 2D AIThe SynGAP1 missense variant H1343N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign 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 | 0.910643 | Disordered | 0.983646 | Binding | 0.350 | 0.677 | 0.875 | -3.077 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -1.09 | Neutral | 0.444 | Benign | 0.071 | Benign | 4.06 | Benign | 0.00 | Affected | 0.2398 | 0.3299 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.4027C>G | H1343D 2D AIThe SynGAP1 missense variant H1343D 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only SIFT predicts a pathogenic impact. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. AlphaMissense‑Optimized also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.983646 | Binding | 0.350 | 0.677 | 0.875 | -3.136 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -1.29 | Neutral | 0.444 | Benign | 0.071 | Benign | 4.07 | Benign | 0.00 | Affected | 0.3011 | 0.2403 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.4027C>T | H1343Y 2D AIThe SynGAP1 missense variant H1343Y is reported in gnomAD (ID 6‑33451901‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, 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 points to a benign impact for H1343Y, 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 | 0.910643 | Disordered | 0.983646 | Binding | 0.350 | 0.677 | 0.875 | 6-33451901-C-T | -3.479 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.040 | Likely Benign | -0.85 | Neutral | 0.444 | Benign | 0.071 | Benign | 4.06 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1030 | 0.4792 | 2 | 0 | 1.9 | 26.03 | ||||||||||||||||||||||||||||||||||||
| c.4028A>C | H1343P 2D AIThe SynGAP1 missense variant H1343P 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 conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.983646 | Binding | 0.350 | 0.677 | 0.875 | -2.696 | Likely Benign | 0.094 | Likely Benign | Likely Benign | 0.126 | Likely Benign | -1.23 | Neutral | 0.659 | Possibly Damaging | 0.104 | Benign | 4.02 | Benign | 0.00 | Affected | 0.2333 | 0.4220 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.4028A>G | H1343R 2D AIThe SynGAP1 missense variant H1343R 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 | 0.910643 | Disordered | 0.983646 | Binding | 0.350 | 0.677 | 0.875 | -2.179 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -1.16 | Neutral | 0.659 | Possibly Damaging | 0.071 | Benign | 4.08 | Benign | 0.00 | Affected | 0.2301 | 0.2602 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.4028A>T | H1343L 2D AIThe SynGAP1 missense variant H1343L is reported in gnomAD (ID 6‑33451902‑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 substitution as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign status. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the available predictions points to a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.983646 | Binding | 0.350 | 0.677 | 0.875 | 6-33451902-A-T | -1.552 | Likely Benign | 0.132 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -1.28 | Neutral | 0.053 | Benign | 0.012 | Benign | 4.07 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1222 | 0.5869 | -3 | -2 | 7.0 | -23.98 | ||||||||||||||||||||||||||||||||||||
| c.4029C>A | H1343Q 2D AIThe SynGAP1 missense variant H1343Q is reported in gnomAD (ID 6‑33451903‑C‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign impact, and this 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 | 0.910643 | Disordered | 0.983646 | Binding | 0.350 | 0.677 | 0.875 | 6-33451903-C-A | -2.900 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -1.04 | Neutral | 0.659 | Possibly Damaging | 0.104 | Benign | 4.06 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2126 | 0.3716 | 0 | 3 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||||
| c.4029C>G | H1343Q 2D AIThe SynGAP1 missense variant H1343Q is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that predict a pathogenic effect are polyPhen2_HumDiv and SIFT. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of predictions, including the high‑accuracy tools, suggest that H1343Q 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 | 0.910643 | Disordered | 0.983646 | Binding | 0.350 | 0.677 | 0.875 | -2.900 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.033 | Likely Benign | -1.04 | Neutral | 0.659 | Possibly Damaging | 0.104 | Benign | 4.06 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2126 | 0.3716 | 0 | 3 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||
| c.3238G>A | A1080T 2D AIThe SynGAP1 missense variant A1080T (ClinVar ID 1473274.0) is listed as “Uncertain” in ClinVar and is present in gnomAD (ID 6‑33443790‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence strongly suggests the variant is most likely benign, which does not contradict the current ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.981457 | Binding | 0.303 | 0.900 | 0.750 | Conflicting | 2 | 6-33443790-G-A | 17 | 1.06e-5 | -3.928 | Likely Benign | 0.133 | Likely Benign | Likely Benign | 0.144 | Likely Benign | -0.19 | Neutral | 0.253 | Benign | 0.042 | Benign | 4.10 | Benign | 0.60 | Tolerated | 3.77 | 5 | 0.1564 | 0.7103 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||
| c.3238G>C | A1080P 2D AIThe SynGAP1 missense variant A1080P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for A1080P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.981457 | Binding | 0.303 | 0.900 | 0.750 | -2.429 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.170 | Likely Benign | -1.15 | Neutral | 0.996 | Probably Damaging | 0.833 | Possibly Damaging | 3.96 | Benign | 0.02 | Affected | 0.1884 | 0.5324 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3238G>T | A1080S 2D AIThe SynGAP1 missense variant A1080S is listed in ClinVar (ID 2703014.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443790‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign effect, and this conclusion does not contradict the ClinVar designation, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.981457 | Binding | 0.303 | 0.900 | 0.750 | Uncertain | 1 | 6-33443790-G-T | 1 | 6.26e-7 | -3.277 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.103 | Likely Benign | 0.01 | Neutral | 0.702 | Possibly Damaging | 0.346 | Benign | 4.16 | Benign | 0.08 | Tolerated | 3.77 | 5 | 0.2498 | 0.5915 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||
