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.2345A>G | D782G 2D  AIThe SynGAP1 missense variant D782G is not 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 effect: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Pathogenic” verdict (3 pathogenic vs. 1 benign). AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. Based on the overall pattern of predictions, the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.604312 | Disordered | 0.768342 | Binding | 0.285 | 0.883 | 0.625 | -6.811 | Likely Benign | 0.858 | Likely Pathogenic | Ambiguous | 0.291 | Likely Benign | -3.27 | Deleterious | 0.995 | Probably Damaging | 0.950 | Probably Damaging | 1.95 | Pathogenic | 0.02 | Affected | 0.3816 | 0.6318 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2345A>T | D782V 2D  AIThe SynGAP1 missense variant D782V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (which reports “Likely Pathogenic”). The high‑accuracy AlphaMissense‑Optimized tool yields an uncertain result, and the Foldetta stability assessment is unavailable. Overall, the consensus of the available predictions strongly favors a pathogenic effect for D782V. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.604312 | Disordered | 0.768342 | Binding | 0.285 | 0.883 | 0.625 | -8.250 | Likely Pathogenic | 0.931 | Likely Pathogenic | Ambiguous | 0.462 | Likely Benign | -3.59 | Deleterious | 0.999 | Probably Damaging | 0.979 | Probably Damaging | 1.92 | Pathogenic | 0.00 | Affected | 0.0803 | 0.6477 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.2346C>A | D782E 2D  AIThe SynGAP1 missense variant D782E is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority (2 benign vs. 1 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.604312 | Disordered | 0.768342 | Binding | 0.285 | 0.883 | 0.625 | -4.447 | Likely Benign | 0.486 | Ambiguous | Likely Benign | 0.127 | Likely Benign | -1.75 | Neutral | 0.561 | Possibly Damaging | 0.207 | Benign | 2.14 | Pathogenic | 0.01 | Affected | 0.1351 | 0.7036 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2346C>G | D782E 2D AIThe SynGAP1 missense variant D782E is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a majority benign vote (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 not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.604312 | Disordered | 0.768342 | Binding | 0.285 | 0.883 | 0.625 | -4.447 | Likely Benign | 0.486 | Ambiguous | Likely Benign | 0.127 | Likely Benign | -1.75 | Neutral | 0.561 | Possibly Damaging | 0.207 | Benign | 2.14 | Pathogenic | 0.01 | Affected | 0.1351 | 0.7036 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3808G>A | E1270K 2D  AIThe SynGAP1 missense variant E1270K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: REVEL predicts a benign outcome, whereas all other evaluated algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence indicates that E1270K 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 | 0.490133 | Structured | 0.771865 | Binding | 0.805 | 0.659 | 0.250 | -12.549 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.413 | Likely Benign | -3.37 | Deleterious | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.07 | Pathogenic | 0.00 | Affected | 0.1780 | 0.6276 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3808G>C | E1270Q 2D  AIThe SynGAP1 missense variant E1270Q 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 only REVEL, which scores the substitution as benign. In contrast, the majority of in silico predictors—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—classify the change as pathogenic. The high‑accuracy AlphaMissense‑Optimized assessment is uncertain, while the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic outcome. Foldetta predictions are unavailable for this variant. Overall, the preponderance of pathogenic predictions, together with the SGM Consensus result, indicates that E1270Q is most likely pathogenic; this conclusion does not contradict ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.490133 | Structured | 0.771865 | Binding | 0.805 | 0.659 | 0.250 | -8.645 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 0.330 | Likely Benign | -2.53 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.06 | Pathogenic | 0.00 | Affected | 0.0919 | 0.5858 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||
| c.3809A>C | E1270A 2D  AIThe SynGAP1 missense change E1270A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: REVEL is the only score that flags the variant as benign, whereas PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a pathogenic effect, and the SGM‑Consensus also indicates a likely pathogenic outcome. No Foldetta (FoldX‑MD/Rosetta stability) result is available, so it does not influence the assessment. Overall, the preponderance of evidence points to a pathogenic impact for E1270A, and this conclusion is consistent with the absence of a ClinVar entry (i.e., no contradictory clinical classification). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.490133 | Structured | 0.771865 | Binding | 0.805 | 0.659 | 0.250 | -12.081 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.388 | Likely Benign | -5.04 | Deleterious | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.06 | Pathogenic | 0.00 | Affected | 0.3024 | 0.5126 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||
| c.3809A>G | E1270G 2D  AIThe SynGAP1 missense variant E1270G is listed in gnomAD (ID 6‑33447857‑A‑G) and has no ClinVar entry. 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic, while Foldetta’s protein‑folding stability analysis is unavailable. Based on the preponderance of pathogenic predictions and the absence of a benign consensus, the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.490133 | Structured | 0.771865 | Binding | 0.805 | 0.659 | 0.250 | 6-33447857-A-G | -12.022 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.385 | Likely Benign | -5.90 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.05 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2415 | 0.5452 | -2 | 0 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||
| c.3809A>T | E1270V 2D  AIThe SynGAP1 missense variant E1270V 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 E1270V 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 | 0.490133 | Structured | 0.771865 | Binding | 0.805 | 0.659 | 0.250 | -13.293 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.408 | Likely Benign | -5.90 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.02 | Pathogenic | 0.00 | Affected | 0.0570 | 0.6461 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||
| c.3810G>C | E1270D 2D  AIThe SynGAP1 missense variant E1270D 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 impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus also reports it as likely pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.490133 | Structured | 0.771865 | Binding | 0.805 | 0.659 | 0.250 | -9.379 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.220 | Likely Benign | -2.53 | Deleterious | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 2.26 | Pathogenic | 0.00 | Affected | 0.1655 | 0.3271 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3810G>T | E1270D 2D AIThe SynGAP1 missense variant E1270D is catalogued in gnomAD (6-33447858‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: the single benign prediction comes from REVEL, while all other evaluated algorithms—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic.” The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence indicates that E1270D is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.490133 | Structured | 0.771865 | Binding | 0.805 | 0.659 | 0.250 | 6-33447858-G-T | -9.379 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.219 | Likely Benign | -2.53 | Deleterious | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 2.26 | Pathogenic | 0.00 | Affected | 0.1655 | 0.3271 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||
| c.3817C>A | L1273M 2D  AIThe SynGAP1 missense variant L1273M is catalogued in gnomAD (ID 6‑33447865‑C‑A) 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) resolves to benign, and the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect for the variant. This conclusion is not contradicted by ClinVar, as no ClinVar classification exists for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.599170 | Disordered | 0.773625 | Binding | 0.747 | 0.677 | 0.500 | 6-33447865-C-A | -5.375 | Likely Benign | 0.503 | Ambiguous | Likely Benign | 0.161 | Likely Benign | -1.68 | Neutral | 0.983 | Probably Damaging | 0.874 | Possibly Damaging | 2.14 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.0824 | 0.3932 | 2 | 4 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||
| c.3817C>G | L1273V 2D  AIThe SynGAP1 missense variant L1273V is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans pathogenic (two pathogenic versus one benign vote). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence, particularly the SGM Consensus, indicates 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. | 0.599170 | Disordered | 0.773625 | Binding | 0.747 | 0.677 | 0.500 | -6.014 | Likely Benign | 0.539 | Ambiguous | Likely Benign | 0.111 | Likely Benign | -2.50 | Deleterious | 0.773 | Possibly Damaging | 0.287 | Benign | 2.20 | Pathogenic | 0.00 | Affected | 0.1556 | 0.3178 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3818T>A | L1273Q 2D  AIThe SynGAP1 missense variant L1273Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic and the SGM‑Consensus is labeled Likely Pathogenic; Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.599170 | Disordered | 0.773625 | Binding | 0.747 | 0.677 | 0.500 | -6.813 | Likely Benign | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.423 | Likely Benign | -5.05 | Deleterious | 0.997 | Probably Damaging | 0.950 | Probably Damaging | 2.13 | Pathogenic | 0.00 | Affected | 0.1139 | 0.1119 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3818T>C | L1273P 2D  AIThe SynGAP1 missense variant L1273P is not reported in ClinVar (ClinVar status: not listed) but is present in the gnomAD database (gnomAD ID: 6‑33447866‑T‑C). Functional prediction tools uniformly indicate a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool in the dataset predicts a benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as likely pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the consensus of predictive algorithms strongly supports a pathogenic classification, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.599170 | Disordered | 0.773625 | Binding | 0.747 | 0.677 | 0.500 | 6-33447866-T-C | -9.443 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.523 | Likely Pathogenic | -5.87 | Deleterious | 0.997 | Probably Damaging | 0.950 | Probably Damaging | 2.12 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.3836 | 0.1343 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||
| c.3818T>G | L1273R 2D  AIThe SynGAP1 missense variant L1273R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all 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 assessment is not contradicted by any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.599170 | Disordered | 0.773625 | Binding | 0.747 | 0.677 | 0.500 | -6.252 | Likely Benign | 0.946 | Likely Pathogenic | Ambiguous | 0.431 | Likely Benign | -5.05 | Deleterious | 0.997 | Probably Damaging | 0.934 | Probably Damaging | 2.13 | Pathogenic | 0.00 | Affected | 0.1369 | 0.0761 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3442A>C | M1148L 2D  AIThe SynGAP1 missense variant M1148L is not reported in ClinVar (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. Overall, the majority of evidence points to a benign effect, and there is no conflict with ClinVar status because no ClinVar classification exists. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.774279 | Binding | 0.343 | 0.835 | 0.875 | -1.777 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -1.13 | Neutral | 0.016 | Benign | 0.016 | Benign | 2.62 | Benign | 0.00 | Affected | 4.32 | 2 | 0.1641 | 0.4135 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.3442A>G | M1148V 2D  AIThe SynGAP1 missense variant M1148V is catalogued in ClinVar with no submitted interpretation and is present in gnomAD (ID 6‑33444477‑A‑G). 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, 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 results are not available. Overall, the consensus of available predictions indicates that M1148V is most likely benign, and this conclusion does not contradict any ClinVar status, as no pathogenic claim has been reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.774279 | Binding | 0.343 | 0.835 | 0.875 | 6-33444477-A-G | 3 | 1.86e-6 | -2.358 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.057 | Likely Benign | -1.47 | Neutral | 0.016 | Benign | 0.026 | Benign | 2.59 | Benign | 0.00 | Affected | 4.32 | 2 | 0.3154 | 0.3371 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||||||||||||||
| c.3442A>T | M1148L 2D AIThe SynGAP1 missense variant M1148L is listed in ClinVar (ID 1010061.0) 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, 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 stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this is consistent with the ClinVar “Uncertain” designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.774279 | Binding | 0.343 | 0.835 | 0.875 | Uncertain | 1 | -1.777 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -1.13 | Neutral | 0.016 | Benign | 0.016 | Benign | 2.62 | Benign | 0.00 | Affected | 4.32 | 2 | 0.1641 | 0.4135 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||
| c.3443T>A | M1148K 2D  AIThe SynGAP1 missense variant M1148K is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this 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 | 0.762850 | Disordered | 0.774279 | Binding | 0.343 | 0.835 | 0.875 | -2.527 | Likely Benign | 0.624 | Likely Pathogenic | Likely Benign | 0.105 | Likely Benign | -1.58 | Neutral | 0.144 | Benign | 0.085 | Benign | 2.55 | Benign | 0.00 | Affected | 0.1539 | 0.1056 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||||||
| c.3443T>C | M1148T 2D  AIThe SynGAP1 missense variant M1148T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.774279 | Binding | 0.343 | 0.835 | 0.875 | -0.972 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.151 | Likely Benign | -1.50 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.56 | Benign | 0.00 | Affected | 0.2063 | 0.2214 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||||||||||||
| c.3443T>G | M1148R 2D  AIThe SynGAP1 missense variant M1148R is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. 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 is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.774279 | Binding | 0.343 | 0.835 | 0.875 | -2.303 | Likely Benign | 0.669 | Likely Pathogenic | Likely Benign | 0.129 | Likely Benign | -1.77 | Neutral | 0.255 | Benign | 0.113 | Benign | 2.54 | Benign | 0.00 | Affected | 0.1624 | 0.0888 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||||||
| c.3444G>A | M1148I 2D  AIThe SynGAP1 missense variant M1148I is not reported in ClinVar (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, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), 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 as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar annotation 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 | 0.762850 | Disordered | 0.774279 | Binding | 0.343 | 0.835 | 0.875 | -3.017 | Likely Benign | 0.348 | Ambiguous | Likely Benign | 0.021 | Likely Benign | -1.55 | Neutral | 0.144 | Benign | 0.062 | Benign | 2.57 | Benign | 0.00 | Affected | 0.1453 | 0.3041 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3444G>C | M1148I 2D AIThe SynGAP1 missense variant M1148I has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and AlphaMissense‑Optimized all indicate a benign or likely benign outcome. Only SIFT predicts a pathogenic effect, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus also reports likely benign, and Foldetta data 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 classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.774279 | Binding | 0.343 | 0.835 | 0.875 | -3.017 | Likely Benign | 0.348 | Ambiguous | Likely Benign | 0.021 | Likely Benign | -1.55 | Neutral | 0.144 | Benign | 0.062 | Benign | 2.57 | Benign | 0.00 | Affected | 0.1453 | 0.3041 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3444G>T | M1148I 2D AIThe SynGAP1 missense variant M1148I has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and AlphaMissense‑Optimized all indicate a benign or likely benign outcome. Only SIFT predicts a pathogenic effect, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus also reports likely benign, and Foldetta data 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 classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.774279 | Binding | 0.343 | 0.835 | 0.875 | -3.017 | Likely Benign | 0.348 | Ambiguous | Likely Benign | 0.021 | Likely Benign | -1.55 | Neutral | 0.144 | Benign | 0.062 | Benign | 2.57 | Benign | 0.00 | Affected | 0.1453 | 0.3041 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| 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.3820C>A | R1274S 2D  AIThe SynGAP1 missense variant R1274S is not reported in ClinVar (status: “None”) but is present in gnomAD (ID 6‑33447868‑C‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are limited: AlphaMissense‑Optimized remains uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of available predictions (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. | 0.613573 | Disordered | 0.779985 | Binding | 0.746 | 0.688 | 0.625 | 6-33447868-C-A | -3.149 | Likely Benign | 0.830 | Likely Pathogenic | Ambiguous | 0.139 | Likely Benign | -3.19 | Deleterious | 0.997 | Probably Damaging | 0.993 | Probably Damaging | 2.52 | Benign | 0.01 | Affected | 3.77 | 5 | 0.3056 | 0.1830 | -1 | 0 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||
| c.3820C>G | R1274G 2D  AIThe SynGAP1 R1274G 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, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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 predicts a pathogenic outcome. AlphaMissense‑Optimized alone predicts benign, while Foldetta results are unavailable. Overall, the majority of evidence (seven pathogenic versus three benign predictions) indicates that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.613573 | Disordered | 0.779985 | Binding | 0.746 | 0.688 | 0.625 | -3.288 | Likely Benign | 0.579 | Likely Pathogenic | Likely Benign | 0.145 | Likely Benign | -4.36 | Deleterious | 0.997 | Probably Damaging | 0.993 | Probably Damaging | 2.49 | Pathogenic | 0.01 | Affected | 0.3316 | 0.2310 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3820C>T | R1274C 2D  AIThe SynGAP1 missense variant R1274C is listed in ClinVar with an “Uncertain” significance and is present in gnomAD (ID 6‑33447868‑C‑T). Prediction tools that agree on benign impact include REVEL, ESM1b, and AlphaMissense‑Optimized, while those that predict pathogenicity are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). AlphaMissense‑Default remains uncertain, and Foldetta results are unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as pathogenic, and no Foldetta data to weigh in. Overall, the majority of evaluated tools (seven pathogenic vs. three benign) suggest a pathogenic effect. This consensus does not contradict the ClinVar “Uncertain” status, which remains inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.613573 | Disordered | 0.779985 | Binding | 0.746 | 0.688 | 0.625 | Uncertain | 1 | 6-33447868-C-T | -6.467 | Likely Benign | 0.439 | Ambiguous | Likely Benign | 0.170 | Likely Benign | -5.22 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.46 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.3232 | 0.1517 | -4 | -3 | 7.0 | -53.05 | |||||||||||||||||||||||||||||||||||
| c.3821G>A | R1274H 2D  AIThe SynGAP1 missense variant R1274H (ClinVar ID 2803246.0) is classified as Benign in ClinVar and is present in gnomAD (ID 6‑33447869‑G‑A). Functional prediction tools show mixed results: benign calls come from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive. No Foldetta stability prediction is available for this residue. Overall, the majority of conventional tools predict pathogenicity, and the high‑accuracy AlphaMissense‑Optimized result is benign, leaving the evidence mixed. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, contradicting its ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.613573 | Disordered | 0.779985 | Binding | 0.746 | 0.688 | 0.625 | Likely Benign | 1 | 6-33447869-G-A | 4 | 2.58e-6 | -5.259 | Likely Benign | 0.256 | Likely Benign | Likely Benign | 0.149 | Likely Benign | -3.20 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 2.49 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.2201 | 0.0936 | 0 | 2 | 1.3 | -19.05 | |||||||||||||||||||||||||||||||||
| c.3821G>C | R1274P 2D  AIThe SynGAP1 missense variant R1274P is not 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 effect: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the preponderance of evidence indicates that R1274P is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.613573 | Disordered | 0.779985 | Binding | 0.746 | 0.688 | 0.625 | -6.145 | Likely Benign | 0.955 | Likely Pathogenic | Ambiguous | 0.179 | Likely Benign | -4.02 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.48 | Pathogenic | 0.01 | Affected | 0.2166 | 0.3095 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3821G>T | R1274L 2D  AIThe SynGAP1 missense variant R1274L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta results are unavailable. Overall, the majority of reliable predictors and the high‑accuracy consensus favor a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.613573 | Disordered | 0.779985 | Binding | 0.746 | 0.688 | 0.625 | -5.318 | Likely Benign | 0.457 | Ambiguous | Likely Benign | 0.165 | Likely Benign | -4.48 | Deleterious | 0.997 | Probably Damaging | 0.993 | Probably Damaging | 2.50 | Benign | 0.01 | Affected | 0.1657 | 0.3006 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2443C>A | R815S 2D AISynGAP1 R815S is listed in ClinVar as Benign (ID 3645150.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. Two tools report uncertainty: ESM1b and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM Consensus as Benign, and Foldetta (combining FoldX‑MD and Rosetta) has no available result. Overall, the majority of predictions lean toward pathogenicity, whereas the consensus and high‑accuracy tools suggest benignity. Thus, the variant is most likely pathogenic based on the prevailing predictions, contradicting its ClinVar benign designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.394753 | Structured | 0.780568 | Binding | 0.278 | 0.907 | 0.250 | Benign | 1 | -7.324 | In-Between | 0.950 | Likely Pathogenic | Ambiguous | 0.138 | Likely Benign | -1.86 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.67 | Benign | 0.02 | Affected | 0.2937 | 0.4164 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||
| c.2443C>G | R815G 2D AISynGAP1 missense variant R815G is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on benign effect include REVEL and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. Uncertain calls are made by ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.394753 | Structured | 0.780568 | Binding | 0.278 | 0.907 | 0.250 | Uncertain | 1 | -7.983 | In-Between | 0.854 | Likely Pathogenic | Ambiguous | 0.146 | Likely Benign | -3.22 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.62 | Benign | 0.02 | Affected | 4.32 | 4 | 0.3481 | 0.4015 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||
| c.2443C>T | R815C 2D AIThe SynGAP1 missense variant R815C is listed in ClinVar (ID 660618.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33442995‑C‑T). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized result is “Uncertain.” The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of predictions indicates a pathogenic effect, which does not contradict the ClinVar “Uncertain” classification but suggests that the variant is more likely pathogenic rather than benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.394753 | Structured | 0.780568 | Binding | 0.278 | 0.907 | 0.250 | Uncertain | 1 | 6-33442995-C-T | 5 | 3.10e-6 | -9.373 | Likely Pathogenic | 0.828 | Likely Pathogenic | Ambiguous | 0.174 | Likely Benign | -3.89 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.59 | Benign | 0.00 | Affected | 4.32 | 4 | 0.3389 | 0.3682 | -4 | -3 | 7.0 | -53.05 | |||||||||||||||||||||||||||||||
| c.2444G>A | R815H 2D AIThe SynGAP1 missense variant R815H (ClinVar ID 833773.0) is classified as benign in ClinVar and is present in gnomAD (6‑33442996‑G‑A). Functional prediction tools cluster into two groups: benign predictions from REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar) and SIFT. Two tools report uncertainty: ESM1b and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta stability assessment are unavailable. Overall, the balance of evidence favors a benign effect, consistent with the ClinVar annotation and with no conflict regarding its status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.394753 | Structured | 0.780568 | Binding | 0.278 | 0.907 | 0.250 | Likely Benign | 2 | 6-33442996-G-A | 24 | 1.49e-5 | -7.474 | In-Between | 0.553 | Ambiguous | Likely Benign | 0.157 | Likely Benign | -1.81 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.61 | Benign | 0.02 | Affected | 4.32 | 4 | 0.2944 | 0.2281 | 2 | 0 | 1.3 | -19.05 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.2444G>C | R815P 2D AIThe SynGAP1 missense variant R815P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default) predict a pathogenic impact. The remaining tools, ESM1b and AlphaMissense‑Optimized, return uncertain results. High‑accuracy assessments further support a deleterious interpretation: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as pathogenic; AlphaMissense‑Optimized remains uncertain, and Foldetta data are unavailable. Overall, the preponderance of evidence indicates that R815P is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.394753 | Structured | 0.780568 | Binding | 0.278 | 0.907 | 0.250 | -7.495 | In-Between | 0.858 | Likely Pathogenic | Ambiguous | 0.153 | Likely Benign | -2.85 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.65 | Benign | 0.02 | Affected | 0.2113 | 0.4897 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2444G>T | R815L 2D AISynGAP1 missense variant R815L is listed in ClinVar (ID 2505666.0) with an uncertain significance annotation and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of tools indicates a pathogenic effect, which contrasts with the ClinVar uncertain classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.394753 | Structured | 0.780568 | Binding | 0.278 | 0.907 | 0.250 | Uncertain | 1 | -8.546 | Likely Pathogenic | 0.865 | Likely Pathogenic | Ambiguous | 0.175 | Likely Benign | -3.06 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.63 | Benign | 0.03 | Affected | 4.32 | 4 | 0.1817 | 0.5132 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||
| c.3793A>G | R1265G 2D AIThe SynGAP1 missense variant R1265G is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all label the change as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, while a Foldetta stability analysis is unavailable. Based on the unanimous pathogenic predictions and the lack of any benign calls, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status (which has no entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.414856 | Structured | 0.782497 | Binding | 0.887 | 0.592 | 0.000 | -12.732 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.523 | Likely Pathogenic | -5.80 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.27 | Pathogenic | 0.00 | Affected | 0.3520 | 0.3759 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3793A>T | R1265W 2D  AIThe SynGAP1 missense variant R1265W is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool in the dataset predicts a benign outcome, so the benign group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates a pathogenic change, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic. Foldetta results are not available, so they do not influence the conclusion. Overall, the variant is most likely pathogenic based on the consensus of predictive tools, and this assessment is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.414856 | Structured | 0.782497 | Binding | 0.887 | 0.592 | 0.000 | -14.584 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.505 | Likely Pathogenic | -6.54 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.23 | Pathogenic | 0.00 | Affected | 0.1166 | 0.3868 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||||||
| c.3794G>A | R1265K 2D  AIThe SynGAP1 missense variant R1265K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score 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. Based on the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.414856 | Structured | 0.782497 | Binding | 0.887 | 0.592 | 0.000 | -5.223 | Likely Benign | 0.951 | Likely Pathogenic | Ambiguous | 0.344 | Likely Benign | -2.49 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.38 | Pathogenic | 0.00 | Affected | 0.4829 | 0.3632 | 3 | 2 | 0.6 | -28.01 | |||||||||||||||||||||||||||||||||||||||
| c.3794G>C | R1265T 2D  AIThe SynGAP1 missense variant R1265T is reported in ClinVar as Pathogenic (ClinVar ID 522047.0) and is not found in gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool in the dataset predicts a benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenicity, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Pathogenic 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 supports a pathogenic classification, which is consistent with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.414856 | Structured | 0.782497 | Binding | 0.887 | 0.592 | 0.000 | Likely Pathogenic | 1 | -10.129 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.529 | Likely Pathogenic | -4.97 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.29 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1947 | 0.4618 | -1 | -1 | 3.8 | -55.08 | ||||||||||||||||||||||||||||||||||
| c.3794G>T | R1265M 2D  AIThe SynGAP1 missense variant R1265M is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus confirms a likely pathogenic status; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that R1265M is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.414856 | Structured | 0.782497 | Binding | 0.887 | 0.592 | 0.000 | -13.657 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.495 | Likely Benign | -4.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.25 | Pathogenic | 0.00 | Affected | 0.1442 | 0.4082 | 0 | -1 | 6.4 | -24.99 | ||||||||||||||||||||||||||||||||||||||
| c.3795G>C | R1265S 2D AIThe SynGAP1 missense variant R1265S is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus also reports it as likely pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.414856 | Structured | 0.782497 | Binding | 0.887 | 0.592 | 0.000 | -9.874 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.289 | Likely Benign | -4.96 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.40 | Pathogenic | 0.00 | Affected | 0.3525 | 0.3993 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3795G>T | R1265S 2D AIThe SynGAP1 missense variant R1265S is not reported in ClinVar and has no entry in gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus also reports it as likely pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.414856 | Structured | 0.782497 | Binding | 0.887 | 0.592 | 0.000 | -9.874 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.289 | Likely Benign | -4.96 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.40 | Pathogenic | 0.00 | Affected | 0.3525 | 0.3993 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||
| c.2263A>C | M755L 2D AIThe SynGAP1 missense variant M755L 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 | 0.490133 | Structured | 0.783855 | Binding | 0.336 | 0.873 | 0.375 | -1.298 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.067 | Likely Benign | 0.03 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.39 | Benign | 0.22 | Tolerated | 0.1167 | 0.3311 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2263A>G | M755V 2D AIThe SynGAP1 missense variant M755V 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. 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 | 0.490133 | Structured | 0.783855 | Binding | 0.336 | 0.873 | 0.375 | -3.804 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.80 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.73 | Benign | 0.27 | Tolerated | 0.2809 | 0.2873 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||||||||||||
| c.2263A>T | M755L 2D AIThe SynGAP1 missense variant M755L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral effect. 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 reports a benign effect, and the SGM‑Consensus (majority vote) yields a likely benign classification. Foldetta results are not available, so they do not influence the assessment. Overall, the computational evidence strongly supports a benign interpretation of M755L, 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 | 0.490133 | Structured | 0.783855 | Binding | 0.336 | 0.873 | 0.375 | -1.298 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.067 | Likely Benign | 0.03 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.39 | Benign | 0.22 | Tolerated | 0.1167 | 0.3311 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2264T>A | M755K 2D AIThe SynGAP1 missense variant M755K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus indicates Likely Benign, and Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which contains no conflicting report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.490133 | Structured | 0.783855 | Binding | 0.336 | 0.873 | 0.375 | -5.642 | Likely Benign | 0.531 | Ambiguous | Likely Benign | 0.101 | Likely Benign | -1.88 | Neutral | 0.468 | Possibly Damaging | 0.206 | Benign | 2.63 | Benign | 0.28 | Tolerated | 0.1183 | 0.0688 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||||||
| c.2264T>C | M755T 2D AIThe SynGAP1 missense variant M755T is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all classify the change as benign, and AlphaMissense‑Optimized also predicts benign. No tool predicts pathogenicity; AlphaMissense‑Default is uncertain. The SGM‑Consensus, which aggregates majority votes from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely benign. High‑accuracy assessments further support this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta data are not available. Overall, the computational evidence overwhelmingly suggests 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 | 0.490133 | Structured | 0.783855 | Binding | 0.336 | 0.873 | 0.375 | -4.116 | Likely Benign | 0.358 | Ambiguous | Likely Benign | 0.040 | Likely Benign | -1.23 | Neutral | 0.159 | Benign | 0.053 | Benign | 2.65 | Benign | 0.19 | Tolerated | 0.1944 | 0.1767 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||||||||||||
| c.2264T>G | M755R 2D AIThe SynGAP1 missense variant M755R is not reported in ClinVar (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. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and high‑accuracy tools indicates that the M755R 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 | 0.490133 | Structured | 0.783855 | Binding | 0.336 | 0.873 | 0.375 | -4.247 | Likely Benign | 0.453 | Ambiguous | Likely Benign | 0.104 | Likely Benign | -2.06 | Neutral | 0.468 | Possibly Damaging | 0.206 | Benign | 2.63 | Benign | 0.18 | Tolerated | 0.1407 | 0.0837 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||||||
| c.2265G>A | M755I 2D AIThe SynGAP1 missense variant M755I 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 | 0.490133 | Structured | 0.783855 | Binding | 0.336 | 0.873 | 0.375 | -3.856 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -0.55 | Neutral | 0.039 | Benign | 0.014 | Benign | 2.81 | Benign | 0.14 | Tolerated | 0.1059 | 0.2403 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2265G>C | M755I 2D AIThe SynGAP1 missense variant M755I 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 | 0.490133 | Structured | 0.783855 | Binding | 0.336 | 0.873 | 0.375 | -3.856 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.031 | Likely Benign | -0.55 | Neutral | 0.039 | Benign | 0.014 | Benign | 2.81 | Benign | 0.14 | Tolerated | 0.1059 | 0.2403 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2265G>T | M755I 2D AIThe SynGAP1 missense variant M755I 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 | 0.490133 | Structured | 0.783855 | Binding | 0.336 | 0.873 | 0.375 | -3.856 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -0.55 | Neutral | 0.039 | Benign | 0.014 | Benign | 2.81 | Benign | 0.14 | Tolerated | 0.1059 | 0.2403 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3499G>A | D1167N 2D  AIThe SynGAP1 missense variant D1167N is not reported 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, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evaluated predictors (five pathogenic vs. three benign) lean toward a pathogenic interpretation. This prediction does not contradict any ClinVar status, as the variant is not yet catalogued in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.599170 | Disordered | 0.783999 | Binding | 0.336 | 0.798 | 0.500 | -3.671 | Likely Benign | 0.924 | Likely Pathogenic | Ambiguous | 0.180 | Likely Benign | -1.72 | Neutral | 0.995 | Probably Damaging | 0.963 | Probably Damaging | 2.33 | Pathogenic | 0.01 | Affected | 0.1315 | 0.7940 | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||||
| c.3499G>C | D1167H 2D  AIThe SynGAP1 missense variant D1167H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b. Tools that agree on a pathogenic effect include polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic, two benign). Foldetta predictions are unavailable. Overall, the majority of evaluated tools (six pathogenic vs. three benign) indicate a pathogenic effect. 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. | 0.599170 | Disordered | 0.783999 | Binding | 0.336 | 0.798 | 0.500 | -3.774 | Likely Benign | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.257 | Likely Benign | -2.36 | Neutral | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 2.27 | Pathogenic | 0.00 | Affected | 0.1514 | 0.8433 | 1 | -1 | 0.3 | 22.05 | ||||||||||||||||||||||||||||||||||||||||
| c.3499G>T | D1167Y 2D  AIThe SynGAP1 missense variant D1167Y is not reported 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, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a 2‑to‑2 split and is therefore inconclusive. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑confidence predictors (six pathogenic vs. three benign) indicate that D1167Y is most likely pathogenic. This assessment does not contradict any ClinVar status, as no ClinVar entry exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.599170 | Disordered | 0.783999 | Binding | 0.336 | 0.798 | 0.500 | -4.050 | Likely Benign | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.281 | Likely Benign | -2.46 | Neutral | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 2.25 | Pathogenic | 0.00 | Affected | 0.0640 | 0.7307 | -4 | -3 | 2.2 | 48.09 | ||||||||||||||||||||||||||||||||||||||||
| c.3500A>C | D1167A 2D  AIThe SynGAP1 missense variant D1167A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all indicate likely pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus also reports it as likely pathogenic. Foldetta results are unavailable, so they do not influence the overall assessment. Based on the preponderance of pathogenic predictions and the high‑accuracy tool outputs, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.599170 | Disordered | 0.783999 | Binding | 0.336 | 0.798 | 0.500 | -1.281 | Likely Benign | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.244 | Likely Benign | -3.11 | Deleterious | 0.986 | Probably Damaging | 0.926 | Probably Damaging | 2.30 | Pathogenic | 0.01 | Affected | 0.4156 | 0.7359 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||||||
| c.3500A>G | D1167G 2D AIThe SynGAP1 missense variant D1167G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that D1167G is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.599170 | Disordered | 0.783999 | Binding | 0.336 | 0.798 | 0.500 | -2.967 | Likely Benign | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.246 | Likely Benign | -2.57 | Deleterious | 0.995 | Probably Damaging | 0.949 | Probably Damaging | 2.29 | Pathogenic | 0.01 | Affected | 0.4172 | 0.7305 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3500A>T | D1167V 2D AIThe SynGAP1 missense variant D1167V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Based on the preponderance of pathogenic predictions and the high‑accuracy tool results, the variant is most likely pathogenic; this conclusion is not contradicted by any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.599170 | Disordered | 0.783999 | Binding | 0.336 | 0.798 | 0.500 | -2.750 | Likely Benign | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.288 | Likely Benign | -3.34 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.26 | Pathogenic | 0.00 | Affected | 0.0946 | 0.7515 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.3501C>A | D1167E 2D AIThe SynGAP1 missense variant D1167E is not reported 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 | 0.599170 | Disordered | 0.783999 | Binding | 0.336 | 0.798 | 0.500 | -2.908 | Likely Benign | 0.940 | Likely Pathogenic | Ambiguous | 0.141 | Likely Benign | -1.19 | Neutral | 0.989 | Probably Damaging | 0.924 | Probably Damaging | 2.57 | Benign | 0.24 | Tolerated | 0.1468 | 0.7368 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3501C>G | D1167E 2D AIThe SynGAP1 missense variant D1167E is not reported 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 | 0.599170 | Disordered | 0.783999 | Binding | 0.336 | 0.798 | 0.500 | -2.908 | Likely Benign | 0.940 | Likely Pathogenic | Ambiguous | 0.142 | Likely Benign | -1.19 | Neutral | 0.989 | Probably Damaging | 0.924 | Probably Damaging | 2.57 | Benign | 0.24 | Tolerated | 0.1468 | 0.7368 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2740G>A | D914N 2D AIThe SynGAP1 missense variant D914N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all classify the change as benign or likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns a benign prediction, 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 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 | 0.699094 | Disordered | 0.785987 | Binding | 0.320 | 0.892 | 0.250 | -3.859 | Likely Benign | 0.291 | Likely Benign | Likely Benign | 0.126 | Likely Benign | -1.22 | Neutral | 0.998 | Probably Damaging | 0.966 | Probably Damaging | 2.69 | Benign | 0.02 | Affected | 0.1770 | 0.7848 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2740G>C | D914H 2D AIThe SynGAP1 missense variant D914H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) support a benign classification. This consensus does not contradict ClinVar status, as no ClinVar entry exists for this variant. Thus, based on current computational evidence, the D914H variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.785987 | Binding | 0.320 | 0.892 | 0.250 | -3.755 | Likely Benign | 0.651 | Likely Pathogenic | Likely Benign | 0.184 | Likely Benign | -1.26 | Neutral | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 2.74 | Benign | 0.01 | Affected | 0.1963 | 0.8451 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2740G>T | D914Y 2D AIThe SynGAP1 missense variant D914Y is not 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; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of tools (five pathogenic vs. four benign) and the lack of a benign consensus from the high‑accuracy methods suggest that D914Y is most likely pathogenic. This prediction does not contradict ClinVar status, as the variant has not yet been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.699094 | Disordered | 0.785987 | Binding | 0.320 | 0.892 | 0.250 | -4.768 | Likely Benign | 0.740 | Likely Pathogenic | Likely Benign | 0.239 | Likely Benign | -2.65 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 2.62 | Benign | 0.01 | Affected | 0.0907 | 0.7583 | -4 | -3 | 2.2 | 48.09 | ||||||||||||||||||||||||||||||||||||||||
| c.2741A>C | D914A 2D AIThe SynGAP1 missense variant D914A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus (majority vote 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 D914A, 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 | 0.699094 | Disordered | 0.785987 | Binding | 0.320 | 0.892 | 0.250 | -1.690 | Likely Benign | 0.387 | Ambiguous | Likely Benign | 0.128 | Likely Benign | -1.48 | Neutral | 0.996 | Probably Damaging | 0.953 | Probably Damaging | 2.69 | Benign | 0.05 | Affected | 0.4413 | 0.7086 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2741A>G | D914G 2D AIThe SynGAP1 missense variant D914G 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 D914G, 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 | 0.699094 | Disordered | 0.785987 | Binding | 0.320 | 0.892 | 0.250 | -1.486 | Likely Benign | 0.314 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -1.46 | Neutral | 0.998 | Probably Damaging | 0.966 | Probably Damaging | 2.65 | Benign | 0.02 | Affected | 0.4421 | 0.7257 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2741A>T | D914V 2D AIThe SynGAP1 missense variant D914V is listed in ClinVar (ID 2582846.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, 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) as benign; Foldetta results are unavailable. Overall, the balance 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 | 0.699094 | Disordered | 0.785987 | Binding | 0.320 | 0.892 | 0.250 | Uncertain | 1 | -4.260 | Likely Benign | 0.723 | Likely Pathogenic | Likely Benign | 0.187 | Likely Benign | -2.24 | Neutral | 0.999 | Probably Damaging | 0.986 | Probably Damaging | 2.64 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1316 | 0.7249 | -3 | -2 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||
| c.2742C>A | D914E 2D AIThe SynGAP1 missense variant D914E is reported in gnomAD (ID 6‑33443294‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags it as pathogenic, creating a single discordant call. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification, and AlphaMissense‑Optimized independently predicts benign. Foldetta, a protein‑folding stability method, 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 existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.785987 | Binding | 0.320 | 0.892 | 0.250 | 6-33443294-C-A | 5 | 3.10e-6 | -3.231 | Likely Benign | 0.170 | Likely Benign | Likely Benign | 0.133 | Likely Benign | -0.29 | Neutral | 0.893 | Possibly Damaging | 0.418 | Benign | 2.87 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.1909 | 0.7088 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2742C>G | D914E 2D AIThe SynGAP1 missense variant D914E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence supports a benign classification for D914E, 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 | 0.699094 | Disordered | 0.785987 | Binding | 0.320 | 0.892 | 0.250 | -3.231 | Likely Benign | 0.170 | Likely Benign | Likely Benign | 0.133 | Likely Benign | -0.29 | Neutral | 0.893 | Possibly Damaging | 0.418 | Benign | 2.87 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.1909 | 0.7088 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.2410G>A | D804N 2D AIThe SynGAP1 D804N variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Those 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—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of conventional tools predict a benign impact, and this assessment does not contradict the lack of ClinVar annotation. Thus, based on the current predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.801317 | Disordered | 0.786762 | Binding | 0.294 | 0.900 | 0.625 | -4.681 | Likely Benign | 0.522 | Ambiguous | Likely Benign | 0.104 | Likely Benign | -2.62 | Deleterious | 0.400 | Benign | 0.212 | Benign | 1.22 | Pathogenic | 0.06 | Tolerated | 0.1528 | 0.7393 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2410G>C | D804H 2D AIThe SynGAP1 D804H missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus 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 suggests that D804H is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.801317 | Disordered | 0.786762 | Binding | 0.294 | 0.900 | 0.625 | -5.100 | Likely Benign | 0.821 | Likely Pathogenic | Ambiguous | 0.296 | Likely Benign | -3.79 | Deleterious | 0.999 | Probably Damaging | 0.975 | Probably Damaging | 1.19 | Pathogenic | 0.01 | Affected | 0.1859 | 0.7607 | 1 | -1 | 0.3 | 22.05 | ||||||||||||||||||||||||||||||||||||||
| c.2410G>T | D804Y 2D AIThe SynGAP1 missense variant D804Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and AlphaMissense‑Optimized, whereas the remaining tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic outcome. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, therefore classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains pathogenic; Foldetta results are unavailable. Overall, the majority of predictions support a pathogenic effect, and this conclusion does not contradict any ClinVar annotation (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 | SH3-binding motif | 0.801317 | Disordered | 0.786762 | Binding | 0.294 | 0.900 | 0.625 | -8.356 | Likely Pathogenic | 0.782 | Likely Pathogenic | Likely Benign | 0.357 | Likely Benign | -5.16 | Deleterious | 0.999 | Probably Damaging | 0.983 | Probably Damaging | 1.18 | Pathogenic | 0.01 | Affected | 0.0886 | 0.6653 | -4 | -3 | 2.2 | 48.09 | ||||||||||||||||||||||||||||||||||||||
| c.2411A>C | D804A 2D AIThe SynGAP1 D804A missense variant is catalogued in gnomAD (ID 6‑33442963‑A‑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 are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized indicates a benign change, but the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method 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 pathogenic 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 Pathogenic | SH3-binding motif | 0.801317 | Disordered | 0.786762 | Binding | 0.294 | 0.900 | 0.625 | 6-33442963-A-C | -6.086 | Likely Benign | 0.758 | Likely Pathogenic | Likely Benign | 0.269 | Likely Benign | -3.99 | Deleterious | 0.980 | Probably Damaging | 0.858 | Possibly Damaging | 1.21 | Pathogenic | 0.04 | Affected | 3.77 | 5 | 0.3716 | 0.6824 | -2 | 0 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||
| c.2411A>G | D804G 2D AIThe SynGAP1 missense variant D804G is catalogued in gnomAD (ID 6‑33442963‑A‑G) but has no ClinVar entry. Prediction tools cluster into two groups: 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. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.801317 | Disordered | 0.786762 | Binding | 0.294 | 0.900 | 0.625 | 6-33442963-A-G | 1 | 6.20e-7 | -5.051 | Likely Benign | 0.680 | Likely Pathogenic | Likely Benign | 0.287 | Likely Benign | -3.82 | Deleterious | 0.980 | Probably Damaging | 0.858 | Possibly Damaging | 1.21 | Pathogenic | 0.04 | Affected | 3.77 | 5 | 0.3854 | 0.6488 | -1 | 1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||
| c.2411A>T | D804V 2D AIThe SynGAP1 missense variant D804V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—predict a pathogenic impact. The AlphaMissense‑Optimized score is uncertain, providing no definitive evidence. High‑accuracy assessments show that the SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic outcome; AlphaMissense‑Optimized remains inconclusive, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for D804V, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.801317 | Disordered | 0.786762 | Binding | 0.294 | 0.900 | 0.625 | -8.143 | Likely Pathogenic | 0.832 | Likely Pathogenic | Ambiguous | 0.402 | Likely Benign | -4.77 | Deleterious | 0.997 | Probably Damaging | 0.951 | Probably Damaging | 1.19 | Pathogenic | 0.01 | Affected | 0.1196 | 0.6981 | -2 | -3 | 7.7 | -15.96 | ||||||||||||||||||||||||||||||||||||||
| c.2412C>A | D804E 2D AIThe SynGAP1 D804E missense 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign” (3 benign vs. 1 pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote) as benign, and Foldetta results are unavailable. Based on the overall consensus of the available predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.801317 | Disordered | 0.786762 | Binding | 0.294 | 0.900 | 0.625 | -4.155 | Likely Benign | 0.243 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -2.03 | Neutral | 0.400 | Benign | 0.138 | Benign | 1.26 | Pathogenic | 0.04 | Affected | 0.1765 | 0.6850 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2412C>G | D804E 2D AIThe SynGAP1 D804E missense 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign” (3 benign vs. 1 pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote) as benign, and Foldetta results are unavailable. Based on the overall consensus of the available predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.801317 | Disordered | 0.786762 | Binding | 0.294 | 0.900 | 0.625 | -4.155 | Likely Benign | 0.243 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -2.03 | Neutral | 0.400 | Benign | 0.138 | Benign | 1.26 | Pathogenic | 0.04 | Affected | 0.1765 | 0.6850 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3445C>A | P1149T 2D  AIThe SynGAP1 missense variant P1149T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign status. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for P1149T, 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 | 0.762850 | Disordered | 0.786938 | Binding | 0.424 | 0.837 | 0.625 | -3.317 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -0.98 | Neutral | 0.649 | Possibly Damaging | 0.355 | Benign | 2.71 | Benign | 0.04 | Affected | 0.1755 | 0.5537 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3445C>G | P1149A 2D  AIThe SynGAP1 missense variant P1149A 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 | 0.762850 | Disordered | 0.786938 | Binding | 0.424 | 0.837 | 0.625 | -3.179 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.037 | Likely Benign | -0.72 | Neutral | 0.025 | Benign | 0.022 | Benign | 2.76 | Benign | 0.07 | Tolerated | 0.3403 | 0.4352 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3445C>T | P1149S 2D  AIThe SynGAP1 missense variant P1149S 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 for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.786938 | Binding | 0.424 | 0.837 | 0.625 | -2.650 | Likely Benign | 0.184 | Likely Benign | Likely Benign | 0.067 | Likely Benign | 0.14 | Neutral | 0.068 | Benign | 0.065 | Benign | 3.18 | Benign | 0.48 | Tolerated | 0.3460 | 0.4826 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3446C>A | P1149Q 2D  AIThe SynGAP1 missense variant P1149Q 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 a benign prediction, 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 | 0.762850 | Disordered | 0.786938 | Binding | 0.424 | 0.837 | 0.625 | -4.235 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -1.48 | Neutral | 0.990 | Probably Damaging | 0.798 | Possibly Damaging | 2.67 | Benign | 0.01 | Affected | 0.1515 | 0.4580 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3446C>G | P1149R 2D  AIThe SynGAP1 missense variant P1149R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for P1149R, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.786938 | Binding | 0.424 | 0.837 | 0.625 | -4.340 | Likely Benign | 0.706 | Likely Pathogenic | Likely Benign | 0.101 | Likely Benign | -1.94 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 2.67 | Benign | 0.01 | Affected | 0.1525 | 0.3671 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3446C>T | P1149L 2D  AIThe SynGAP1 missense variant P1149L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign status. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for P1149L, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.786938 | Binding | 0.424 | 0.837 | 0.625 | -3.438 | Likely Benign | 0.318 | Likely Benign | Likely Benign | 0.108 | Likely Benign | -1.90 | Neutral | 0.818 | Possibly Damaging | 0.381 | Benign | 2.67 | Benign | 0.01 | Affected | 0.2235 | 0.5918 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3805G>A | V1269M 2D  AIThe SynGAP1 missense variant V1269M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (majority vote) is pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic effect for V1269M, and 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 | 0.433034 | Structured | 0.787464 | Binding | 0.843 | 0.647 | 0.125 | -3.743 | Likely Benign | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.300 | Likely Benign | -2.53 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.08 | Pathogenic | 0.00 | Affected | 0.0582 | 0.3676 | 2 | 1 | -2.3 | 32.06 | ||||||||||||||||||||||||||||||||||||||