| c.3239C>A | A1080E 2D  AIThe SynGAP1 missense variant A1080E is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33443791‑C‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM. Tools that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. High‑accuracy evidence therefore points to a benign or uncertain impact: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus is benign, and Foldetta data are missing. Overall, the balance of predictions leans toward a benign effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.981457 | Binding | 0.303 | 0.900 | 0.750 | 6-33443791-C-A | -3.672 | Likely Benign | 0.855 | Likely Pathogenic | Ambiguous | 0.090 | Likely Benign | -1.50 | Neutral | 0.901 | Possibly Damaging | 0.540 | Possibly Damaging | 4.00 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1394 | 0.2437 | -1 | 0 | -5.3 | 58.04 | ||||||||||||||||||||||||||||||||||||
| c.3239C>G | A1080G 2D AIThe SynGAP1 missense variant A1080G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable. Overall, the consensus of the majority of prediction algorithms and the high‑accuracy tools points to a benign effect for A1080G, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.981457 | Binding | 0.303 | 0.900 | 0.750 | -3.515 | Likely Benign | 0.213 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -0.80 | Neutral | 0.901 | Possibly Damaging | 0.355 | Benign | 4.00 | Benign | 0.04 | Affected | 0.2153 | 0.4958 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3239C>T | A1080V 2D AIThe SynGAP1 missense variant A1080V is listed in gnomAD (ID 6‑33443791‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; no Foldetta stability data are available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.981457 | Binding | 0.303 | 0.900 | 0.750 | 6-33443791-C-T | -4.087 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -1.06 | Neutral | 0.481 | Possibly Damaging | 0.144 | Benign | 3.99 | Benign | 0.04 | Affected | 3.77 | 5 | 0.1298 | 0.6056 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||
| c.3259T>A | S1087T 2D AIThe SynGAP1 missense variant S1087T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to the variant being most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | -4.455 | Likely Benign | 0.128 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -1.01 | Neutral | 0.790 | Possibly Damaging | 0.266 | Benign | 2.66 | Benign | 0.25 | Tolerated | 0.1333 | 0.6503 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3259T>C | S1087P 2D AIThe SynGAP1 missense variant S1087P is reported in gnomAD (ID 6‑33443811‑T‑C) and has no ClinVar entry. All available in silico predictors classify it as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Based on the unanimous benign predictions and lack of ClinVar pathogenic annotation, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | 6-33443811-T-C | 1 | 6.34e-7 | -2.946 | Likely Benign | 0.133 | Likely Benign | Likely Benign | 0.135 | Likely Benign | -1.92 | Neutral | 0.006 | Benign | 0.008 | Benign | 2.56 | Benign | 0.12 | Tolerated | 3.77 | 5 | 0.1803 | 0.5700 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||
| c.3259T>G | S1087A 2D AIThe SynGAP1 missense variant S1087A is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Based on the consensus of all available predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | -3.649 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.057 | Likely Benign | -1.03 | Neutral | 0.447 | Benign | 0.139 | Benign | 2.64 | Benign | 0.34 | Tolerated | 0.4464 | 0.5405 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3260C>A | S1087Y 2D AIThe SynGAP1 missense variant S1087Y is catalogued in gnomAD (ID 6‑33443812‑C‑A) and has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as benign, and no Foldetta stability result is available. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | 6-33443812-C-A | -4.194 | Likely Benign | 0.587 | Likely Pathogenic | Likely Benign | 0.107 | Likely Benign | -2.41 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.56 | Benign | 0.02 | Affected | 3.77 | 5 | 0.0671 | 0.5845 | -2 | -3 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||
| c.3260C>G | S1087C 2D AIThe SynGAP1 missense variant S1087C is catalogued in gnomAD (ID 6‑33443812‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact, while ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | 6-33443812-C-G | 1 | 6.34e-7 | -7.369 | In-Between | 0.194 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -2.22 | Neutral | 0.997 | Probably Damaging | 0.840 | Possibly Damaging | 2.55 | Benign | 0.05 | Affected | 3.77 | 5 | 0.0979 | 0.6118 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||
| c.3260C>T | S1087F 2D AISynGAP1 missense variant S1087F is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of reliable predictors and the two high‑accuracy tools suggest a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | Uncertain | 1 | -3.843 | Likely Benign | 0.497 | Ambiguous | Likely Benign | 0.105 | Likely Benign | -2.75 | Deleterious | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.56 | Benign | 0.03 | Affected | 3.77 | 5 | 0.0645 | 0.6029 | -2 | -3 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||
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