| c.3805G>C | V1269L 2D  AIThe SynGAP1 missense variant V1269L 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 other in silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy tools points to a pathogenic effect, and 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 | 0.433034 | Structured | 0.787464 | Binding | 0.843 | 0.647 | 0.125 | -3.572 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.299 | Likely Benign | -2.53 | Deleterious | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 2.14 | Pathogenic | 0.00 | Affected | 0.0683 | 0.4082 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3805G>T | V1269L 2D AIThe SynGAP1 missense variant V1269L 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 other in silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support 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 preponderance of predictions points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.433034 | Structured | 0.787464 | Binding | 0.843 | 0.647 | 0.125 | -3.572 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.299 | Likely Benign | -2.53 | Deleterious | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 2.14 | Pathogenic | 0.00 | Affected | 0.0683 | 0.4082 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3806T>A | V1269E 2D  AIThe SynGAP1 missense change V1269E is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that flag the variant as benign include only REVEL, whereas the remaining predictors—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classify it as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a “Likely Pathogenic” outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus as likely pathogenic; the Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a pathogenic effect, which does not contradict the ClinVar designation of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.433034 | Structured | 0.787464 | Binding | 0.843 | 0.647 | 0.125 | Uncertain | 1 | -11.418 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.403 | Likely Benign | -5.05 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.09 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.0899 | 0.1557 | -2 | -2 | -7.7 | 29.98 | ||||||||||||||||||||||||||||||||||
| c.3806T>C | V1269A 2D  AIThe SynGAP1 missense variant V1269A is not 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 larger group predicts pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and no Foldetta data. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.433034 | Structured | 0.787464 | Binding | 0.843 | 0.647 | 0.125 | -6.115 | Likely Benign | 0.954 | Likely Pathogenic | Ambiguous | 0.291 | Likely Benign | -3.38 | Deleterious | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 2.15 | Pathogenic | 0.00 | Affected | 0.2699 | 0.2312 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||||||||||||||
| c.3806T>G | V1269G 2D  AIThe SynGAP1 missense variant V1269G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include only REVEL, whereas all other evaluated algorithms—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenicity. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus is pathogenic; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.433034 | Structured | 0.787464 | Binding | 0.843 | 0.647 | 0.125 | -9.927 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 0.420 | Likely Benign | -5.91 | Deleterious | 0.995 | Probably Damaging | 0.999 | Probably Damaging | 2.10 | Pathogenic | 0.00 | Affected | 0.2180 | 0.2557 | -1 | -3 | -4.6 | -42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3823C>G | R1275G 2D AIThe SynGAP1 missense variant R1275G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, as well as the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for R1275G, 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 | 0.648219 | Disordered | 0.790317 | Binding | 0.723 | 0.697 | 0.500 | -6.302 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.130 | Likely Benign | -3.58 | Deleterious | 0.800 | Possibly Damaging | 0.277 | Benign | 2.54 | Benign | 0.01 | Affected | 0.3272 | 0.2486 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3823C>T | R1275W 2D AIThe SynGAP1 missense variant R1275W is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33447871‑C‑T). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas a majority (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b) predict a pathogenic impact; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a split vote (2 pathogenic, 1 benign, 1 uncertain). Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the balance of evidence leans toward a pathogenic classification, and this assessment does not contradict ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.648219 | Disordered | 0.790317 | Binding | 0.723 | 0.697 | 0.500 | 6-33447871-C-T | 3 | 1.93e-6 | -9.895 | Likely Pathogenic | 0.513 | Ambiguous | Likely Benign | 0.161 | Likely Benign | -4.76 | Deleterious | 0.999 | Probably Damaging | 0.875 | Possibly Damaging | 2.51 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1269 | 0.2372 | -3 | 2 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.3824G>A | R1275Q 2D  AIThe SynGAP1 missense variant R1275Q is listed in ClinVar with an uncertain significance (ClinVar ID 1720188.0) and is present in gnomAD (6‑33447872‑G‑A). Consensus from multiple in‑silico predictors shows a split: benign calls from REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, whereas pathogenic calls come from polyPhen‑2 HumDiv and SIFT. High‑accuracy tools reinforce the benign trend: 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 majority of evidence points to a benign effect, and this assessment does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.648219 | Disordered | 0.790317 | Binding | 0.723 | 0.697 | 0.500 | Uncertain | 1 | 6-33447872-G-A | 2 | 1.29e-6 | -4.928 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.103 | Likely Benign | -1.72 | Neutral | 0.898 | Possibly Damaging | 0.147 | Benign | 2.59 | Benign | 0.03 | Affected | 3.77 | 5 | 0.2592 | 0.1336 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.3824G>C | R1275P 2D AIThe SynGAP1 missense variant R1275P is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33447872‑G‑C). Prediction tools that agree on a benign effect are REVEL and FATHMM, while those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. Uncertain predictions come from ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact. This conclusion is consistent with the lack of ClinVar annotation, as there is no contradictory status to report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.648219 | Disordered | 0.790317 | Binding | 0.723 | 0.697 | 0.500 | 6-33447872-G-C | -7.155 | In-Between | 0.823 | Likely Pathogenic | Ambiguous | 0.145 | Likely Benign | -3.55 | Deleterious | 0.966 | Probably Damaging | 0.651 | Possibly Damaging | 2.53 | Benign | 0.01 | Affected | 3.77 | 5 | 0.2211 | 0.3083 | -2 | 0 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||
| c.3824G>T | R1275L 2D AIThe SynGAP1 missense variant R1275L is listed in ClinVar as benign and is present in gnomAD (ID 6‑33447872‑G‑T). Functional prediction tools show a split: benign calls come from REVEL, ESM1b, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar, while pathogenic calls come from PROVEAN, polyPhen2_HumDiv, and SIFT. Grouping by agreement, the benign‑predicted tools outnumber the pathogenic ones (5 vs 3). High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta results are unavailable. Overall, the computational evidence leans toward a benign effect, consistent with the ClinVar classification and showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.648219 | Disordered | 0.790317 | Binding | 0.723 | 0.697 | 0.500 | Likely Benign | 1 | 6-33447872-G-T | 1 | 6.45e-7 | -6.052 | Likely Benign | 0.446 | Ambiguous | Likely Benign | 0.117 | Likely Benign | -4.04 | Deleterious | 0.800 | Possibly Damaging | 0.277 | Benign | 2.55 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1687 | 0.3181 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||
| 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.2341A>C | M781L 2D AIThe SynGAP1 missense variant M781L 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 | 0.580690 | Disordered | 0.792850 | Binding | 0.342 | 0.889 | 0.625 | -2.334 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -0.41 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.83 | Benign | 0.88 | Tolerated | 0.1530 | 0.3669 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2341A>G | M781V 2D AIThe SynGAP1 missense variant M781V is catalogued in gnomAD (ID 6‑33442893‑A‑G) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool examined—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classifies the substitution as benign. No pathogenic predictions are reported. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the evidence overwhelmingly supports a benign effect, and this conclusion does not contradict any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.580690 | Disordered | 0.792850 | Binding | 0.342 | 0.889 | 0.625 | 6-33442893-A-G | 4 | 2.48e-6 | -2.624 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.174 | Likely Benign | 0.00 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.03 | Benign | 0.90 | Tolerated | 3.64 | 6 | 0.3081 | 0.2705 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||||||||||||||
| c.2341A>T | M781L 2D AIThe SynGAP1 missense variant M781L 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 predicts pathogenicity. High‑accuracy assessments corroborate this benign classification: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign status. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this prediction 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 | 0.580690 | Disordered | 0.792850 | Binding | 0.342 | 0.889 | 0.625 | -2.334 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -0.41 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.83 | Benign | 0.88 | Tolerated | 0.1530 | 0.3669 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2342T>A | M781K 2D AIThe SynGAP1 missense variant M781K is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.580690 | Disordered | 0.792850 | Binding | 0.342 | 0.889 | 0.625 | -6.321 | Likely Benign | 0.734 | Likely Pathogenic | Likely Benign | 0.258 | Likely Benign | -1.47 | Neutral | 0.138 | Benign | 0.150 | Benign | 2.72 | Benign | 0.20 | Tolerated | 0.1550 | 0.0688 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||||||
| c.2342T>C | M781T 2D AIThe SynGAP1 missense variant M781T is catalogued in gnomAD (ID 6‑33442894‑T‑C) and has no ClinVar entry. Across the evaluated in‑silico tools, every predictor classifies 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 reports a pathogenic or likely pathogenic outcome. The high‑accuracy consensus methods 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 predictor, has no available result for this variant. Based on the unanimous benign predictions and the lack of any 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 | 0.580690 | Disordered | 0.792850 | Binding | 0.342 | 0.889 | 0.625 | 6-33442894-T-C | 1 | 6.21e-7 | -3.774 | Likely Benign | 0.310 | Likely Benign | Likely Benign | 0.175 | Likely Benign | -0.86 | Neutral | 0.015 | Benign | 0.037 | Benign | 2.75 | Benign | 0.59 | Tolerated | 3.64 | 6 | 0.2267 | 0.1599 | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||||||||||||||||
| c.2342T>G | M781R 2D AIThe SynGAP1 missense variant M781R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign 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 | 0.580690 | Disordered | 0.792850 | Binding | 0.342 | 0.889 | 0.625 | -4.990 | Likely Benign | 0.697 | Likely Pathogenic | Likely Benign | 0.265 | Likely Benign | -1.72 | Neutral | 0.327 | Benign | 0.206 | Benign | 2.71 | Benign | 0.14 | Tolerated | 0.1685 | 0.0837 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||||||
| c.2343G>A | M781I 2D AIThe SynGAP1 missense variant M781I is listed in ClinVar (ID 2802065.0) as Benign and is not reported in gnomAD. All available in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the predictions strongly support a benign effect, consistent with the ClinVar designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.580690 | Disordered | 0.792850 | Binding | 0.342 | 0.889 | 0.625 | Benign | 1 | -2.484 | Likely Benign | 0.323 | Likely Benign | Likely Benign | 0.101 | Likely Benign | 0.05 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.89 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1405 | 0.2793 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||
| c.2343G>C | M781I 2D AIThe SynGAP1 missense variant M781I is catalogued in gnomAD (ID 6‑33442895‑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 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, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant, so its status is 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 | 0.580690 | Disordered | 0.792850 | Binding | 0.342 | 0.889 | 0.625 | 6-33442895-G-C | 1 | 6.21e-7 | -2.484 | Likely Benign | 0.323 | Likely Benign | Likely Benign | 0.101 | Likely Benign | 0.05 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.89 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1405 | 0.2793 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||
| c.2343G>T | M781I 2D AIThe SynGAP1 missense variant M781I 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, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the evidence strongly suggests that M781I 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 | 0.580690 | Disordered | 0.792850 | Binding | 0.342 | 0.889 | 0.625 | -2.484 | Likely Benign | 0.323 | Likely Benign | Likely Benign | 0.101 | Likely Benign | 0.05 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.89 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1405 | 0.2793 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.3448G>A | A1150T 2D  AIThe SynGAP1 missense variant A1150T is 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 unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.795712 | Binding | 0.371 | 0.831 | 0.625 | -3.467 | Likely Benign | 0.176 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -2.06 | Neutral | 0.905 | Possibly Damaging | 0.687 | Possibly Damaging | 2.34 | Pathogenic | 0.03 | Affected | 0.1540 | 0.7182 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3448G>C | A1150P 2D  AIThe SynGAP1 missense variant A1150P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (SGM‑Consensus, REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic predictions (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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) is labeled Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign effect for A1150P, and this conclusion is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.795712 | Binding | 0.371 | 0.831 | 0.625 | -2.250 | Likely Benign | 0.180 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -0.74 | Neutral | 0.995 | Probably Damaging | 0.940 | Probably Damaging | 2.48 | Pathogenic | 0.25 | Tolerated | 0.1896 | 0.5294 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3448G>T | A1150S 2D  AIThe SynGAP1 missense variant A1150S is reported in gnomAD (ID 6‑33444483‑G‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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 absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.795712 | Binding | 0.371 | 0.831 | 0.625 | 6-33444483-G-T | 7 | 4.34e-6 | -2.656 | Likely Benign | 0.126 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -1.49 | Neutral | 0.951 | Possibly Damaging | 0.752 | Possibly Damaging | 2.37 | Pathogenic | 0.10 | Tolerated | 3.77 | 5 | 0.2656 | 0.5694 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||
| c.3449C>A | A1150D 2D  AIThe SynGAP1 missense variant A1150D is not reported 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, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evaluated tools (five pathogenic vs. three benign) predict a pathogenic impact. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.762850 | Disordered | 0.795712 | Binding | 0.371 | 0.831 | 0.625 | -3.923 | Likely Benign | 0.859 | Likely Pathogenic | Ambiguous | 0.156 | Likely Benign | -2.30 | Neutral | 0.995 | Probably Damaging | 0.940 | Probably Damaging | 2.30 | Pathogenic | 0.01 | Affected | 0.1754 | 0.2143 | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.3449C>G | A1150G 2D  AIThe SynGAP1 A1150G 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, 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 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 ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.795712 | Binding | 0.371 | 0.831 | 0.625 | -3.089 | Likely Benign | 0.253 | Likely Benign | Likely Benign | 0.158 | Likely Benign | -2.37 | Neutral | 0.983 | Probably Damaging | 0.818 | Possibly Damaging | 2.32 | Pathogenic | 0.09 | Tolerated | 0.2263 | 0.4741 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3449C>T | A1150V 2D  AIThe SynGAP1 missense variant A1150V is listed in ClinVar (ID 589625.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33444484‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are SIFT and FATHMM. High‑accuracy assessments further support a benign outcome: 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, did not provide a result for this variant. Overall, the majority of computational evidence indicates that A1150V is most likely benign, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.795712 | Binding | 0.371 | 0.831 | 0.625 | Uncertain | 1 | 6-33444484-C-T | 3 | 1.86e-6 | -3.648 | Likely Benign | 0.192 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -2.22 | Neutral | 0.114 | Benign | 0.055 | Benign | 2.32 | Pathogenic | 0.04 | Affected | 3.77 | 5 | 0.1242 | 0.6335 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||
| c.3826G>A | D1276N 2D AIThe SynGAP1 missense variant D1276N is not 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, more tools (five) predict pathogenicity than benign (three), and the high‑accuracy consensus also leans pathogenic. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.802156 | Binding | 0.636 | 0.705 | 0.625 | 3.371 | Likely Benign | 0.473 | Ambiguous | Likely Benign | 0.242 | Likely Benign | -3.68 | Deleterious | 0.899 | Possibly Damaging | 0.581 | Possibly Damaging | 1.22 | Pathogenic | 0.00 | Affected | 0.0883 | 0.5213 | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||||
| c.3826G>C | D1276H 2D AIThe SynGAP1 missense variant D1276H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates majority votes from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further highlight discordance: AlphaMissense‑Optimized predicts a benign effect, whereas the SGM‑Consensus (a high‑accuracy consensus) indicates Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions support a pathogenic 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 Pathogenic | 0.666105 | Disordered | 0.802156 | Binding | 0.636 | 0.705 | 0.625 | 0.715 | Likely Benign | 0.778 | Likely Pathogenic | Likely Benign | 0.321 | Likely Benign | -5.08 | Deleterious | 0.996 | Probably Damaging | 0.898 | Possibly Damaging | 1.19 | Pathogenic | 0.00 | Affected | 0.1077 | 0.5697 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.3826G>T | D1276Y 2D AIThe SynGAP1 missense variant D1276Y is catalogued in gnomAD (ID 6‑33447874‑G‑T) but has no ClinVar entry. Functional prediction tools fall into two groups: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus indicates a likely pathogenic effect; Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar status, as none is currently reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.666105 | Disordered | 0.802156 | Binding | 0.636 | 0.705 | 0.625 | 6-33447874-G-T | -1.558 | Likely Benign | 0.768 | Likely Pathogenic | Likely Benign | 0.325 | Likely Benign | -6.66 | Deleterious | 0.999 | Probably Damaging | 0.928 | Probably Damaging | 1.18 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.0385 | 0.5082 | -3 | -4 | 2.2 | 48.09 | ||||||||||||||||||||||||||||||||||||
| c.3827A>C | D1276A 2D AIThe SynGAP1 missense variant D1276A has no ClinVar entry and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support this split: AlphaMissense‑Optimized reports a benign effect, whereas the SGM‑Consensus (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 computational evidence points to a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently contains no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.666105 | Disordered | 0.802156 | Binding | 0.636 | 0.705 | 0.625 | -0.008 | Likely Benign | 0.710 | Likely Pathogenic | Likely Benign | 0.319 | Likely Benign | -5.87 | Deleterious | 0.816 | Possibly Damaging | 0.495 | Possibly Damaging | 1.21 | Pathogenic | 0.00 | Affected | 0.3458 | 0.5050 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||||||
| c.3827A>G | D1276G 2D AIThe SynGAP1 missense variant D1276G is not 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 include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains Likely Pathogenic; Foldetta results are unavailable. Overall, the majority of predictions and the SGM‑Consensus support a pathogenic interpretation, and there is no ClinVar record to contradict this assessment. 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 | 0.666105 | Disordered | 0.802156 | Binding | 0.636 | 0.705 | 0.625 | 0.509 | Likely Benign | 0.601 | Likely Pathogenic | Likely Benign | 0.293 | Likely Benign | -4.93 | Deleterious | 0.899 | Possibly Damaging | 0.655 | Possibly Damaging | 1.21 | Pathogenic | 0.00 | Affected | 0.3429 | 0.5247 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3827A>T | D1276V 2D AIThe SynGAP1 D1276V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. The SGM‑Consensus, 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 (combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Based on the preponderance of pathogenic predictions and the SGM‑Consensus result, the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.666105 | Disordered | 0.802156 | Binding | 0.636 | 0.705 | 0.625 | -0.725 | Likely Benign | 0.851 | Likely Pathogenic | Ambiguous | 0.331 | Likely Benign | -6.66 | Deleterious | 0.984 | Probably Damaging | 0.825 | Possibly Damaging | 1.19 | Pathogenic | 0.00 | Affected | 0.0614 | 0.5207 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.3828C>A | D1276E 2D AIThe SynGAP1 missense variant D1276E is catalogued in gnomAD (ID 6‑33447876‑C‑A) but has no ClinVar submission. Functional prediction tools show a split assessment: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Optimized, whereas pathogenic calls arise from PROVEAN, SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. A high‑accuracy consensus (SGM) that aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic verdict. AlphaMissense‑Optimized alone predicts benign, and no Foldetta stability data are available. Overall, the majority of individual predictors favor a benign effect, but the SGM consensus contradicts this by labeling the variant pathogenic. Because ClinVar contains no classification, there is no external evidence to resolve the discrepancy. Thus, based on the current computational evidence, the variant is most likely benign, though the SGM consensus suggests a possible pathogenic interpretation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.802156 | Binding | 0.636 | 0.705 | 0.625 | 6-33447876-C-A | -0.388 | Likely Benign | 0.416 | Ambiguous | Likely Benign | 0.091 | Likely Benign | -2.64 | Deleterious | 0.027 | Benign | 0.020 | Benign | 1.26 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1027 | 0.5365 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.3828C>G | D1276E 2D AIThe SynGAP1 missense variant D1276E is not reported in ClinVar and is absent from gnomAD. Consensus from routine in silico predictors shows a split: benign calls from REVEL, polyPhen‑2 (HumDiv and HumVar), and ESM1b, versus pathogenic calls from PROVEAN, SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans pathogenic. Foldetta, a protein‑folding stability method, has no available output for this residue. Overall, the balance of evidence tilts toward a benign interpretation, and this conclusion is not in conflict with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.802156 | Binding | 0.636 | 0.705 | 0.625 | -0.388 | Likely Benign | 0.416 | Ambiguous | Likely Benign | 0.092 | Likely Benign | -2.64 | Deleterious | 0.027 | Benign | 0.020 | Benign | 1.26 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1027 | 0.5365 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3796C>A | L1266M 2D AIThe SynGAP1 missense variant L1266M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and PROVEAN, whereas a larger set—polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized yields an uncertain result, SGM‑Consensus remains likely pathogenic, and Foldetta data are unavailable. Overall, the majority of evidence points toward a pathogenic effect for L1266M. This conclusion does not conflict with ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.433034 | Structured | 0.802655 | Binding | 0.868 | 0.602 | 0.000 | -8.257 | Likely Pathogenic | 0.938 | Likely Pathogenic | Ambiguous | 0.126 | Likely Benign | -1.67 | Neutral | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 2.12 | Pathogenic | 0.00 | Affected | 0.0627 | 0.3113 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3796C>G | L1266V 2D AIThe SynGAP1 missense variant L1266V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: REVEL predicts a benign outcome, whereas all other evaluated algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.433034 | Structured | 0.802655 | Binding | 0.868 | 0.602 | 0.000 | -10.024 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.125 | Likely Benign | -2.53 | Deleterious | 0.995 | Probably Damaging | 0.890 | Possibly Damaging | 2.16 | Pathogenic | 0.00 | Affected | 0.1301 | 0.3118 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3797T>A | L1266Q 2D AIThe SynGAP1 missense variant L1266Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated predictors—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN)—classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also indicates likely pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence points to a pathogenic effect for L1266Q, and 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 | 0.433034 | Structured | 0.802655 | Binding | 0.868 | 0.602 | 0.000 | -16.101 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.374 | Likely Benign | -5.02 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.12 | Pathogenic | 0.00 | Affected | 0.0906 | 0.1249 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||||||
| c.3797T>C | L1266P 2D AIThe SynGAP1 missense variant L1266P is reported in gnomAD (6‑33447845‑T‑C) but has no ClinVar entry. Prediction tools cluster into two groups: benign predictions are made only by REVEL, whereas all other evaluated algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic effect. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized returns a pathogenic score, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Pathogenic.” The Foldetta stability analysis is unavailable for this variant. Overall, the consensus of both general and high‑accuracy predictors points to a pathogenic 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 Pathogenic | Coiled-coil | 0.433034 | Structured | 0.802655 | Binding | 0.868 | 0.602 | 0.000 | 6-33447845-T-C | -16.566 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.424 | Likely Benign | -5.83 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.10 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.3150 | 0.2283 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||
| c.3797T>G | L1266R 2D AISynGAP1 missense variant L1266R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic, and the SGM‑Consensus confirms a likely pathogenic classification. Foldetta results are unavailable for this variant. Overall, the preponderance of evidence from multiple in silico predictors and high‑accuracy tools points to a pathogenic effect, with no conflict from ClinVar status (which has no entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.433034 | Structured | 0.802655 | Binding | 0.868 | 0.602 | 0.000 | -16.676 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.391 | Likely Benign | -5.04 | Deleterious | 0.996 | Probably Damaging | 0.951 | Probably Damaging | 2.13 | Pathogenic | 0.00 | Affected | 0.1063 | 0.0891 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||
| c.3802C>A | L1268M 2D AIThe SynGAP1 missense variant L1268M is reported in gnomAD (ID 6‑33447850‑C‑A) and has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; a Foldetta stability analysis is not available. Overall, the preponderance of evidence from multiple in silico predictors and consensus methods indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.458154 | Structured | 0.804315 | Binding | 0.859 | 0.629 | 0.000 | 6-33447850-C-A | -4.689 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.07 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.67 | Benign | 0.08 | Tolerated | 3.77 | 5 | 0.0627 | 0.2297 | 2 | 4 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||
| c.3802C>G | L1268V 2D AIThe SynGAP1 missense variant L1268V 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) indicates a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports likely benign. Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for the variant, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.458154 | Structured | 0.804315 | Binding | 0.859 | 0.629 | 0.000 | -4.137 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -0.24 | Neutral | 0.649 | Possibly Damaging | 0.157 | Benign | 2.73 | Benign | 0.25 | Tolerated | 0.1331 | 0.2289 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3803T>A | L1268Q 2D AIThe SynGAP1 missense variant L1268Q 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, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also indicates benign. Foldetta results are not available, so they do not influence the assessment. Overall, the preponderance of evidence points to a benign impact 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 Benign | Coiled-coil | 0.458154 | Structured | 0.804315 | Binding | 0.859 | 0.629 | 0.000 | -5.707 | Likely Benign | 0.143 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.50 | Neutral | 0.990 | Probably Damaging | 0.637 | Possibly Damaging | 2.68 | Benign | 0.08 | Tolerated | 0.0988 | 0.0558 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||||||
| c.3803T>C | L1268P 2D AIThe SynGAP1 missense variant L1268P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑accuracy predictors (5 vs. 4) indicate a pathogenic impact. This conclusion is not contradicted by ClinVar status, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.458154 | Structured | 0.804315 | Binding | 0.859 | 0.629 | 0.000 | -9.062 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.091 | Likely Benign | -1.03 | Neutral | 0.970 | Probably Damaging | 0.637 | Possibly Damaging | 2.65 | Benign | 0.24 | Tolerated | 0.3261 | 0.1053 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3803T>G | L1268R 2D AIThe SynGAP1 missense change L1268R is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign) all support a neutral impact. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome, while ESM1b remains uncertain. High‑accuracy tools reinforce the benign assessment: AlphaMissense‑Optimized returns a benign prediction and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. Foldetta results are not available, so they do not influence the interpretation. Overall, the preponderance of evidence points to a benign effect for L1268R, and 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 | Coiled-coil | 0.458154 | Structured | 0.804315 | Binding | 0.859 | 0.629 | 0.000 | -7.010 | In-Between | 0.293 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.79 | Neutral | 0.970 | Probably Damaging | 0.637 | Possibly Damaging | 2.68 | Benign | 0.08 | Tolerated | 0.1135 | 0.0558 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||
| 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.3451T>A | S1151T 2D  AIThe SynGAP1 missense variant S1151T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. Foldetta, 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 | 0.741537 | Disordered | 0.805072 | Binding | 0.394 | 0.839 | 0.625 | -3.874 | Likely Benign | 0.124 | Likely Benign | Likely Benign | 0.080 | Likely Benign | -0.06 | Neutral | 0.798 | Possibly Damaging | 0.535 | Possibly Damaging | 2.72 | Benign | 0.30 | Tolerated | 0.1450 | 0.5903 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3451T>C | S1151P 2D  AIThe SynGAP1 missense variant S1151P 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 this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are not available. Overall, the consensus of the available predictions indicates that the variant is most likely benign, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.741537 | Disordered | 0.805072 | Binding | 0.394 | 0.839 | 0.625 | -3.031 | Likely Benign | 0.298 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -1.47 | Neutral | 0.995 | Probably Damaging | 0.892 | Possibly Damaging | 2.67 | Benign | 0.11 | Tolerated | 0.1953 | 0.5320 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3451T>G | S1151A 2D  AIThe SynGAP1 missense variant S1151A 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” consensus. High‑accuracy assessments further support a benign classification: 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 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 | 0.741537 | Disordered | 0.805072 | Binding | 0.394 | 0.839 | 0.625 | -3.311 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.084 | Likely Benign | -0.13 | Neutral | 0.889 | Possibly Damaging | 0.535 | Possibly Damaging | 2.75 | Benign | 0.42 | Tolerated | 0.4711 | 0.5087 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3452C>A | S1151Y 2D  AIThe SynGAP1 missense variant S1151Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. AlphaMissense‑Optimized also predicts a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑confidence tools and the consensus prediction favor a benign impact, and there is no ClinVar entry to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.741537 | Disordered | 0.805072 | Binding | 0.394 | 0.839 | 0.625 | -4.456 | Likely Benign | 0.642 | Likely Pathogenic | Likely Benign | 0.166 | Likely Benign | -0.87 | Neutral | 0.995 | Probably Damaging | 0.925 | Probably Damaging | 2.68 | Benign | 0.05 | Affected | 0.0778 | 0.5287 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.3452C>G | S1151C 2D  AIThe SynGAP1 missense variant S1151C is reported in gnomAD (ID 6‑33444487‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (polyPhen‑2 HumDiv and HumVar) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.741537 | Disordered | 0.805072 | Binding | 0.394 | 0.839 | 0.625 | 6-33444487-C-G | 1 | 6.20e-7 | -6.778 | Likely Benign | 0.225 | Likely Benign | Likely Benign | 0.181 | Likely Benign | -0.86 | Neutral | 0.999 | Probably Damaging | 0.944 | Probably Damaging | 2.67 | Benign | 0.07 | Tolerated | 3.77 | 5 | 0.1056 | 0.5260 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||
| c.3452C>T | S1151F 2D  AIThe SynGAP1 missense variant S1151F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.741537 | Disordered | 0.805072 | Binding | 0.394 | 0.839 | 0.625 | -4.433 | Likely Benign | 0.661 | Likely Pathogenic | Likely Benign | 0.170 | Likely Benign | -0.60 | Neutral | 0.995 | Probably Damaging | 0.925 | Probably Damaging | 2.70 | Benign | 0.19 | Tolerated | 0.0749 | 0.5370 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.3829C>A | H1277N 2D  AIThe SynGAP1 missense variant H1277N is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33447877‑C‑A). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.775545 | Disordered | 0.805725 | Binding | 0.562 | 0.718 | 0.750 | 6-33447877-C-A | -3.347 | Likely Benign | 0.193 | Likely Benign | Likely Benign | 0.114 | Likely Benign | -4.96 | Deleterious | 0.224 | Benign | 0.120 | Benign | 2.14 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1562 | 0.1250 | 1 | 2 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||
| c.3829C>G | H1277D 2D  AIThe SynGAP1 missense variant H1277D is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33447877‑C‑G). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), and ESM1b, while those that predict a pathogenic effect are PROVEAN, SIFT, and FATHMM. AlphaMissense‑Default is uncertain, whereas AlphaMissense‑Optimized predicts benign. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a pathogenic outcome (two pathogenic, one benign, one uncertain). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑accuracy and consensus predictions indicate a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.775545 | Disordered | 0.805725 | Binding | 0.562 | 0.718 | 0.750 | 6-33447877-C-G | -4.632 | Likely Benign | 0.537 | Ambiguous | Likely Benign | 0.172 | Likely Benign | -6.38 | Deleterious | 0.411 | Benign | 0.091 | Benign | 2.14 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2389 | 0.1266 | -1 | 1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||
| c.3829C>T | H1277Y 2D  AIThe SynGAP1 missense variant H1277Y is not 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 (5 benign vs 4 pathogenic predictions) leans toward a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.775545 | Disordered | 0.805725 | Binding | 0.562 | 0.718 | 0.750 | -4.288 | Likely Benign | 0.232 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -4.32 | Deleterious | 0.812 | Possibly Damaging | 0.298 | Benign | 2.36 | Pathogenic | 0.00 | Affected | 0.0742 | 0.3034 | 0 | 2 | 1.9 | 26.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3830A>C | H1277P 2D  AIThe SynGAP1 missense variant H1277P is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33447878‑A‑C). 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 classifying the variant as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of predictions lean toward a benign impact, and this is consistent with the lack of a ClinVar pathogenic 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. | 0.775545 | Disordered | 0.805725 | Binding | 0.562 | 0.718 | 0.750 | 6-33447878-A-C | -3.829 | Likely Benign | 0.324 | Likely Benign | Likely Benign | 0.237 | Likely Benign | -7.14 | Deleterious | 0.586 | Possibly Damaging | 0.287 | Benign | 2.12 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2266 | 0.3393 | -2 | 0 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||
| c.3830A>G | H1277R 2D  AIThe SynGAP1 missense variant H1277R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two benign vs. two pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.775545 | Disordered | 0.805725 | Binding | 0.562 | 0.718 | 0.750 | -2.940 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.164 | Likely Benign | -5.60 | Deleterious | 0.259 | Benign | 0.066 | Benign | 2.15 | Pathogenic | 0.00 | Affected | 0.1710 | 0.1562 | 2 | 0 | -1.3 | 19.05 | ||||||||||||||||||||||||||||||||||||||||
| c.3830A>T | H1277L 2D  AIThe SynGAP1 missense variant H1277L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two benign vs. two pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.775545 | Disordered | 0.805725 | Binding | 0.562 | 0.718 | 0.750 | -2.949 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.215 | Likely Benign | -7.93 | Deleterious | 0.224 | Benign | 0.091 | Benign | 2.17 | Pathogenic | 0.00 | Affected | 0.0822 | 0.4158 | -2 | -3 | 7.0 | -23.98 | ||||||||||||||||||||||||||||||||||||||||
| c.3831C>A | H1277Q 2D  AIThe SynGAP1 missense variant H1277Q is reported in gnomAD (ID 6‑33447879‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b; pathogenic predictions come from PROVEAN, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while 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 majority of evidence points toward a benign effect, and this conclusion does not conflict with the absence of a ClinVar classification. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.775545 | Disordered | 0.805725 | Binding | 0.562 | 0.718 | 0.750 | 6-33447879-C-A | -3.323 | Likely Benign | 0.325 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -5.34 | Deleterious | 0.004 | Benign | 0.010 | Benign | 2.14 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1311 | 0.2351 | 0 | 3 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||
| c.3831C>G | H1277Q 2D AIThe SynGAP1 missense variant H1277Q 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, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b; pathogenic predictions come from PROVEAN, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs. 2 pathogenic). Foldetta results are not available. Overall, the majority of evidence points toward a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.775545 | Disordered | 0.805725 | Binding | 0.562 | 0.718 | 0.750 | -3.323 | Likely Benign | 0.325 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -5.34 | Deleterious | 0.004 | Benign | 0.010 | Benign | 2.14 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1311 | 0.2351 | 0 | 3 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||||||
| c.2266C>A | Q756K 2D AIThe SynGAP1 missense variant Q756K is not reported 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 as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for Q756K, 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 | 0.458154 | Structured | 0.806299 | Binding | 0.340 | 0.866 | 0.250 | -6.059 | Likely Benign | 0.340 | Likely Benign | Likely Benign | 0.199 | Likely Benign | -1.47 | Neutral | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 1.60 | Pathogenic | 0.21 | Tolerated | 0.1816 | 0.4797 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2266C>G | Q756E 2D AIThe SynGAP1 missense variant Q756E is 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 Q756E, 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 | 0.458154 | Structured | 0.806299 | Binding | 0.340 | 0.866 | 0.250 | -4.149 | Likely Benign | 0.172 | Likely Benign | Likely Benign | 0.174 | Likely Benign | -1.19 | Neutral | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 1.58 | Pathogenic | 0.23 | Tolerated | 0.1465 | 0.2853 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2267A>C | Q756P 2D AIThe SynGAP1 missense variant Q756P has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM all predict a pathogenic impact. 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, PROVEAN) also indicates a likely benign outcome. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.458154 | Structured | 0.806299 | Binding | 0.340 | 0.866 | 0.250 | -4.226 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.315 | Likely Benign | -0.93 | Neutral | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 1.54 | Pathogenic | 0.23 | Tolerated | 0.2590 | 0.5186 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2267A>G | Q756R 2D AIThe SynGAP1 missense variant Q756R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for Q756R, and 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 | 0.458154 | Structured | 0.806299 | Binding | 0.340 | 0.866 | 0.250 | -5.044 | Likely Benign | 0.307 | Likely Benign | Likely Benign | 0.245 | Likely Benign | -1.77 | Neutral | 0.994 | Probably Damaging | 0.988 | Probably Damaging | 1.58 | Pathogenic | 0.14 | Tolerated | 0.1500 | 0.2440 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.2267A>T | Q756L 2D AIThe SynGAP1 missense variant Q756L is not reported 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 labeled “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for Q756L, 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 | 0.458154 | Structured | 0.806299 | Binding | 0.340 | 0.866 | 0.250 | -3.697 | Likely Benign | 0.339 | Likely Benign | Likely Benign | 0.274 | Likely Benign | -1.95 | Neutral | 0.994 | Probably Damaging | 0.988 | Probably Damaging | 1.56 | Pathogenic | 0.08 | Tolerated | 0.0797 | 0.5700 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2268G>C | Q756H 2D AIThe SynGAP1 missense variant Q756H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign 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 | 0.458154 | Structured | 0.806299 | Binding | 0.340 | 0.866 | 0.250 | -4.625 | Likely Benign | 0.276 | Likely Benign | Likely Benign | 0.197 | Likely Benign | -2.17 | Neutral | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 1.54 | Pathogenic | 0.05 | Affected | 0.1545 | 0.4404 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2268G>T | Q756H 2D AIThe SynGAP1 missense variant Q756H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign 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 | 0.458154 | Structured | 0.806299 | Binding | 0.340 | 0.866 | 0.250 | -4.625 | Likely Benign | 0.276 | Likely Benign | Likely Benign | 0.197 | Likely Benign | -2.17 | Neutral | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 1.54 | Pathogenic | 0.05 | Affected | 0.1545 | 0.4404 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3832C>A | P1278T 2D AIThe SynGAP1 missense variant P1278T is catalogued in gnomAD (ID 6‑33447880‑C‑A) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized returns a benign prediction, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status remains unavailable. Overall, the computational evidence overwhelmingly supports a benign effect, and this assessment does not contradict any ClinVar classification. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.806955 | Binding | 0.532 | 0.722 | 0.750 | 6-33447880-C-A | -5.505 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.064 | Likely Benign | -0.60 | Neutral | 0.059 | Benign | 0.026 | Benign | 2.73 | Benign | 0.11 | Tolerated | 3.77 | 5 | 0.1825 | 0.4053 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3832C>G | P1278A 2D AIThe SynGAP1 missense variant P1278A 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, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.806955 | Binding | 0.532 | 0.722 | 0.750 | -4.187 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.100 | Likely Benign | 0.89 | Neutral | 0.001 | Benign | 0.002 | Benign | 3.15 | Benign | 1.00 | Tolerated | 0.3597 | 0.3353 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3832C>T | P1278S 2D AIThe SynGAP1 missense variant P1278S 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 | 0.788093 | Disordered | 0.806955 | Binding | 0.532 | 0.722 | 0.750 | -4.383 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.077 | Likely Benign | 0.28 | Neutral | 0.004 | Benign | 0.003 | Benign | 2.96 | Benign | 0.35 | Tolerated | 0.3616 | 0.3697 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3833C>A | P1278H 2D  AIThe SynGAP1 missense variant P1278H is reported in gnomAD (variant ID 6‑33447881‑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, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict pathogenic. High‑accuracy assessments confirm the benign prediction: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the same set of benign predictions) is benign; Foldetta results are unavailable. 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 and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.806955 | Binding | 0.532 | 0.722 | 0.750 | 6-33447881-C-A | 7 | 4.51e-6 | -5.691 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.087 | Likely Benign | -1.69 | Neutral | 0.938 | Possibly Damaging | 0.477 | Possibly Damaging | 2.67 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1997 | 0.3155 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||
| c.3833C>G | P1278R 2D AIThe SynGAP1 missense variant P1278R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign status. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for P1278R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.806955 | Binding | 0.532 | 0.722 | 0.750 | -4.246 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -1.11 | Neutral | 0.586 | Possibly Damaging | 0.114 | Benign | 2.69 | Benign | 0.05 | Affected | 0.1640 | 0.2282 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3833C>T | P1278L 2D AIThe SynGAP1 missense variant P1278L 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 | 0.788093 | Disordered | 0.806955 | Binding | 0.532 | 0.722 | 0.750 | -4.903 | Likely Benign | 0.116 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -1.86 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.69 | Benign | 0.07 | Tolerated | 0.2338 | 0.4996 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2743G>A | G915S 2D AIThe SynGAP1 missense variant G915S is listed in ClinVar as Benign (ClinVar ID 652083.0) and is present in the gnomAD database (gnomAD ID 6‑33443295‑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 predict benign. Only polyPhen‑2 HumDiv reports a pathogenic prediction, representing the sole discordant signal. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that the variant is most likely benign, and this conclusion is consistent with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.657645 | Disordered | 0.808641 | Binding | 0.302 | 0.880 | 0.375 | Benign | 1 | 6-33443295-G-A | 9 | 5.58e-6 | -3.557 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.050 | Likely Benign | -0.88 | Neutral | 0.801 | Possibly Damaging | 0.201 | Benign | 2.73 | Benign | 0.31 | Tolerated | 3.77 | 5 | 0.2393 | 0.4875 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||
| c.2743G>C | G915R 2D AIThe SynGAP1 missense variant G915R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for G915R, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.657645 | Disordered | 0.808641 | Binding | 0.302 | 0.880 | 0.375 | -4.528 | Likely Benign | 0.656 | Likely Pathogenic | Likely Benign | 0.104 | Likely Benign | -2.31 | Neutral | 0.999 | Probably Damaging | 0.969 | Probably Damaging | 2.69 | Benign | 0.00 | Affected | 0.0805 | 0.4204 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2743G>T | G915C 2D AIThe SynGAP1 missense variant G915C is listed in ClinVar with no submitted interpretation and is present in gnomAD (variant ID 6-33443295-G‑T). Functional prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (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 (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.657645 | Disordered | 0.808641 | Binding | 0.302 | 0.880 | 0.375 | 6-33443295-G-T | 1 | 6.20e-7 | -6.446 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.103 | Likely Benign | -2.84 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 2.64 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1023 | 0.4471 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||
| c.2744G>A | G915D 2D AIThe SynGAP1 missense variant G915D is not reported 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 G915D, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.657645 | Disordered | 0.808641 | Binding | 0.302 | 0.880 | 0.375 | -3.409 | Likely Benign | 0.502 | Ambiguous | Likely Benign | 0.134 | Likely Benign | -1.75 | Neutral | 0.978 | Probably Damaging | 0.871 | Possibly Damaging | 2.70 | Benign | 0.01 | Affected | 0.1574 | 0.1559 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2744G>C | G915A 2D AIThe SynGAP1 missense variant G915A 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 returns Benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign effect for G915A, 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 | 0.657645 | Disordered | 0.808641 | Binding | 0.302 | 0.880 | 0.375 | -4.007 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -1.22 | Neutral | 0.900 | Possibly Damaging | 0.622 | Possibly Damaging | 2.87 | Benign | 0.05 | Affected | 0.3454 | 0.4930 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2744G>T | G915V 2D AIThe SynGAP1 missense variant G915V is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (6‑33443296‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (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 (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also as benign; the Foldetta stability analysis is unavailable. Overall, the majority of predictions, including the most reliable tools, indicate a benign impact. This consensus does not contradict ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.657645 | Disordered | 0.808641 | Binding | 0.302 | 0.880 | 0.375 | 6-33443296-G-T | -4.586 | Likely Benign | 0.189 | Likely Benign | Likely Benign | 0.149 | Likely Benign | -2.52 | Deleterious | 0.997 | Probably Damaging | 0.918 | Probably Damaging | 2.68 | Benign | 0.01 | Affected | 3.77 | 5 | 0.0927 | 0.4291 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||
| 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.3454G>A | E1152K 2D AIThe SynGAP1 missense variant E1152K is reported in gnomAD (ID 6‑33444489‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic.” High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a deleterious effect, and the SGM‑Consensus confirms a likely pathogenic outcome. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the collective evidence points to a pathogenic effect, and this conclusion is not contradicted by ClinVar, which contains no classification for E1152K. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.741537 | Disordered | 0.811118 | Binding | 0.395 | 0.846 | 0.500 | 6-33444489-G-A | 1 | 6.20e-7 | -3.612 | Likely Benign | 0.966 | Likely Pathogenic | Likely Pathogenic | 0.300 | Likely Benign | -2.64 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.38 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.2942 | 0.6397 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||
| c.3454G>C | E1152Q 2D AIThe SynGAP1 missense variant E1152Q is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (five pathogenic vs. three benign) lean toward a pathogenic interpretation. This 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. | 0.741537 | Disordered | 0.811118 | Binding | 0.395 | 0.846 | 0.500 | -2.798 | Likely Benign | 0.830 | Likely Pathogenic | Ambiguous | 0.291 | Likely Benign | -1.98 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.37 | Pathogenic | 0.03 | Affected | 0.1747 | 0.6395 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||||
| c.3455A>C | E1152A 2D AIThe SynGAP1 missense variant E1152A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Overall, the balance of evidence points to a pathogenic effect for E1152A. 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 | 0.741537 | Disordered | 0.811118 | Binding | 0.395 | 0.846 | 0.500 | -2.482 | Likely Benign | 0.927 | Likely Pathogenic | Ambiguous | 0.349 | Likely Benign | -3.82 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.37 | Pathogenic | 0.02 | Affected | 0.4434 | 0.6557 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3455A>G | E1152G 2D AIThe SynGAP1 missense variant E1152G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Overall, the balance of evidence points to a pathogenic effect for E1152G. 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. | Likely Pathogenic | 0.741537 | Disordered | 0.811118 | Binding | 0.395 | 0.846 | 0.500 | -2.663 | Likely Benign | 0.918 | Likely Pathogenic | Ambiguous | 0.373 | Likely Benign | -3.85 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.36 | Pathogenic | 0.01 | Affected | 0.3242 | 0.5249 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3455A>T | E1152V 2D AIThe SynGAP1 missense variant E1152V is not 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, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.741537 | Disordered | 0.811118 | Binding | 0.395 | 0.846 | 0.500 | -3.304 | Likely Benign | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.408 | Likely Benign | -4.65 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.33 | Pathogenic | 0.00 | Affected | 0.1247 | 0.6384 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.3456G>C | E1152D 2D AIThe SynGAP1 missense variant E1152D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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. 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 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 | 0.741537 | Disordered | 0.811118 | Binding | 0.395 | 0.846 | 0.500 | -3.488 | Likely Benign | 0.669 | Likely Pathogenic | Likely Benign | 0.171 | Likely Benign | -0.45 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.76 | Benign | 0.51 | Tolerated | 0.2151 | 0.4770 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3456G>T | E1152D 2D AIThe SynGAP1 missense variant E1152D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta, 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, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.741537 | Disordered | 0.811118 | Binding | 0.395 | 0.846 | 0.500 | -3.488 | Likely Benign | 0.669 | Likely Pathogenic | Likely Benign | 0.171 | Likely Benign | -0.45 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.76 | Benign | 0.51 | Tolerated | 0.2151 | 0.4770 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3496G>A | A1166T 2D AIThe SynGAP1 missense variant A1166T is not reported in ClinVar and has no gnomAD entry. Consensus and most in silico predictors classify it as benign: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate a benign effect. In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by ClinVar data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.575842 | Disordered | 0.811691 | Binding | 0.381 | 0.803 | 0.375 | -3.615 | Likely Benign | 0.748 | Likely Pathogenic | Likely Benign | 0.343 | Likely Benign | -1.13 | Neutral | 0.995 | Probably Damaging | 0.963 | Probably Damaging | 5.37 | Benign | 0.26 | Tolerated | 0.1328 | 0.6418 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3496G>C | A1166P 2D AIThe SynGAP1 missense variant A1166P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as Pathogenic, whereas the SGM‑Consensus (majority vote) indicates Likely Benign; Foldetta results are unavailable. Overall, the predictions are mixed, with a slight bias toward benign, and there is no ClinVar entry to contradict the current assessment. Thus, the variant is most likely benign based on the collective evidence, though high‑accuracy tools provide conflicting signals. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.575842 | Disordered | 0.811691 | Binding | 0.381 | 0.803 | 0.375 | -2.890 | Likely Benign | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.468 | Likely Benign | -1.09 | Neutral | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 5.29 | Benign | 0.23 | Tolerated | 0.1774 | 0.4237 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3496G>T | A1166S 2D AIThe SynGAP1 missense variant A1166S is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy methods that are available—AlphaMissense‑Optimized and the SGM‑Consensus—both support a benign classification. Consequently, the variant is most likely benign according to the majority of predictive evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.575842 | Disordered | 0.811691 | Binding | 0.381 | 0.803 | 0.375 | -2.587 | Likely Benign | 0.396 | Ambiguous | Likely Benign | 0.308 | Likely Benign | -0.59 | Neutral | 0.995 | Probably Damaging | 0.949 | Probably Damaging | 5.41 | Benign | 0.35 | Tolerated | 0.2568 | 0.5239 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3497C>A | A1166D 2D AIThe SynGAP1 missense variant A1166D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, while the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence (five benign vs. four pathogenic) and the consensus score lean toward a benign interpretation, with no conflict with ClinVar status. Thus, the variant is most likely benign, although the AlphaMissense‑Optimized prediction introduces some uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.575842 | Disordered | 0.811691 | Binding | 0.381 | 0.803 | 0.375 | -4.204 | Likely Benign | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.417 | Likely Benign | -1.56 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 5.29 | Benign | 0.42 | Tolerated | 0.1709 | 0.2104 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.3497C>G | A1166G 2D AISynGAP1 missense variant A1166G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv 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 consensus of the majority of tools and the high‑accuracy predictions indicate that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.575842 | Disordered | 0.811691 | Binding | 0.381 | 0.803 | 0.375 | -3.679 | Likely Benign | 0.745 | Likely Pathogenic | Likely Benign | 0.355 | Likely Benign | -1.17 | Neutral | 0.361 | Benign | 0.307 | Benign | 5.34 | Benign | 0.31 | Tolerated | 0.2244 | 0.3977 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3497C>T | A1166V 2D AIThe SynGAP1 A1166V missense variant has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports 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 effect. The variant’s predicted benign status does not contradict any ClinVar annotation, as none exists. Thus, based on current computational predictions, the A1166V variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.575842 | Disordered | 0.811691 | Binding | 0.381 | 0.803 | 0.375 | -4.305 | Likely Benign | 0.843 | Likely Pathogenic | Ambiguous | 0.291 | Likely Benign | -1.04 | Neutral | 0.995 | Probably Damaging | 0.963 | Probably Damaging | 5.43 | Benign | 0.40 | Tolerated | 0.0967 | 0.5384 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.3799A>C | M1267L 2D AIThe SynGAP1 missense variant M1267L is not 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 results are unavailable. Overall, the majority of evidence (five pathogenic‑predicting tools versus three benign) indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.429200 | Structured | 0.812047 | Binding | 0.847 | 0.614 | 0.000 | -1.766 | Likely Benign | 0.399 | Ambiguous | Likely Benign | 0.293 | Likely Benign | -2.52 | Deleterious | 0.813 | Possibly Damaging | 0.456 | Possibly Damaging | 2.36 | Pathogenic | 0.00 | Affected | 0.1392 | 0.3626 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3799A>G | M1267V 2D AIThe SynGAP1 missense variant M1267V is not 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, 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) indicate a pathogenic effect. This prediction is not contradicted by ClinVar status, as the variant is not yet catalogued there. Thus, based on current computational evidence, the M1267V variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.429200 | Structured | 0.812047 | Binding | 0.847 | 0.614 | 0.000 | -2.249 | Likely Benign | 0.537 | Ambiguous | Likely Benign | 0.254 | Likely Benign | -3.34 | Deleterious | 0.959 | Probably Damaging | 0.672 | Possibly Damaging | 2.35 | Pathogenic | 0.00 | Affected | 0.3057 | 0.3241 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||||||||||||
| c.3799A>T | M1267L 2D AIThe SynGAP1 missense variant M1267L is not 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 (five pathogenic‑predicting tools versus three benign‑predicting tools) indicates that M1267L is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.429200 | Structured | 0.812047 | Binding | 0.847 | 0.614 | 0.000 | -1.766 | Likely Benign | 0.399 | Ambiguous | Likely Benign | 0.293 | Likely Benign | -2.52 | Deleterious | 0.813 | Possibly Damaging | 0.456 | Possibly Damaging | 2.36 | Pathogenic | 0.00 | Affected | 0.1392 | 0.3626 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3800T>A | M1267K 2D AIThe SynGAP1 missense variant M1267K 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, and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a pathogenic outcome (3/4 pathogenic). AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. Overall, the majority of evidence points to a deleterious effect, classifying the variant as most likely pathogenic. 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 Pathogenic | Coiled-coil | 0.429200 | Structured | 0.812047 | Binding | 0.847 | 0.614 | 0.000 | -6.415 | Likely Benign | 0.917 | Likely Pathogenic | Ambiguous | 0.366 | Likely Benign | -5.01 | Deleterious | 0.884 | Possibly Damaging | 0.581 | Possibly Damaging | 2.31 | Pathogenic | 0.00 | Affected | 0.1373 | 0.0488 | 0 | -1 | -5.8 | -3.02 | ||||||||||||||||||||||||||||||||||||||
| c.3800T>C | M1267T 2D AIThe SynGAP1 missense variant M1267T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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 a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote) likewise indicates likely pathogenicity. No Foldetta stability prediction is available for this variant. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.429200 | Structured | 0.812047 | Binding | 0.847 | 0.614 | 0.000 | -5.315 | Likely Benign | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.270 | Likely Benign | -5.00 | Deleterious | 0.982 | Probably Damaging | 0.672 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | 0.2036 | 0.1934 | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||||||||||||||||||||
| c.3800T>G | M1267R 2D AIThe SynGAP1 missense variant M1267R 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, and AlphaMissense‑Default. Grouping by consensus, two tools predict benign and six predict pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as likely pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic impact, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.429200 | Structured | 0.812047 | Binding | 0.847 | 0.614 | 0.000 | -4.990 | Likely Benign | 0.899 | Likely Pathogenic | Ambiguous | 0.366 | Likely Benign | -5.03 | Deleterious | 0.982 | Probably Damaging | 0.757 | Possibly Damaging | 2.30 | Pathogenic | 0.00 | Affected | 0.1555 | 0.0837 | 0 | -1 | -6.4 | 24.99 | ||||||||||||||||||||||||||||||||||||||
| c.3801G>A | M1267I 2D AIThe SynGAP1 missense variant M1267I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for M1267I. This conclusion is not contradicted by ClinVar status, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.429200 | Structured | 0.812047 | Binding | 0.847 | 0.614 | 0.000 | -1.432 | Likely Benign | 0.936 | Likely Pathogenic | Ambiguous | 0.205 | Likely Benign | -3.33 | Deleterious | 0.959 | Probably Damaging | 0.672 | Possibly Damaging | 2.33 | Pathogenic | 0.00 | Affected | 0.1254 | 0.2741 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3801G>C | M1267I 2D AIThe SynGAP1 missense variant M1267I 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 (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) remains Likely Pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for M1267I. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.429200 | Structured | 0.812047 | Binding | 0.847 | 0.614 | 0.000 | -1.432 | Likely Benign | 0.936 | Likely Pathogenic | Ambiguous | 0.205 | Likely Benign | -3.33 | Deleterious | 0.959 | Probably Damaging | 0.672 | Possibly Damaging | 2.33 | Pathogenic | 0.00 | Affected | 0.1254 | 0.2741 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3801G>T | M1267I 2D AIThe SynGAP1 missense variant M1267I 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 (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) remains Likely Pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for M1267I. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.429200 | Structured | 0.812047 | Binding | 0.847 | 0.614 | 0.000 | -1.432 | Likely Benign | 0.936 | Likely Pathogenic | Ambiguous | 0.205 | Likely Benign | -3.33 | Deleterious | 0.959 | Probably Damaging | 0.672 | Possibly Damaging | 2.33 | Pathogenic | 0.00 | Affected | 0.1254 | 0.2741 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.2338T>A | S780T 2D AIThe SynGAP1 missense variant S780T is reported in ClinVar as “Not submitted” and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, while Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.812415 | Binding | 0.283 | 0.883 | 0.500 | -4.911 | Likely Benign | 0.157 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -0.63 | Neutral | 0.951 | Possibly Damaging | 0.614 | Possibly Damaging | 2.66 | Benign | 0.84 | Tolerated | 0.1445 | 0.6631 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2338T>C | S780P 2D AIThe SynGAP1 missense variant S780P is reported in gnomAD (ID 6‑33442890‑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. 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, SGM‑Consensus is 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 | 0.599170 | Disordered | 0.812415 | Binding | 0.283 | 0.883 | 0.500 | 6-33442890-T-C | 1 | 6.22e-7 | -6.055 | Likely Benign | 0.234 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -1.11 | Neutral | 0.995 | Probably Damaging | 0.892 | Possibly Damaging | 2.64 | Benign | 0.30 | Tolerated | 3.64 | 6 | 0.2086 | 0.6171 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||
| c.2338T>G | S780A 2D AIThe SynGAP1 missense variant S780A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that S780A 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 | 0.599170 | Disordered | 0.812415 | Binding | 0.283 | 0.883 | 0.500 | -5.627 | Likely Benign | 0.164 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -0.40 | Neutral | 0.798 | Possibly Damaging | 0.340 | Benign | 2.69 | Benign | 0.74 | Tolerated | 0.4936 | 0.5522 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2339C>A | S780Y 2D AIThe SynGAP1 missense variant S780Y is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default; ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.599170 | Disordered | 0.812415 | Binding | 0.283 | 0.883 | 0.500 | -7.682 | In-Between | 0.656 | Likely Pathogenic | Likely Benign | 0.091 | Likely Benign | -1.71 | Neutral | 0.995 | Probably Damaging | 0.925 | Probably Damaging | 2.61 | Benign | 0.11 | Tolerated | 0.0810 | 0.6428 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||||||
| c.2339C>G | S780C 2D AIThe SynGAP1 missense variant S780C is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33442891‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). No tool in the dataset predicts a pathogenic outcome; ESM1b is inconclusive and therefore treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while Foldetta results are not reported and thus unavailable. Based on the collective predictions, the variant is most likely benign, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.812415 | Binding | 0.283 | 0.883 | 0.500 | Uncertain | 4 | 6-33442891-C-G | 16 | 9.94e-6 | -7.603 | In-Between | 0.278 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.41 | Neutral | 0.065 | Benign | 0.043 | Benign | 2.59 | Benign | 0.10 | Tolerated | 3.64 | 6 | 0.1063 | 0.6581 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||
| c.2339C>T | S780F 2D AIThe SynGAP1 missense variant S780F is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic) and therefore unavailable as evidence. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is also unavailable for this variant. Overall, the majority of available predictions (five benign vs. four pathogenic) lean toward a benign impact. There is no ClinVar annotation to contradict this assessment, so the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.599170 | Disordered | 0.812415 | Binding | 0.283 | 0.883 | 0.500 | -8.055 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 0.104 | Likely Benign | -1.42 | Neutral | 0.995 | Probably Damaging | 0.925 | Probably Damaging | 2.61 | Benign | 0.10 | Tolerated | 0.0768 | 0.6706 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||||
| c.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.3859C>A | P1287T 2D AIThe SynGAP1 missense variant P1287T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33447907‑C‑A). 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, 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 | 0.827927 | Disordered | 0.813701 | Binding | 0.538 | 0.777 | 0.750 | Uncertain | 1 | 6-33447907-C-A | -3.940 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.22 | Neutral | 0.126 | Benign | 0.041 | Benign | 2.78 | Benign | 0.04 | Affected | 3.77 | 5 | 0.1189 | 0.3995 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||
| c.3859C>G | P1287A 2D AIThe SynGAP1 missense variant P1287A 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, 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 | 0.827927 | Disordered | 0.813701 | Binding | 0.538 | 0.777 | 0.750 | -3.064 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.090 | Likely Benign | 0.51 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.91 | Benign | 0.57 | Tolerated | 0.2885 | 0.3222 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3859C>T | P1287S 2D AIThe SynGAP1 missense variant P1287S is catalogued in gnomAD (ID 6‑33447907‑C‑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 variant 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 of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the collective predictions, 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 | 0.827927 | Disordered | 0.813701 | Binding | 0.538 | 0.777 | 0.750 | 6-33447907-C-T | -3.258 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.055 | Likely Benign | 0.70 | Neutral | 0.004 | Benign | 0.004 | Benign | 2.96 | Benign | 0.96 | Tolerated | 3.77 | 5 | 0.2820 | 0.3566 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||
| c.3860C>A | P1287H 2D AIThe SynGAP1 missense variant P1287H is recorded in gnomAD (6‑33447908‑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, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) is not available for this variant. Based on the aggregate 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 | 0.827927 | Disordered | 0.813701 | Binding | 0.538 | 0.777 | 0.750 | 6-33447908-C-A | -3.606 | Likely Benign | 0.135 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -1.36 | Neutral | 0.938 | Possibly Damaging | 0.596 | Possibly Damaging | 2.80 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1306 | 0.3448 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||
| c.3860C>G | P1287R 2D AIThe SynGAP1 missense variant P1287R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign status. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for P1287R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.813701 | Binding | 0.538 | 0.777 | 0.750 | -2.180 | Likely Benign | 0.165 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -1.37 | Neutral | 0.586 | Possibly Damaging | 0.172 | Benign | 2.77 | Benign | 0.01 | Affected | 0.1337 | 0.2427 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3860C>T | P1287L 2D AIThe SynGAP1 missense variant P1287L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33447908‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.813701 | Binding | 0.538 | 0.777 | 0.750 | Conflicting | 2 | 6-33447908-C-T | -2.800 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -1.66 | Neutral | 0.021 | Benign | 0.017 | Benign | 2.76 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1861 | 0.4727 | -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.3862A>C | K1288Q 2D AIThe SynGAP1 missense variant K1288Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a 2‑to‑2 split and is therefore inconclusive. Foldetta, a protein‑folding stability method that combines FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence is divided, with an equal number of benign and pathogenic calls, leaving the variant’s clinical significance uncertain. This uncertainty does not contradict ClinVar, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.827927 | Disordered | 0.814714 | Binding | 0.538 | 0.784 | 0.625 | -2.369 | Likely Benign | 0.172 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -2.51 | Deleterious | 0.991 | Probably Damaging | 0.987 | Probably Damaging | 2.11 | Pathogenic | 0.00 | Affected | 0.4149 | 0.0657 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3862A>G | K1288E 2D AISynGAP1 missense variant K1288E is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33447910‑A‑G). Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this change. Overall, the preponderance of evidence points to a pathogenic effect, which is consistent with the ClinVar designation of uncertain significance rather than a clear benign classification. Thus, the variant is most likely pathogenic, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.827927 | Disordered | 0.814714 | Binding | 0.538 | 0.784 | 0.625 | Uncertain | 1 | 6-33447910-A-G | 5 | 3.22e-6 | -2.751 | Likely Benign | 0.407 | Ambiguous | Likely Benign | 0.185 | Likely Benign | -3.27 | Deleterious | 0.979 | Probably Damaging | 0.973 | Probably Damaging | 2.13 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.3627 | 0.0676 | 1 | 0 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||
| c.3863A>C | K1288T 2D AIThe SynGAP1 missense variant K1288T is not 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 predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, more tools (five) predict pathogenicity than benign (three), and the high‑accuracy consensus also leans pathogenic. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.827927 | Disordered | 0.814714 | Binding | 0.538 | 0.784 | 0.625 | -2.616 | Likely Benign | 0.477 | Ambiguous | Likely Benign | 0.227 | Likely Benign | -4.84 | Deleterious | 0.991 | Probably Damaging | 0.982 | Probably Damaging | 2.09 | Pathogenic | 0.00 | Affected | 0.2066 | 0.2614 | 0 | -1 | 3.2 | -27.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3863A>G | K1288R 2D AIThe SynGAP1 missense variant K1288R is not reported 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 a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.814714 | Binding | 0.538 | 0.784 | 0.625 | -2.367 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.141 | Likely Benign | -2.22 | Neutral | 0.979 | Probably Damaging | 0.973 | Probably Damaging | 2.14 | Pathogenic | 0.00 | Affected | 0.4189 | 0.0782 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||||||||||||
| c.3863A>T | K1288M 2D AIThe SynGAP1 missense variant K1288M is not 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 predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus indicates a likely pathogenic outcome; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of computational predictions (seven pathogenic vs. three benign) point to a pathogenic impact for K1288M. This conclusion is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.827927 | Disordered | 0.814714 | Binding | 0.538 | 0.784 | 0.625 | -3.355 | Likely Benign | 0.660 | Likely Pathogenic | Likely Benign | 0.246 | Likely Benign | -4.89 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.06 | Pathogenic | 0.00 | Affected | 0.0985 | 0.3140 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.3864G>C | K1288N 2D AIThe SynGAP1 missense variant K1288N has no ClinVar entry 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. AlphaMissense‑Optimized is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no result for this variant. High‑accuracy assessments therefore show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as unavailable. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.827927 | Disordered | 0.814714 | Binding | 0.538 | 0.784 | 0.625 | -3.670 | Likely Benign | 0.801 | Likely Pathogenic | Ambiguous | 0.128 | Likely Benign | -4.05 | Deleterious | 0.991 | Probably Damaging | 0.987 | Probably Damaging | 2.10 | Pathogenic | 0.00 | Affected | 0.3513 | 0.1101 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3864G>T | K1288N 2D AIThe SynGAP1 missense variant K1288N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and ESM1b, while the majority of tools predict a pathogenic effect: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy assessments therefore show an uncertain AlphaMissense‑Optimized prediction, a Likely Pathogenic SGM‑Consensus, and no Foldetta data. Overall, the preponderance of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.827927 | Disordered | 0.814714 | Binding | 0.538 | 0.784 | 0.625 | -3.670 | Likely Benign | 0.801 | Likely Pathogenic | Ambiguous | 0.128 | Likely Benign | -4.05 | Deleterious | 0.991 | Probably Damaging | 0.987 | Probably Damaging | 2.10 | Pathogenic | 0.00 | Affected | 0.3513 | 0.1101 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2440G>A | A814T 2D AIThe SynGAP1 missense variant A814T is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome, while Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -3.600 | Likely Benign | 0.227 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -1.24 | Neutral | 0.103 | Benign | 0.047 | Benign | 2.64 | Benign | 0.09 | Tolerated | 0.1400 | 0.6655 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||||
| c.2440G>C | A814P 2D AIThe SynGAP1 missense variant A814P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic 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 (majority vote) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple independent predictors points to a benign effect for A814P, 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 | 0.411940 | Structured | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -5.247 | Likely Benign | 0.351 | Ambiguous | Likely Benign | 0.210 | Likely Benign | -1.88 | Neutral | 0.984 | Probably Damaging | 0.855 | Possibly Damaging | 2.64 | Benign | 0.05 | Affected | 0.1845 | 0.4941 | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||||||||||
| c.2440G>T | A814S 2D AIThe SynGAP1 missense variant A814S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports 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 | SH3-binding motif | 0.411940 | Structured | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -2.542 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -1.22 | Neutral | 0.640 | Possibly Damaging | 0.386 | Benign | 2.63 | Benign | 0.06 | Tolerated | 0.2670 | 0.5366 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||||
| c.2441C>A | A814D 2D AIThe SynGAP1 missense variant A814D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a tie and thus unavailable, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no reported result. Overall, the balance of evidence from the consensus of standard predictors points to a pathogenic effect. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.411940 | Structured | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -5.641 | Likely Benign | 0.939 | Likely Pathogenic | Ambiguous | 0.158 | Likely Benign | -2.56 | Deleterious | 0.968 | Probably Damaging | 0.810 | Possibly Damaging | 2.59 | Benign | 0.01 | Affected | 0.1740 | 0.2167 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2441C>G | A814G 2D AIThe SynGAP1 missense variant A814G 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. 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 | SH3-binding motif | 0.411940 | Structured | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -3.659 | Likely Benign | 0.312 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -1.83 | Neutral | 0.896 | Possibly Damaging | 0.649 | Possibly Damaging | 2.60 | Benign | 0.05 | Affected | 0.2336 | 0.4504 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2441C>T | A814V 2D AIThe SynGAP1 missense variant A814V 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 (HumDiv and HumVar) 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, so these do not influence the overall inference. Overall, the preponderance of evidence points to a benign effect for A814V, and 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 | 0.411940 | Structured | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -4.147 | Likely Benign | 0.374 | Ambiguous | Likely Benign | 0.119 | Likely Benign | -0.14 | Neutral | 0.811 | Possibly Damaging | 0.489 | Possibly Damaging | 2.71 | Benign | 0.83 | Tolerated | 0.1088 | 0.6197 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||||
| 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.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.3844G>A | E1282K 2D AIThe SynGAP1 missense variant E1282K is catalogued in gnomAD (ID 6‑33447892‑G‑A) 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 a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status remains unavailable. Overall, the computational evidence overwhelmingly supports a benign effect for E1282K, and this conclusion does not contradict any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.817364 | Binding | 0.465 | 0.725 | 0.875 | 6-33447892-G-A | -3.805 | Likely Benign | 0.226 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -1.17 | Neutral | 0.126 | Benign | 0.026 | Benign | 2.73 | Benign | 0.16 | Tolerated | 3.77 | 5 | 0.1821 | 0.5809 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||
| c.3844G>C | E1282Q 2D AIThe SynGAP1 missense variant E1282Q 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 | 0.754692 | Disordered | 0.817364 | Binding | 0.465 | 0.725 | 0.875 | -2.785 | Likely Benign | 0.106 | Likely Benign | Likely Benign | 0.079 | Likely Benign | 1.05 | Neutral | 0.004 | Benign | 0.003 | Benign | 2.70 | Benign | 0.31 | Tolerated | 0.0965 | 0.5651 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3845A>C | E1282A 2D AIThe SynGAP1 missense variant E1282A is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classifies the substitution as benign. No pathogenic predictions are present. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts 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, was not available for this variant. Overall, the computational evidence overwhelmingly supports a benign impact, and this conclusion does not contradict any ClinVar status, as none exists for E1282A. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.817364 | Binding | 0.465 | 0.725 | 0.875 | -1.980 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.118 | Likely Benign | 0.52 | Neutral | 0.026 | Benign | 0.018 | Benign | 2.94 | Benign | 0.38 | Tolerated | 0.3411 | 0.5358 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3845A>G | E1282G 2D AIThe SynGAP1 missense variant E1282G is reported in gnomAD (ID 6‑33447893‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it to be pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Taken together, the overwhelming majority of predictions support a benign impact, and there is no ClinVar classification to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.817364 | Binding | 0.465 | 0.725 | 0.875 | 6-33447893-A-G | -2.649 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.219 | Likely Benign | -1.25 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.68 | Benign | 0.00 | Affected | 0.2729 | 0.5284 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||||
| c.3845A>T | E1282V 2D AIThe SynGAP1 missense variant E1282V is reported in gnomAD (ID 6‑33447893‑A‑T) but has no ClinVar entry. In silico prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all 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 (majority‑vote method) is 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 (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.817364 | Binding | 0.465 | 0.725 | 0.875 | 6-33447893-A-T | -2.790 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -1.71 | Neutral | 0.369 | Benign | 0.078 | Benign | 2.72 | Benign | 0.04 | Affected | 0.0656 | 0.5905 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||
| c.3846G>C | E1282D 2D AIThe SynGAP1 missense variant E1282D is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6-33447894-G-C). All available 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. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm 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 reported result for this variant, so its status is unavailable. Overall, the computational evidence overwhelmingly supports a benign effect, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.817364 | Binding | 0.465 | 0.725 | 0.875 | Uncertain | 1 | 6-33447894-G-C | 1 | 6.44e-7 | -3.879 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -1.26 | Neutral | 0.112 | Benign | 0.036 | Benign | 2.70 | Benign | 0.39 | Tolerated | 3.77 | 5 | 0.1826 | 0.3464 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||
| c.3846G>T | E1282D 2D AIThe SynGAP1 missense variant E1282D is reported in gnomAD (ID 6‑33447894‑G‑T) but has no ClinVar entry. All in‑silico predictors reviewed—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as benign. No tool predicts pathogenicity, so the benign group includes every listed predictor, while the pathogenic group is empty. High‑accuracy assessments further support a benign effect: 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 any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.817364 | Binding | 0.465 | 0.725 | 0.875 | 6-33447894-G-T | -3.879 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -1.26 | Neutral | 0.112 | Benign | 0.036 | Benign | 2.70 | Benign | 0.39 | Tolerated | 3.77 | 5 | 0.1826 | 0.3464 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.3355G>A | G1119R 2D AIThe SynGAP1 missense variant G1119R is listed in ClinVar as benign and is present in gnomAD (ID 6‑33443907‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and ESM1b predict a pathogenic impact. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, aligning with the ClinVar classification; there is no contradiction between the predictions and the reported ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.827927 | Disordered | 0.818538 | Binding | 0.339 | 0.928 | 0.875 | Benign | 1 | 6-33443907-G-A | 64 | 4.23e-5 | -8.489 | Likely Pathogenic | 0.473 | Ambiguous | Likely Benign | 0.303 | Likely Benign | 0.10 | Neutral | 0.969 | Probably Damaging | 0.462 | Possibly Damaging | 4.03 | Benign | 0.10 | Tolerated | 4.32 | 2 | 0.1112 | 0.4733 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||
| c.3355G>C | G1119R 2D AIThe SynGAP1 missense variant G1119R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. AlphaMissense‑Default is uncertain. High‑accuracy assessment shows AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.827927 | Disordered | 0.818538 | Binding | 0.339 | 0.928 | 0.875 | -8.489 | Likely Pathogenic | 0.473 | Ambiguous | Likely Benign | 0.289 | Likely Benign | 0.10 | Neutral | 0.969 | Probably Damaging | 0.462 | Possibly Damaging | 4.03 | Benign | 0.10 | Tolerated | 4.32 | 2 | 0.1112 | 0.4733 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3355G>T | G1119W 2D  AIThe SynGAP1 missense variant G1119W is reported in gnomAD (ID 6‑33443907‑G‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are unavailable. Overall, the majority of computational evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.818538 | Binding | 0.339 | 0.928 | 0.875 | 6-33443907-G-T | -10.904 | Likely Pathogenic | 0.336 | Likely Benign | Likely Benign | 0.386 | Likely Benign | -1.19 | Neutral | 0.997 | Probably Damaging | 0.949 | Probably Damaging | 3.90 | Benign | 0.02 | Affected | 4.32 | 2 | 0.0948 | 0.4059 | -2 | -7 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||
| c.3356G>A | G1119E 2D  AIThe SynGAP1 missense variant G1119E is reported in gnomAD (variant ID 6-33443908‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only ESM1b predicts a pathogenic outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that G1119E is most likely benign, and this conclusion is not contradicted by any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.818538 | Binding | 0.339 | 0.928 | 0.875 | 6-33443908-G-A | 1 | 6.61e-7 | -9.151 | Likely Pathogenic | 0.338 | Likely Benign | Likely Benign | 0.284 | Likely Benign | -0.41 | Neutral | 0.005 | Benign | 0.013 | Benign | 3.93 | Benign | 0.12 | Tolerated | 4.32 | 2 | 0.1654 | 0.4259 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| c.3356G>C | G1119A 2D AIThe SynGAP1 missense variant G1119A 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 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 | 0.818538 | Binding | 0.339 | 0.928 | 0.875 | -6.703 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.201 | Likely Benign | -0.33 | Neutral | 0.393 | Benign | 0.187 | Benign | 3.93 | Benign | 1.00 | Tolerated | 0.3591 | 0.4957 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3356G>T | G1119V 2D AIThe SynGAP1 missense variant G1119V 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. 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: 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 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 | 0.827927 | Disordered | 0.818538 | Binding | 0.339 | 0.928 | 0.875 | -6.428 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.352 | Likely Benign | -0.94 | Neutral | 0.918 | Possibly Damaging | 0.604 | Possibly Damaging | 3.91 | Benign | 0.31 | Tolerated | 0.1493 | 0.3707 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3847C>A | P1283T 2D AIThe SynGAP1 missense variant P1283T is catalogued in gnomAD (ID 6‑33447895‑C‑A) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized returns a benign prediction, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Therefore, 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 | 0.762850 | Disordered | 0.819686 | Binding | 0.484 | 0.732 | 0.875 | 6-33447895-C-A | -4.781 | Likely Benign | 0.064 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -0.45 | Neutral | 0.451 | Benign | 0.193 | Benign | 2.76 | Benign | 0.11 | Tolerated | 3.77 | 5 | 0.1269 | 0.3784 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3847C>G | P1283A 2D AIThe SynGAP1 missense variant P1283A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign. Foldetta results are unavailable, so they do not influence the overall assessment. Consequently, the variant is most likely benign based on the collective predictions, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.819686 | Binding | 0.484 | 0.732 | 0.875 | -3.656 | Likely Benign | 0.055 | Likely Benign | Likely Benign | 0.070 | Likely Benign | 1.42 | Neutral | 0.004 | Benign | 0.004 | Benign | 2.79 | Benign | 1.00 | Tolerated | 0.2874 | 0.3370 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3847C>T | P1283S 2D AIThe SynGAP1 missense variant P1283S is catalogued in gnomAD (ID 6‑33447895‑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, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Therefore, the variant is most likely benign, and this assessment does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.819686 | Binding | 0.484 | 0.732 | 0.875 | 6-33447895-C-T | -4.289 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.040 | Likely Benign | 0.06 | Neutral | 0.292 | Benign | 0.110 | Benign | 2.86 | Benign | 0.30 | Tolerated | 3.77 | 5 | 0.2837 | 0.3719 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||
| c.3848C>A | P1283Q 2D AIThe SynGAP1 missense variant P1283Q is reported in gnomAD (variant ID 6‑33447896‑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 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’s protein‑folding stability analysis is unavailable. Overall, the preponderance of evidence indicates that the variant is most likely benign, 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 | 0.762850 | Disordered | 0.819686 | Binding | 0.484 | 0.732 | 0.875 | 6-33447896-C-A | -4.028 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -1.11 | Neutral | 0.991 | Probably Damaging | 0.567 | Possibly Damaging | 2.72 | Benign | 0.04 | Affected | 3.77 | 5 | 0.1195 | 0.2926 | -1 | 0 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||
| c.3848C>G | P1283R 2D AIThe SynGAP1 missense variant P1283R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.819686 | Binding | 0.484 | 0.732 | 0.875 | -3.643 | Likely Benign | 0.130 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -1.40 | Neutral | 0.911 | Possibly Damaging | 0.567 | Possibly Damaging | 2.72 | Benign | 0.05 | Affected | 0.1377 | 0.2211 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3848C>T | P1283L 2D AIThe SynGAP1 missense variant P1283L is listed in ClinVar (ID 536994.0) as Benign and is present in gnomAD (gnomAD ID 6‑33447896‑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: 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. Overall, the computational evidence overwhelmingly supports a benign effect, aligning with the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.819686 | Binding | 0.484 | 0.732 | 0.875 | Benign | 1 | 6-33447896-C-T | 32 | 2.06e-5 | -3.740 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.047 | Likely Benign | -1.04 | Neutral | 0.005 | Benign | 0.003 | Benign | 2.76 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0.1878 | 0.4716 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||
| c.3457C>G | R1153G 2D AIThe SynGAP1 missense variant R1153G 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—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence indicates that R1153G is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.762850 | Disordered | 0.820118 | Binding | 0.361 | 0.848 | 0.625 | -3.010 | Likely Benign | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.309 | Likely Benign | -5.05 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 1.48 | Pathogenic | 0.00 | Affected | 0.3408 | 0.3475 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3457C>T | R1153W 2D AIThe SynGAP1 missense variant R1153W is listed in ClinVar (ID 521099.0) with an uncertain significance designation and is present in the gnomAD database (variant ID 6‑33444492‑C‑T). Functional prediction tools cluster into two groups: benign predictions from REVEL and ESM1b, and pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus method SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely pathogenic. AlphaMissense‑Optimized independently predicts pathogenicity. No Foldetta stability assessment is available for this residue. Taken together, the majority of evidence points to a pathogenic effect, which is in contrast to the ClinVar uncertain classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.762850 | Disordered | 0.820118 | Binding | 0.361 | 0.848 | 0.625 | Uncertain | 2 | 6-33444492-C-T | 2 | 1.24e-6 | -5.812 | Likely Benign | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.317 | Likely Benign | -5.88 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.46 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1205 | 0.3340 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||
| c.3458G>A | R1153Q 2D AIThe SynGAP1 missense variant R1153Q 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, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized model rates the variant as uncertain, and the SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies it as Likely Pathogenic. No Foldetta stability assessment is available for this residue. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict the ClinVar status. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.762850 | Disordered | 0.820118 | Binding | 0.361 | 0.848 | 0.625 | -3.349 | Likely Benign | 0.938 | Likely Pathogenic | Ambiguous | 0.285 | Likely Benign | -2.86 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 1.50 | Pathogenic | 0.00 | Affected | 0.3115 | 0.2175 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||||||||||||||
| c.3458G>C | R1153P 2D AIThe SynGAP1 missense variant R1153P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence indicates that R1153P is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.762850 | Disordered | 0.820118 | Binding | 0.361 | 0.848 | 0.625 | -2.431 | Likely Benign | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.384 | Likely Benign | -5.01 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.47 | Pathogenic | 0.00 | Affected | 0.2043 | 0.4315 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3458G>T | R1153L 2D AIThe SynGAP1 missense variant R1153L is not reported in ClinVar and is absent from 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 AlphaMissense‑Optimized. When predictions are grouped by consensus, the majority of algorithms (seven of nine) favor a deleterious effect, while only two suggest a benign outcome. High‑accuracy assessments further support a damaging interpretation: AlphaMissense‑Optimized predicts pathogenicity, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta results are not available. Overall, the evidence points to a pathogenic impact for R1153L, 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 Pathogenic | 0.762850 | Disordered | 0.820118 | Binding | 0.361 | 0.848 | 0.625 | -3.595 | Likely Benign | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.470 | Likely Benign | -5.05 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 1.48 | Pathogenic | 0.00 | Affected | 0.1913 | 0.4400 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3841G>A | A1281T 2D AIThe SynGAP1 missense variant A1281T is reported in gnomAD (6‑33447889‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only polyPhen‑2 HumDiv 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 reinforce this view: 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 the available predictions points to a benign effect, and this is not in conflict with the ClinVar status, which is currently unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.821556 | Binding | 0.434 | 0.721 | 0.875 | 6-33447889-G-A | 1 | 6.44e-7 | -4.366 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.090 | Likely Benign | -0.68 | Neutral | 0.818 | Possibly Damaging | 0.355 | Benign | 2.67 | Benign | 0.16 | Tolerated | 4.32 | 4 | 0.1479 | 0.5644 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.3841G>C | A1281P 2D AIThe SynGAP1 missense variant A1281P 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 classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.821556 | Binding | 0.434 | 0.721 | 0.875 | -3.367 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.51 | Neutral | 0.149 | Benign | 0.043 | Benign | 2.64 | Benign | 0.14 | Tolerated | 0.2110 | 0.3522 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3841G>T | A1281S 2D AIThe SynGAP1 missense variant A1281S is reported in gnomAD (6‑33447889‑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, 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 preponderance of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.821556 | Binding | 0.434 | 0.721 | 0.875 | 6-33447889-G-T | -4.175 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -0.22 | Neutral | 0.649 | Possibly Damaging | 0.266 | Benign | 2.69 | Benign | 0.33 | Tolerated | 4.32 | 4 | 0.2815 | 0.4356 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.3842C>A | A1281D 2D AIThe SynGAP1 missense variant A1281D is reported in gnomAD (ID 6‑33447890‑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: 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 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 | 0.823549 | Disordered | 0.821556 | Binding | 0.434 | 0.721 | 0.875 | 6-33447890-C-A | -5.183 | Likely Benign | 0.178 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.76 | Neutral | 0.901 | Possibly Damaging | 0.516 | Possibly Damaging | 2.68 | Benign | 0.15 | Tolerated | 4.32 | 4 | 0.2105 | 0.2462 | -2 | 0 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||
| c.3842C>G | A1281G 2D AIThe SynGAP1 missense variant A1281G is reported as “Likely Benign” by the SGM‑Consensus tool and is absent from ClinVar and gnomAD. All standard in‑silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) classify the change as benign, so the benign‑prediction group contains every listed tool, while no tool predicts pathogenicity. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign. Foldetta results are unavailable. Overall, 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 | 0.823549 | Disordered | 0.821556 | Binding | 0.434 | 0.721 | 0.875 | -3.829 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.31 | Neutral | 0.006 | Benign | 0.008 | Benign | 2.66 | Benign | 0.27 | Tolerated | 0.2382 | 0.3215 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3842C>T | A1281V 2D AIThe SynGAP1 missense variant A1281V is reported in gnomAD (ID 6‑33447890‑C‑T) and 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 algorithm in the dataset returned a pathogenic or likely pathogenic label, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign status. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its influence is unavailable. Overall, the 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 | 0.823549 | Disordered | 0.821556 | Binding | 0.434 | 0.721 | 0.875 | 6-33447890-C-T | -4.021 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.037 | Likely Benign | -0.79 | Neutral | 0.057 | Benign | 0.026 | Benign | 2.65 | Benign | 0.15 | Tolerated | 4.32 | 4 | 0.1151 | 0.4578 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||
| 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.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.3850C>A | L1284M 2D AIThe SynGAP1 missense variant L1284M is reported in gnomAD (ID 6‑33447898‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from the four benign‑oriented tools). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) 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 conclusion does not contradict any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.824557 | Binding | 0.441 | 0.748 | 0.875 | 6-33447898-C-A | -5.332 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.49 | Neutral | 0.970 | Probably Damaging | 0.637 | Possibly Damaging | 2.61 | Benign | 0.03 | Affected | 3.77 | 5 | 0.0731 | 0.2092 | 2 | 4 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||
| c.3850C>G | L1284V 2D AIThe SynGAP1 missense variant L1284V 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 | 0.812494 | Disordered | 0.824557 | Binding | 0.441 | 0.748 | 0.875 | -4.329 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.064 | Likely Benign | 0.90 | Neutral | 0.008 | Benign | 0.006 | Benign | 2.92 | Benign | 1.00 | Tolerated | 0.1419 | 0.1883 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3851T>A | L1284Q 2D AIThe SynGAP1 missense variant L1284Q is not 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 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 tools specifically show AlphaMissense‑Optimized as benign, while SGM Consensus and Foldetta remain unavailable. Overall, the majority of predictions (five pathogenic vs. four benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.812494 | Disordered | 0.824557 | Binding | 0.441 | 0.748 | 0.875 | -4.730 | Likely Benign | 0.094 | Likely Benign | Likely Benign | 0.138 | Likely Benign | -2.80 | Deleterious | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.48 | Pathogenic | 0.01 | Affected | 0.1065 | 0.0488 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||||||||
| c.3851T>C | L1284P 2D AIThe SynGAP1 missense variant L1284P is not reported in ClinVar (no ClinVar ID) but is present in gnomAD (ID 6‑33447899‑T‑C). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it yields a 2‑to‑2 split. Foldetta results are unavailable. Overall, the balance of evidence slightly favors a pathogenic interpretation (five pathogenic versus four benign predictions). This assessment does not conflict with ClinVar, as the variant has no ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.812494 | Disordered | 0.824557 | Binding | 0.441 | 0.748 | 0.875 | 6-33447899-T-C | -2.451 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.191 | Likely Benign | -3.05 | Deleterious | 0.990 | Probably Damaging | 0.722 | Possibly Damaging | 2.48 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.3307 | 0.0848 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||
| c.3851T>G | L1284R 2D AIThe SynGAP1 missense variant L1284R is not 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, was not available 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 has not yet been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.812494 | Disordered | 0.824557 | Binding | 0.441 | 0.748 | 0.875 | -4.203 | Likely Benign | 0.156 | Likely Benign | Likely Benign | 0.163 | Likely Benign | -3.11 | Deleterious | 0.990 | Probably Damaging | 0.722 | Possibly Damaging | 2.48 | Pathogenic | 0.00 | Affected | 0.1216 | 0.0488 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||||
| 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.2413C>A | L805M 2D AIThe SynGAP1 missense variant L805M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and no Foldetta stability data are available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.775545 | Disordered | 0.827669 | Binding | 0.341 | 0.903 | 0.625 | -4.229 | Likely Benign | 0.133 | Likely Benign | Likely Benign | 0.034 | Likely Benign | -0.67 | Neutral | 0.029 | Benign | 0.033 | Benign | 2.39 | Pathogenic | 0.00 | Affected | 0.0911 | 0.3867 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||||
| c.2413C>G | L805V 2D AIThe SynGAP1 missense variant L805V is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity 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, 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 (majority vote) is also benign. Foldetta results are not available, so they do not influence the conclusion. Overall, the preponderance of evidence indicates that 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 | SH3-binding motif | 0.775545 | Disordered | 0.827669 | Binding | 0.341 | 0.903 | 0.625 | -2.445 | Likely Benign | 0.094 | Likely Benign | Likely Benign | 0.027 | Likely Benign | -1.16 | Neutral | 0.003 | Benign | 0.008 | Benign | 2.65 | Benign | 0.00 | Affected | 0.1553 | 0.3493 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2414T>A | L805Q 2D AIThe SynGAP1 missense variant L805Q 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, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts a benign effect, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans pathogenic (2 pathogenic vs. 1 benign, 1 uncertain). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the balance of evidence (five pathogenic vs. three benign predictions, with a pathogenic SGM Consensus) 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. | SH3-binding motif | 0.775545 | Disordered | 0.827669 | Binding | 0.341 | 0.903 | 0.625 | -6.244 | Likely Benign | 0.427 | Ambiguous | Likely Benign | 0.152 | Likely Benign | -2.66 | Deleterious | 0.927 | Possibly Damaging | 0.690 | Possibly Damaging | 2.37 | Pathogenic | 0.00 | Affected | 0.1215 | 0.1265 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2414T>C | L805P 2D AIThe SynGAP1 missense variant L805P 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, and AlphaMissense‑Optimized, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, a pathogenic outcome from the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and no Foldetta data are available. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.775545 | Disordered | 0.827669 | Binding | 0.341 | 0.903 | 0.625 | Uncertain | 1 | -4.661 | Likely Benign | 0.444 | Ambiguous | Likely Benign | 0.272 | Likely Benign | -3.40 | Deleterious | 0.975 | Probably Damaging | 0.767 | Possibly Damaging | 2.36 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.3128 | 0.1650 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||
| c.2414T>G | L805R 2D AIThe SynGAP1 missense variant L805R is not 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. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all indicate pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, whereas the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it as likely pathogenic; Foldetta results are unavailable. Overall, the balance of evidence from the broader set of predictors leans toward pathogenicity, and this conclusion does not contradict any existing ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.775545 | Disordered | 0.827669 | Binding | 0.341 | 0.903 | 0.625 | -6.640 | Likely Benign | 0.569 | Likely Pathogenic | Likely Benign | 0.196 | Likely Benign | -3.00 | Deleterious | 0.927 | Possibly Damaging | 0.617 | Possibly Damaging | 2.37 | Pathogenic | 0.00 | Affected | 0.1372 | 0.0908 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||
| c.3865A>C | K1289Q 2D AIThe SynGAP1 missense variant K1289Q 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 | 0.733139 | Disordered | 0.828700 | Binding | 0.548 | 0.787 | 0.625 | -2.940 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.066 | Likely Benign | 1.55 | Neutral | 0.004 | Benign | 0.004 | Benign | 3.09 | Benign | 1.00 | Tolerated | 0.4002 | 0.0590 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3865A>G | K1289E 2D AIThe SynGAP1 missense variant K1289E is not reported in ClinVar (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 overall consensus of the majority of tools and the high‑accuracy predictions, the variant is most likely benign. This assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.828700 | Binding | 0.548 | 0.787 | 0.625 | -3.088 | Likely Benign | 0.265 | Likely Benign | Likely Benign | 0.138 | Likely Benign | -0.19 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.62 | Benign | 0.04 | Affected | 0.3559 | 0.0514 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3866A>C | K1289T 2D AIThe SynGAP1 missense variant K1289T is not reported in ClinVar and is absent from gnomAD. Consensus 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 (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. No Foldetta stability prediction is available for this residue. Overall, the majority of computational evidence points to a benign impact, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.828700 | Binding | 0.548 | 0.787 | 0.625 | -3.618 | Likely Benign | 0.250 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -2.18 | Neutral | 0.369 | Benign | 0.120 | Benign | 2.58 | Benign | 0.02 | Affected | 0.2047 | 0.2447 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||||||
| c.3866A>G | K1289R 2D AIThe SynGAP1 missense variant K1289R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts 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 a likely benign effect. Foldetta results are unavailable. Overall, the computational evidence strongly suggests 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 | 0.733139 | Disordered | 0.828700 | Binding | 0.548 | 0.787 | 0.625 | -2.127 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.090 | Likely Benign | -0.62 | Neutral | 0.001 | Benign | 0.003 | Benign | 2.66 | Benign | 0.11 | Tolerated | 0.4046 | 0.0715 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||||||||||||
| c.3866A>T | K1289M 2D AIThe SynGAP1 missense variant K1289M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic impact. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence—including the SGM consensus and AlphaMissense‑Optimized—points to a benign effect. 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 | 0.733139 | Disordered | 0.828700 | Binding | 0.548 | 0.787 | 0.625 | -4.372 | Likely Benign | 0.373 | Ambiguous | Likely Benign | 0.071 | Likely Benign | -1.79 | Neutral | 0.938 | Possibly Damaging | 0.596 | Possibly Damaging | 2.55 | Benign | 0.01 | Affected | 0.1015 | 0.2780 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.3867G>C | K1289N 2D AIThe SynGAP1 missense variant K1289N is reported in ClinVar as “Not submitted” and is not present in 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) indicates a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, SGM‑Consensus also predicts likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the collective predictions, K1289N 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 | 0.733139 | Disordered | 0.828700 | Binding | 0.548 | 0.787 | 0.625 | -4.244 | Likely Benign | 0.481 | Ambiguous | Likely Benign | 0.043 | Likely Benign | -1.56 | Neutral | 0.224 | Benign | 0.120 | Benign | 2.59 | Benign | 0.02 | Affected | 0.3442 | 0.0940 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3867G>T | K1289N 2D AIThe SynGAP1 missense variant K1289N is reported in ClinVar as “Not submitted” and is not present in 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) indicates a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, SGM‑Consensus also predicts likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the collective predictions, K1289N 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 | 0.733139 | Disordered | 0.828700 | Binding | 0.548 | 0.787 | 0.625 | -4.244 | Likely Benign | 0.481 | Ambiguous | Likely Benign | 0.043 | Likely Benign | -1.56 | Neutral | 0.224 | Benign | 0.120 | Benign | 2.59 | Benign | 0.02 | Affected | 0.3442 | 0.0940 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||||
| 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.2269G>A | G757S 2D AIThe SynGAP1 missense variant G757S 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. 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 not available. Overall, the collective predictions strongly suggest 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 | 0.436924 | Structured | 0.830995 | Binding | 0.310 | 0.869 | 0.375 | -1.492 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.058 | Likely Benign | 0.47 | Neutral | 0.007 | Benign | 0.008 | Benign | 2.73 | Benign | 0.29 | Tolerated | 0.2595 | 0.3877 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2269G>C | G757R 2D AIThe SynGAP1 missense variant G757R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic outcome. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports likely benign; Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.830995 | Binding | 0.310 | 0.869 | 0.375 | -2.254 | Likely Benign | 0.534 | Ambiguous | Likely Benign | 0.158 | Likely Benign | -0.04 | Neutral | 0.801 | Possibly Damaging | 0.494 | Possibly Damaging | 2.79 | Benign | 0.05 | Affected | 0.0903 | 0.3481 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2269G>T | G757C 2D AIThe SynGAP1 missense variant G757C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.830995 | Binding | 0.310 | 0.869 | 0.375 | -6.652 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.179 | Likely Benign | -1.74 | Neutral | 0.997 | Probably Damaging | 0.870 | Possibly Damaging | 2.65 | Benign | 0.04 | Affected | 0.1302 | 0.3630 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.2270G>A | G757D 2D AIThe SynGAP1 missense variant G757D is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign. Only polyPhen‑2 HumDiv flags it as pathogenic, while AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Taken together, the preponderance of evidence supports a benign interpretation, and this assessment does not contradict any ClinVar annotation (none is present). Therefore, the variant is most likely benign, with no conflict with ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.830995 | Binding | 0.310 | 0.869 | 0.375 | -4.613 | Likely Benign | 0.387 | Ambiguous | Likely Benign | 0.150 | Likely Benign | -0.90 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 2.71 | Benign | 0.11 | Tolerated | 0.1826 | 0.1611 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2270G>C | G757A 2D AIThe SynGAP1 missense change G757A is catalogued in ClinVar (ID 3635272.0) with an uncertain significance designation and is not reported in gnomAD. Functional prediction algorithms 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. No tool in the dataset predicts pathogenicity. High‑accuracy consensus methods corroborate this view: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect, and AlphaMissense‑Optimized also predicts benign. The Foldetta stability assessment is unavailable for this variant. Taken together, the evidence overwhelmingly supports a benign interpretation, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.830995 | Binding | 0.310 | 0.869 | 0.375 | Uncertain | 1 | -2.626 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -0.45 | Neutral | 0.267 | Benign | 0.127 | Benign | 2.73 | Benign | 0.35 | Tolerated | 0.3690 | 0.3842 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.2270G>T | G757V 2D AIThe SynGAP1 missense variant G757V is not reported 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 | 0.436924 | Structured | 0.830995 | Binding | 0.310 | 0.869 | 0.375 | -4.840 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.087 | Likely Benign | -1.47 | Neutral | 0.801 | Possibly Damaging | 0.494 | Possibly Damaging | 2.68 | Benign | 0.07 | Tolerated | 0.1089 | 0.3512 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3397A>C | I1133L 2D  AIThe SynGAP1 missense variant I1133L 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 I1133L 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 | 0.919029 | Disordered | 0.832785 | Binding | 0.316 | 0.892 | 0.750 | -1.147 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.202 | Likely Benign | -0.26 | Neutral | 0.000 | Benign | 0.001 | Benign | 5.48 | Benign | 0.23 | Tolerated | 0.0911 | 0.4302 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3397A>G | I1133V 2D  AIThe SynGAP1 missense variant I1133V is listed in ClinVar as Benign (ClinVar ID 999690.0) and is present in the gnomAD database (gnomAD ID 6‑33443949‑A‑G). All evaluated in‑silico predictors classify the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized 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, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.832785 | Binding | 0.316 | 0.892 | 0.750 | Benign | 1 | 6-33443949-A-G | 22 | 1.48e-5 | -3.362 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.180 | Likely Benign | 0.06 | Neutral | 0.007 | Benign | 0.007 | Benign | 5.47 | Benign | 0.58 | Tolerated | 4.32 | 3 | 0.1190 | 0.3985 | 4 | 3 | -0.3 | -14.03 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.3397A>T | I1133F 2D  AIThe SynGAP1 missense variant I1133F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect. 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 | 0.919029 | Disordered | 0.832785 | Binding | 0.316 | 0.892 | 0.750 | -2.941 | Likely Benign | 0.164 | Likely Benign | Likely Benign | 0.272 | Likely Benign | -1.21 | Neutral | 0.290 | Benign | 0.124 | Benign | 5.45 | Benign | 0.05 | Affected | 0.0598 | 0.3522 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3398T>A | I1133N 2D  AIThe SynGAP1 missense variant I1133N 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 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 stability analysis is unavailable. Overall, the preponderance of evidence points to a benign effect for I1133N, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.832785 | Binding | 0.316 | 0.892 | 0.750 | -5.887 | Likely Benign | 0.520 | Ambiguous | Likely Benign | 0.290 | Likely Benign | -1.07 | Neutral | 0.453 | Possibly Damaging | 0.162 | Benign | 5.51 | Benign | 0.02 | Affected | 0.0961 | 0.1140 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3398T>C | I1133T 2D  AIThe SynGAP1 missense variant I1133T has no ClinVar entry and is present in gnomAD (ID 6‑33443950‑T‑C). Consensus among most tools is benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict a benign effect, while AlphaMissense‑Default remains uncertain and no tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign,” and Foldetta’s protein‑folding stability analysis is unavailable. Overall, the evidence strongly supports a benign classification, 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 | 0.919029 | Disordered | 0.832785 | Binding | 0.316 | 0.892 | 0.750 | 6-33443950-T-C | -4.522 | Likely Benign | 0.563 | Ambiguous | Likely Benign | 0.275 | Likely Benign | -0.30 | Neutral | 0.026 | Benign | 0.030 | Benign | 5.50 | Benign | 0.18 | Tolerated | 4.32 | 3 | 0.1007 | 0.1975 | -1 | 0 | -5.2 | -12.05 | ||||||||||||||||||||||||||||||||||||
| c.3398T>G | I1133S 2D  AIThe SynGAP1 missense variant I1133S is not reported in ClinVar (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, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is likely benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the collective evidence strongly supports a benign impact for I1133S, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.832785 | Binding | 0.316 | 0.892 | 0.750 | -4.034 | Likely Benign | 0.492 | Ambiguous | Likely Benign | 0.186 | Likely Benign | -0.60 | Neutral | 0.007 | Benign | 0.016 | Benign | 5.70 | Benign | 0.08 | Tolerated | 0.2762 | 0.1110 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||||||||||||
| c.3399C>G | I1133M 2D  AIThe SynGAP1 missense variant I1133M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is benign, and this conclusion does not contradict any ClinVar annotation (none present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.832785 | Binding | 0.316 | 0.892 | 0.750 | -3.409 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.223 | Likely Benign | -0.21 | Neutral | 0.016 | Benign | 0.009 | Benign | 5.45 | Benign | 0.06 | Tolerated | 0.0764 | 0.3685 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| 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.2335A>C | S779R 2D AIThe SynGAP1 missense variant S779R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it yields a 2‑to‑2 split. High‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain, and both the SGM Consensus and Foldetta (which would combine FoldX‑MD and Rosetta outputs) are unavailable. Consequently, the overall prediction is ambiguous. The variant is most likely benign based on the balance of evidence, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.509769 | Disordered | 0.834974 | Binding | 0.321 | 0.890 | 0.375 | -4.044 | Likely Benign | 0.950 | Likely Pathogenic | Ambiguous | 0.103 | Likely Benign | -0.74 | Neutral | 0.846 | Possibly Damaging | 0.627 | Possibly Damaging | 2.29 | Pathogenic | 0.12 | Tolerated | 0.0961 | 0.4046 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.2335A>G | S779G 2D AIThe SynGAP1 missense variant S779G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.834974 | Binding | 0.321 | 0.890 | 0.375 | -4.304 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.103 | Likely Benign | 0.38 | Neutral | 0.393 | Benign | 0.324 | Benign | 2.65 | Benign | 0.53 | Tolerated | 0.2894 | 0.5087 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2335A>T | S779C 2D AIThe SynGAP1 missense variant S779C is not reported 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, 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 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. 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 | 0.509769 | Disordered | 0.834974 | Binding | 0.321 | 0.890 | 0.375 | -6.375 | Likely Benign | 0.196 | Likely Benign | Likely Benign | 0.230 | Likely Benign | -1.88 | Neutral | 0.992 | Probably Damaging | 0.905 | Possibly Damaging | 2.28 | Pathogenic | 0.05 | Affected | 0.1177 | 0.6350 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2336G>A | S779N 2D AIThe SynGAP1 missense variant S779N is listed in gnomAD (ID 6‑33442494‑G‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. A high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a benign majority. The AlphaMissense‑Optimized score is benign, and no Foldetta stability assessment is available. Taken together, the majority of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.509769 | Disordered | 0.834974 | Binding | 0.321 | 0.890 | 0.375 | 6-33442494-G-A | -4.880 | Likely Benign | 0.384 | Ambiguous | Likely Benign | 0.087 | Likely Benign | -0.75 | Neutral | 0.021 | Benign | 0.026 | Benign | 2.30 | Pathogenic | 0.23 | Tolerated | 3.64 | 6 | 0.1327 | 0.4984 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||
| c.2336G>C | S779T 2D AIThe SynGAP1 missense variant S779T 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, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as tolerated or benign. Only two tools—polyPhen‑2 HumDiv and FATHMM—suggest 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 reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign. Foldetta results are not available for this variant. Overall, the consensus of available predictions points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.834974 | Binding | 0.321 | 0.890 | 0.375 | -4.458 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 0.132 | Likely Benign | -0.71 | Neutral | 0.611 | Possibly Damaging | 0.396 | Benign | 2.34 | Pathogenic | 0.79 | Tolerated | 0.1491 | 0.6392 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2336G>T | S779I 2D AIThe SynGAP1 missense variant S779I is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy methods give a benign call from AlphaMissense‑Optimized; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign), and Foldetta results are unavailable. Overall, the majority of tools (five pathogenic vs. four benign) suggest a pathogenic impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.509769 | Disordered | 0.834974 | Binding | 0.321 | 0.890 | 0.375 | -6.261 | Likely Benign | 0.578 | Likely Pathogenic | Likely Benign | 0.198 | Likely Benign | -2.10 | Neutral | 0.918 | Possibly Damaging | 0.827 | Possibly Damaging | 2.28 | Pathogenic | 0.05 | Affected | 0.1046 | 0.6248 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2337C>A | S779R 2D AIThe SynGAP1 missense variant S779R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it yields a 2‑to‑2 split. High‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain, and both the SGM Consensus and Foldetta (which would combine FoldX‑MD and Rosetta outputs) are unavailable. Consequently, the overall prediction is ambiguous. The variant is most likely benign based on the balance of evidence, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.509769 | Disordered | 0.834974 | Binding | 0.321 | 0.890 | 0.375 | -4.044 | Likely Benign | 0.950 | Likely Pathogenic | Ambiguous | 0.119 | Likely Benign | -0.74 | Neutral | 0.846 | Possibly Damaging | 0.627 | Possibly Damaging | 2.29 | Pathogenic | 0.12 | Tolerated | 0.0961 | 0.4046 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.2337C>G | S779R 2D AIThe SynGAP1 missense variant S779R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it yields a 2‑to‑2 split. High‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain, and both the SGM Consensus and Foldetta (which would combine FoldX‑MD and Rosetta outputs) are unavailable. Consequently, the overall prediction is ambiguous. The variant is most likely benign based on the balance of evidence, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.509769 | Disordered | 0.834974 | Binding | 0.321 | 0.890 | 0.375 | -4.044 | Likely Benign | 0.950 | Likely Pathogenic | Ambiguous | 0.124 | Likely Benign | -0.74 | Neutral | 0.846 | Possibly Damaging | 0.627 | Possibly Damaging | 2.29 | Pathogenic | 0.12 | Tolerated | 0.0961 | 0.4046 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3493T>A | S1165T 2D AIThe SynGAP1 missense variant S1165T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote from 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 evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.835017 | Binding | 0.308 | 0.807 | 0.375 | -3.970 | Likely Benign | 0.572 | Likely Pathogenic | Likely Benign | 0.096 | Likely Benign | -0.85 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.59 | Benign | 0.45 | Tolerated | 0.1660 | 0.5579 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3493T>C | S1165P 2D AIThe SynGAP1 missense variant S1165P is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, whereas the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the majority of tools (six benign vs. four pathogenic) indicate that the variant is most likely benign. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.835017 | Binding | 0.308 | 0.807 | 0.375 | -3.476 | Likely Benign | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.147 | Likely Benign | -1.87 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.55 | Benign | 0.23 | Tolerated | 0.2295 | 0.4930 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3493T>G | S1165A 2D AIThe SynGAP1 missense variant S1165A is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of other predictors (polyPhen‑2 HumDiv and HumVar) suggest pathogenic. When predictions are grouped by agreement, the benign‑predicating tools outnumber the pathogenic ones, and the single uncertain call from AlphaMissense‑Default does not alter this balance. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Benign. Foldetta data are unavailable. Overall, the computational 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 | 0.509769 | Disordered | 0.835017 | Binding | 0.308 | 0.807 | 0.375 | -3.308 | Likely Benign | 0.476 | Ambiguous | Likely Benign | 0.106 | Likely Benign | -1.11 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.61 | Benign | 0.60 | Tolerated | 0.5363 | 0.4236 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.3494C>G | S1165W 2D  AIThe SynGAP1 missense variant S1165W has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign); pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome; Foldetta stability analysis is unavailable. Overall, the evidence is split, with an equal number of tools supporting benign versus pathogenic effects. Consequently, the variant is most likely pathogenic based on the current computational predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.835017 | Binding | 0.308 | 0.807 | 0.375 | -6.419 | Likely Benign | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.195 | Likely Benign | -2.29 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.54 | Benign | 0.02 | Affected | 0.0671 | 0.4807 | -2 | -3 | -0.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3494C>T | S1165L 2D  AIThe SynGAP1 missense variant S1165L is listed in ClinVar with an uncertain significance (ClinVar ID 225899.0) and is not reported in gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Grouping by consensus, the benign‑predicted tools outnumber the pathogenic ones. High‑accuracy assessments further clarify the picture: the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, leans toward benign (Likely Benign); AlphaMissense‑Optimized remains uncertain, and Foldetta data are unavailable. Overall, the majority of evidence points to a benign effect, aligning 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 | 0.509769 | Disordered | 0.835017 | Binding | 0.308 | 0.807 | 0.375 | Conflicting | 2 | -2.984 | Likely Benign | 0.793 | Likely Pathogenic | Ambiguous | 0.166 | Likely Benign | -2.01 | Neutral | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 2.60 | Benign | 0.33 | Tolerated | 3.88 | 3 | 0.1133 | 0.4803 | -3 | -2 | 4.6 | 26.08 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||||||||||
| c.2746G>A | V916I 2D  AIThe SynGAP1 missense variant V916I is reported in gnomAD (variant ID 6-33443298‑G‑A) but has no ClinVar entry. Functional prediction tools uniformly classify the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign effect. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability predictor, 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 | 0.642678 | Disordered | 0.835395 | Binding | 0.308 | 0.879 | 0.250 | 6-33443298-G-A | 25 | 1.55e-5 | -4.336 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.05 | Neutral | 0.010 | Benign | 0.015 | Benign | 2.71 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.0905 | 0.4463 | 3 | 4 | 0.3 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2746G>C | V916L 2D AIThe SynGAP1 missense variant V916L 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 for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.835395 | Binding | 0.308 | 0.879 | 0.250 | -2.645 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.064 | Likely Benign | 0.31 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.73 | Benign | 0.09 | Tolerated | 0.1190 | 0.5323 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2746G>T | V916F 2D  AIThe SynGAP1 missense variant V916F 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 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 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 | 0.642678 | Disordered | 0.835395 | Binding | 0.308 | 0.879 | 0.250 | -4.011 | Likely Benign | 0.123 | Likely Benign | Likely Benign | 0.121 | Likely Benign | -1.18 | Neutral | 0.642 | Possibly Damaging | 0.265 | Benign | 2.67 | Benign | 0.02 | Affected | 0.0729 | 0.4593 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||||||||||||
| c.2747T>A | V916D 2D  AIThe SynGAP1 missense variant V916D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic outcome. AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus indicates Likely Benign, and Foldetta (which integrates FoldX‑MD and Rosetta outputs) is not available for this variant. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.835395 | Binding | 0.308 | 0.879 | 0.250 | -2.653 | Likely Benign | 0.392 | Ambiguous | Likely Benign | 0.139 | Likely Benign | -1.48 | Neutral | 0.975 | Probably Damaging | 0.767 | Possibly Damaging | 2.69 | Benign | 0.01 | Affected | 0.1580 | 0.1113 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||||||||||||
| c.2747T>C | V916A 2D AIThe SynGAP1 missense variant V916A is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a benign outcome: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. No tool in the dataset indicates a pathogenic effect, so the pathogenic‑prediction group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign,” and the Foldetta stability analysis is not available. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.835395 | Binding | 0.308 | 0.879 | 0.250 | -2.524 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -0.18 | Neutral | 0.244 | Benign | 0.171 | Benign | 2.91 | Benign | 1.00 | Tolerated | 0.3455 | 0.2841 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| c.2747T>G | V916G 2D AIThe SynGAP1 missense variant V916G is not reported 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‑Default, and AlphaMissense‑Optimized. 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 (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.642678 | Disordered | 0.835395 | Binding | 0.308 | 0.879 | 0.250 | -1.950 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -0.63 | Neutral | 0.666 | Possibly Damaging | 0.917 | Probably Damaging | 2.69 | Benign | 0.05 | Affected | 0.2420 | 0.2681 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||||||||||||
| 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.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.2437C>A | L813M 2D AIThe SynGAP1 missense variant L813M 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 change as 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 a pathogenic effect. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus remains likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact 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 | SH3-binding motif | 0.411940 | Structured | 0.838481 | Binding | 0.292 | 0.905 | 0.250 | -4.893 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -0.53 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.58 | Benign | 0.23 | Tolerated | 0.0814 | 0.3922 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||||
| c.2437C>G | L813V 2D AIThe SynGAP1 missense variant L813V 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” consensus. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.838481 | Binding | 0.292 | 0.905 | 0.250 | -4.809 | Likely Benign | 0.215 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -0.98 | Neutral | 0.994 | Probably Damaging | 0.856 | Possibly Damaging | 2.62 | Benign | 0.28 | Tolerated | 0.1704 | 0.3744 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2438T>A | L813Q 2D AIThe SynGAP1 missense variant L813Q 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, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the balance of evidence points to a benign impact for the variant, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.838481 | Binding | 0.292 | 0.905 | 0.250 | -5.380 | Likely Benign | 0.660 | Likely Pathogenic | Likely Benign | 0.137 | Likely Benign | -1.30 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.67 | Benign | 0.10 | Tolerated | 0.1122 | 0.1105 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||||||
| c.2438T>C | L813P 2D AIThe SynGAP1 missense variant L813P 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 (HumDiv and HumVar) predict a pathogenic impact, and AlphaMissense‑Default remains uncertain. No Foldetta stability assessment is available, so it does not influence the overall interpretation. Overall, the preponderance of evidence points to a benign effect for the variant, and this conclusion is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.838481 | Binding | 0.292 | 0.905 | 0.250 | -2.572 | Likely Benign | 0.554 | Ambiguous | Likely Benign | 0.122 | Likely Benign | -1.96 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.58 | Benign | 0.21 | Tolerated | 0.3564 | 0.1458 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||
| c.2438T>G | L813R 2D AIThe SynGAP1 missense variant L813R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and Foldetta results are unavailable. Taken together, 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 | SH3-binding motif | 0.411940 | Structured | 0.838481 | Binding | 0.292 | 0.905 | 0.250 | -4.697 | Likely Benign | 0.786 | Likely Pathogenic | Ambiguous | 0.160 | Likely Benign | -1.57 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.68 | Benign | 0.11 | Tolerated | 0.1261 | 0.0947 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||
| c.3460A>C | T1154P 2D AIThe SynGAP1 missense variant T1154P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence indicates that T1154P is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.685117 | Disordered | 0.838654 | Binding | 0.382 | 0.851 | 0.625 | -2.513 | Likely Benign | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.368 | Likely Benign | -4.42 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.72 | Pathogenic | 0.00 | Affected | 0.1667 | 0.3732 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3460A>G | T1154A 2D AIThe SynGAP1 missense variant T1154A is not 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that T1154A is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar status is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.685117 | Disordered | 0.838654 | Binding | 0.382 | 0.851 | 0.625 | -3.312 | Likely Benign | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.290 | Likely Benign | -3.55 | Deleterious | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 1.80 | Pathogenic | 0.00 | Affected | 0.3509 | 0.2965 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3460A>T | T1154S 2D AIThe SynGAP1 missense variant T1154S 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, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also reports it as likely pathogenic. Foldetta results are unavailable. Overall, the consensus of the available predictions indicates that T1154S is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.685117 | Disordered | 0.838654 | Binding | 0.382 | 0.851 | 0.625 | -3.253 | Likely Benign | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.192 | Likely Benign | -2.92 | Deleterious | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 1.78 | Pathogenic | 0.00 | Affected | 0.2817 | 0.3206 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3461C>A | T1154K 2D  AIThe SynGAP1 missense variant T1154K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Benign predictions are limited to REVEL and ESM1b. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus classifies the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that T1154K 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 | 0.685117 | Disordered | 0.838654 | Binding | 0.382 | 0.851 | 0.625 | -3.641 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.364 | Likely Benign | -4.25 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.74 | Pathogenic | 0.00 | Affected | 0.1053 | 0.2378 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||||
| c.3461C>G | T1154R 2D  AIThe SynGAP1 missense variant T1154R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence indicates that T1154R is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.685117 | Disordered | 0.838654 | Binding | 0.382 | 0.851 | 0.625 | -3.464 | Likely Benign | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.300 | Likely Benign | -4.05 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.73 | Pathogenic | 0.00 | Affected | 0.0903 | 0.2101 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||||||||||||
| c.3461C>T | T1154I 2D AIThe SynGAP1 missense variant T1154I is not reported in ClinVar and has no gnomAD entry. 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, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method that combines FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.685117 | Disordered | 0.838654 | Binding | 0.382 | 0.851 | 0.625 | -4.489 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.351 | Likely Benign | -4.38 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.74 | Pathogenic | 0.00 | Affected | 0.0927 | 0.4956 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.2434C>A | P812T 2D AIThe SynGAP1 missense variant P812T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT 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 likewise indicates Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.414856 | Structured | 0.842442 | Binding | 0.388 | 0.901 | 0.125 | -6.956 | Likely Benign | 0.524 | Ambiguous | Likely Benign | 0.105 | Likely Benign | -1.50 | Neutral | 0.994 | Probably Damaging | 0.927 | Probably Damaging | 2.73 | Benign | 0.04 | Affected | 0.1413 | 0.6114 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||||
| c.2434C>G | P812A 2D AIThe SynGAP1 missense variant P812A is not reported 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 the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is also benign; Foldetta results are not available. Overall, the majority of evidence points to a benign 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 | SH3-binding motif | 0.414856 | Structured | 0.842442 | Binding | 0.388 | 0.901 | 0.125 | -6.113 | Likely Benign | 0.275 | Likely Benign | Likely Benign | 0.137 | Likely Benign | -1.49 | Neutral | 0.989 | Probably Damaging | 0.869 | Possibly Damaging | 2.75 | Benign | 0.08 | Tolerated | 0.3555 | 0.5350 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||||
| c.2434C>T | P812S 2D AIThe SynGAP1 missense variant P812S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33442986‑C‑T). 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, and no Foldetta stability result is available. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta data are missing. 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 | SH3-binding motif | 0.414856 | Structured | 0.842442 | Binding | 0.388 | 0.901 | 0.125 | Uncertain | 1 | 6-33442986-C-T | 1 | 6.20e-7 | -5.689 | Likely Benign | 0.456 | Ambiguous | Likely Benign | 0.162 | Likely Benign | -0.62 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.89 | Benign | 0.95 | Tolerated | 4.32 | 4 | 0.3417 | 0.5699 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||
| c.2435C>A | P812H 2D AIThe SynGAP1 missense variant P812H is listed in ClinVar with an uncertain significance and is present in the gnomAD database (ID 6‑33442987‑C‑A). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic outcome; ESM1b remains uncertain. High‑accuracy methods give a benign result from AlphaMissense‑Optimized, a pathogenic consensus from the SGM approach (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta data are unavailable. Overall, the balance of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.414856 | Structured | 0.842442 | Binding | 0.388 | 0.901 | 0.125 | Uncertain | 2 | 6-33442987-C-A | 3 | 1.86e-6 | -7.470 | In-Between | 0.698 | Likely Pathogenic | Likely Benign | 0.272 | Likely Benign | -2.81 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 2.68 | Benign | 0.00 | Affected | 4.32 | 4 | 0.1568 | 0.4923 | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||
| c.2435C>G | P812R 2D AIThe SynGAP1 P812R missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, the majority of standard predictors indicate a pathogenic impact, while the most accurate tools provide no definitive evidence. Thus, the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.414856 | Structured | 0.842442 | Binding | 0.388 | 0.901 | 0.125 | -6.784 | Likely Benign | 0.799 | Likely Pathogenic | Ambiguous | 0.222 | Likely Benign | -2.70 | Deleterious | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.77 | Benign | 0.01 | Affected | 0.1285 | 0.3525 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2435C>T | P812L 2D AIThe SynGAP1 P812L missense variant is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID: 6‑33442987‑C‑T). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic, and Foldetta’s protein‑folding stability analysis is unavailable. Overall, the majority of predictions lean toward pathogenicity, which is consistent with the lack of ClinVar reporting but does not contradict it. 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. | SH3-binding motif | 0.414856 | Structured | 0.842442 | Binding | 0.388 | 0.901 | 0.125 | 6-33442987-C-T | 1 | 6.20e-7 | -7.121 | In-Between | 0.591 | Likely Pathogenic | Likely Benign | 0.172 | Likely Benign | -2.61 | Deleterious | 0.978 | Probably Damaging | 0.824 | Possibly Damaging | 2.76 | Benign | 0.01 | Affected | 4.32 | 4 | 0.2131 | 0.6634 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| c.3868A>G | R1290G 2D AIThe SynGAP1 missense variant R1290G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for R1290G, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.844138 | Binding | 0.567 | 0.795 | 0.625 | -4.166 | Likely Benign | 0.223 | Likely Benign | Likely Benign | 0.151 | Likely Benign | -4.32 | Deleterious | 0.625 | Possibly Damaging | 0.266 | Benign | 2.61 | Benign | 0.01 | Affected | 0.2864 | 0.2945 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3868A>T | R1290W 2D AIThe SynGAP1 missense variant R1290W is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) as benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the preponderance of evidence from multiple independent predictors points to a benign impact for R1290W, 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 | 0.784345 | Disordered | 0.844138 | Binding | 0.567 | 0.795 | 0.625 | -5.672 | Likely Benign | 0.294 | Likely Benign | Likely Benign | 0.163 | Likely Benign | -5.15 | Deleterious | 0.994 | Probably Damaging | 0.920 | Probably Damaging | 2.58 | Benign | 0.00 | Affected | 0.0992 | 0.2724 | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3869G>A | R1290K 2D AIThe SynGAP1 missense variant R1290K 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 is consistent with the lack of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.844138 | Binding | 0.567 | 0.795 | 0.625 | -3.749 | Likely Benign | 0.145 | Likely Benign | Likely Benign | 0.037 | Likely Benign | 0.52 | Neutral | 0.004 | Benign | 0.006 | Benign | 3.09 | Benign | 1.00 | Tolerated | 0.3342 | 0.3113 | 3 | 2 | 0.6 | -28.01 | |||||||||||||||||||||||||||||||||||||||
| c.3869G>C | R1290T 2D AIThe SynGAP1 missense variant R1290T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the majority of predictions and the high‑accuracy consensus, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.844138 | Binding | 0.567 | 0.795 | 0.625 | -4.044 | Likely Benign | 0.311 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -3.50 | Deleterious | 0.625 | Possibly Damaging | 0.266 | Benign | 2.64 | Benign | 0.01 | Affected | 0.1607 | 0.3359 | -1 | -1 | 3.8 | -55.08 | |||||||||||||||||||||||||||||||||||||||
| c.3869G>T | R1290M 2D AIThe SynGAP1 missense variant R1290M is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of reliable predictions indicate 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. | 0.784345 | Disordered | 0.844138 | Binding | 0.567 | 0.795 | 0.625 | -4.661 | Likely Benign | 0.390 | Ambiguous | Likely Benign | 0.143 | Likely Benign | -3.47 | Deleterious | 0.977 | Probably Damaging | 0.796 | Possibly Damaging | 2.60 | Benign | 0.00 | Affected | 0.1059 | 0.2899 | 0 | -1 | 6.4 | -24.99 | ||||||||||||||||||||||||||||||||||||||||
| c.3870G>C | R1290S 2D AIThe SynGAP1 missense variant R1290S is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM, while pathogenic predictions come from PROVEAN and SIFT. The high‑accuracy consensus (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‑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 computational evidence indicates a benign effect, and this assessment does not contradict any ClinVar annotation, as none exists for R1290S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.784345 | Disordered | 0.844138 | Binding | 0.567 | 0.795 | 0.625 | -3.507 | Likely Benign | 0.467 | Ambiguous | Likely Benign | 0.120 | Likely Benign | -2.99 | Deleterious | 0.451 | Benign | 0.209 | Benign | 2.65 | Benign | 0.01 | Affected | 0.2655 | 0.2733 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3870G>T | R1290S 2D AIThe SynGAP1 missense variant R1290S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT. AlphaMissense‑Default is uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is benign (2 benign vs. 1 pathogenic, 1 uncertain). High‑accuracy predictions show AlphaMissense‑Optimized as benign and the SGM Consensus as benign; Foldetta results are unavailable. Overall, the consensus of available evidence indicates that R1290S is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.784345 | Disordered | 0.844138 | Binding | 0.567 | 0.795 | 0.625 | -3.507 | Likely Benign | 0.467 | Ambiguous | Likely Benign | 0.120 | Likely Benign | -2.99 | Deleterious | 0.451 | Benign | 0.209 | Benign | 2.65 | Benign | 0.01 | Affected | 0.2655 | 0.2733 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.3394T>A | S1132T 2D AIThe SynGAP1 missense variant S1132T is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification—there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.845506 | Binding | 0.289 | 0.894 | 0.750 | -3.700 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.190 | Likely Benign | -0.71 | Neutral | 0.011 | Benign | 0.017 | Benign | 5.45 | Benign | 0.50 | Tolerated | 0.1552 | 0.6309 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3394T>C | S1132P 2D AIThe SynGAP1 missense variant S1132P is listed in ClinVar with an uncertain significance (ClinVar ID 1341927.0) and is present in the gnomAD database (gnomAD ID 6‑33443946‑T‑C). All available in‑silico predictors uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or likely benign outcomes. 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, 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 classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.845506 | Binding | 0.289 | 0.894 | 0.750 | Conflicting | 3 | 6-33443946-T-C | 1 | 6.74e-7 | -1.423 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 0.301 | Likely Benign | 0.38 | Neutral | 0.003 | Benign | 0.006 | Benign | 5.40 | Benign | 0.28 | Tolerated | 4.32 | 4 | 0.2081 | 0.5700 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||
| c.3394T>G | S1132A 2D AIThe SynGAP1 missense variant S1132A is not reported in ClinVar and is absent from gnomAD, indicating no documented population frequency. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign status. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.845506 | Binding | 0.289 | 0.894 | 0.750 | -3.401 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.213 | Likely Benign | -0.60 | Neutral | 0.061 | Benign | 0.013 | Benign | 5.47 | Benign | 0.55 | Tolerated | 0.4416 | 0.5683 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3395C>A | S1132Y 2D AIThe SynGAP1 missense variant S1132Y is listed in ClinVar as a benign alteration (ClinVar ID 845357.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence supports a benign classification, which aligns with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.845506 | Binding | 0.289 | 0.894 | 0.750 | Likely Benign | 1 | -5.894 | Likely Benign | 0.392 | Ambiguous | Likely Benign | 0.401 | Likely Benign | -1.76 | Neutral | 0.500 | Possibly Damaging | 0.208 | Benign | 5.40 | Benign | 0.09 | Tolerated | 4.32 | 4 | 0.0889 | 0.5233 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||
| c.3395C>G | S1132C 2D AIThe SynGAP1 missense variant S1132C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S1132C, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.845506 | Binding | 0.289 | 0.894 | 0.750 | -6.668 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.318 | Likely Benign | -1.76 | Neutral | 0.977 | Probably Damaging | 0.777 | Possibly Damaging | 5.39 | Benign | 0.06 | Tolerated | 0.1199 | 0.5888 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.3395C>T | S1132F 2D AIThe SynGAP1 missense variant S1132F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.845506 | Binding | 0.289 | 0.894 | 0.750 | -5.458 | Likely Benign | 0.385 | Ambiguous | Likely Benign | 0.310 | Likely Benign | -2.02 | Neutral | 0.006 | Benign | 0.006 | Benign | 5.41 | Benign | 0.05 | Affected | 0.0921 | 0.5506 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.2836G>A | G946R 2D AIThe SynGAP1 missense variant G946R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while ESM1b is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus itself is Likely Benign. Foldetta results are unavailable. Overall, the majority of computational evidence indicates that G946R is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985417 | Disordered | 0.845792 | Binding | 0.357 | 0.920 | 0.750 | -7.127 | In-Between | 0.308 | Likely Benign | Likely Benign | 0.296 | Likely Benign | -0.69 | Neutral | 0.818 | Possibly Damaging | 0.435 | Benign | 4.65 | Benign | 0.00 | Affected | 0.1157 | 0.5133 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2836G>C | G946R 2D AIThe SynGAP1 missense variant G946R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while ESM1b is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus itself is Likely Benign. Foldetta results are unavailable. Overall, the majority of computational evidence indicates that G946R is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985417 | Disordered | 0.845792 | Binding | 0.357 | 0.920 | 0.750 | -7.127 | In-Between | 0.308 | Likely Benign | Likely Benign | 0.296 | Likely Benign | -0.69 | Neutral | 0.818 | Possibly Damaging | 0.435 | Benign | 4.65 | Benign | 0.00 | Affected | 0.1157 | 0.5133 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2837G>A | G946E 2D AIThe SynGAP1 missense variant G946E is listed in ClinVar (ID 1299783.0) as benign and is present in gnomAD (6‑33443389‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while polyPhen‑2 HumDiv, SIFT, and ESM1b predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar designation and showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985417 | Disordered | 0.845792 | Binding | 0.357 | 0.920 | 0.750 | Benign | 3 | 6-33443389-G-A | 13 | 8.05e-6 | -8.793 | Likely Pathogenic | 0.257 | Likely Benign | Likely Benign | 0.341 | Likely Benign | -0.51 | Neutral | 0.818 | Possibly Damaging | 0.355 | Benign | 4.58 | Benign | 0.00 | Affected | 4.32 | 4 | 0.1691 | 0.4859 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||
| c.2837G>C | G946A 2D AIThe SynGAP1 missense variant G946A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for G946A, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985417 | Disordered | 0.845792 | Binding | 0.357 | 0.920 | 0.750 | -7.004 | In-Between | 0.079 | Likely Benign | Likely Benign | 0.191 | Likely Benign | 0.33 | Neutral | 0.649 | Possibly Damaging | 0.209 | Benign | 4.77 | Benign | 0.00 | Affected | 0.3378 | 0.4957 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2837G>T | G946V 2D AIThe SynGAP1 missense variant G946V is not reported 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 G946V, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985417 | Disordered | 0.845792 | Binding | 0.357 | 0.920 | 0.750 | -7.528 | In-Between | 0.109 | Likely Benign | Likely Benign | 0.368 | Likely Benign | -0.30 | Neutral | 0.901 | Possibly Damaging | 0.516 | Possibly Damaging | 4.57 | Benign | 0.00 | Affected | 0.1524 | 0.3707 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.2431C>A | P811T 2D AIThe SynGAP1 missense variant P811T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the majority of evidence points to a benign effect for P811T, 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 | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -5.329 | Likely Benign | 0.488 | Ambiguous | Likely Benign | 0.119 | Likely Benign | -1.94 | Neutral | 0.991 | Probably Damaging | 0.864 | Possibly Damaging | 2.77 | Benign | 0.03 | Affected | 0.1679 | 0.6095 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||||
| c.2431C>G | P811A 2D AIThe SynGAP1 missense variant P811A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence supports a benign classification for P811A, 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 | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -5.120 | Likely Benign | 0.287 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -2.11 | Neutral | 0.939 | Possibly Damaging | 0.670 | Possibly Damaging | 2.76 | Benign | 0.57 | Tolerated | 0.3763 | 0.5485 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||||
| c.2431C>T | P811S 2D AIThe SynGAP1 missense variant P811S 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 (HumDiv and HumVar) predict a pathogenic impact, and AlphaMissense‑Default remains uncertain. No Foldetta stability assessment is available, so it does not contribute to the evidence. Overall, the preponderance of evidence points to a benign effect for P811S, and this conclusion is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -4.733 | Likely Benign | 0.474 | Ambiguous | Likely Benign | 0.128 | Likely Benign | -1.28 | Neutral | 0.982 | Probably Damaging | 0.824 | Possibly Damaging | 2.79 | Benign | 0.78 | Tolerated | 0.3656 | 0.5960 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||||
| c.2432C>A | P811Q 2D AIThe SynGAP1 missense variant P811Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic outcome. 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 effect, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -5.145 | Likely Benign | 0.431 | Ambiguous | Likely Benign | 0.138 | Likely Benign | -2.38 | Neutral | 0.982 | Probably Damaging | 0.875 | Possibly Damaging | 2.78 | Benign | 0.01 | Affected | 0.1523 | 0.5338 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||||
| c.2432C>G | P811R 2D AIThe SynGAP1 missense variant P811R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT; AlphaMissense‑Default remains uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome (2 benign vs. 1 pathogenic, with one uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as benign, while Foldetta (combining FoldX‑MD and Rosetta) has no available result. Overall, the preponderance of evidence points to a benign impact for P811R, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -5.273 | Likely Benign | 0.557 | Ambiguous | Likely Benign | 0.065 | Likely Benign | -2.69 | Deleterious | 0.100 | Benign | 0.066 | Benign | 2.73 | Benign | 0.01 | Affected | 0.1448 | 0.3817 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2432C>T | P811L 2D AIThe SynGAP1 P811L missense variant has no ClinVar entry and is not reported in 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 and HumVar), and SIFT. AlphaMissense‑Default is uncertain. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, leans toward benign (2 benign vs. 1 pathogenic, 1 uncertain). 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 high‑accuracy tools and consensus methods indicates that P811L is most likely benign. This assessment does not contradict ClinVar status, as the variant is not yet reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -6.184 | Likely Benign | 0.491 | Ambiguous | Likely Benign | 0.150 | Likely Benign | -3.98 | Deleterious | 0.982 | Probably Damaging | 0.824 | Possibly Damaging | 2.71 | Benign | 0.01 | Affected | 0.2327 | 0.6621 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2416T>A | F806I 2D  AIThe SynGAP1 missense variant F806I 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 the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic effect; Foldetta results are unavailable. Overall, the balance of evidence from the consensus of prediction algorithms points to a pathogenic impact for F806I. This conclusion is not contradicted by 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 | 0.736850 | Disordered | 0.847454 | Binding | 0.276 | 0.904 | 0.500 | -5.040 | Likely Benign | 0.744 | Likely Pathogenic | Likely Benign | 0.182 | Likely Benign | -3.19 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.15 | Pathogenic | 0.03 | Affected | 0.2583 | 0.1357 | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||||||||||
| c.2416T>C | F806L 2D  AIThe SynGAP1 missense variant F806L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, and ESM1b, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic outcome. 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) is unavailable for this variant. Overall, the balance of evidence—five pathogenic versus three benign predictions, with a consensus pathogenic signal from SGM‑Consensus—suggests that F806L 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. | Likely Pathogenic | SH3-binding motif | 0.736850 | Disordered | 0.847454 | Binding | 0.276 | 0.904 | 0.500 | -3.079 | Likely Benign | 0.941 | Likely Pathogenic | Ambiguous | 0.142 | Likely Benign | -2.96 | Deleterious | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.18 | Pathogenic | 0.32 | Tolerated | 0.2618 | 0.2329 | 2 | 0 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||||
| c.2416T>G | F806V 2D  AIThe SynGAP1 missense variant F806V 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 the majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict it to be pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains pathogenic; a Foldetta stability analysis is unavailable. Overall, the balance of evidence from the majority of prediction algorithms points to a pathogenic impact, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.736850 | Disordered | 0.847454 | Binding | 0.276 | 0.904 | 0.500 | -4.548 | Likely Benign | 0.676 | Likely Pathogenic | Likely Benign | 0.192 | Likely Benign | -3.79 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.16 | Pathogenic | 0.02 | Affected | 0.2464 | 0.1325 | -1 | -1 | 1.4 | -48.04 | ||||||||||||||||||||||||||||||||||||||
| c.2417T>A | F806Y 2D  AIThe SynGAP1 missense variant F806Y is not reported 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, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM all predict a pathogenic outcome; 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 classifies it as benign, and Foldetta results are unavailable. Taken together, the majority of evidence points to a benign effect, 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. | SH3-binding motif | 0.736850 | Disordered | 0.847454 | Binding | 0.276 | 0.904 | 0.500 | -5.229 | Likely Benign | 0.404 | Ambiguous | Likely Benign | 0.162 | Likely Benign | -1.51 | Neutral | 0.997 | Probably Damaging | 0.987 | Probably Damaging | 2.32 | Pathogenic | 0.03 | Affected | 0.1746 | 0.1437 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2417T>C | F806S 2D  AIThe SynGAP1 missense variant F806S is catalogued in gnomAD (ID 6‑33442969‑T‑C) 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, and AlphaMissense‑Default. High‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as 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 effect, and this conclusion does not contradict any ClinVar status because none is reported. Thus, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.736850 | Disordered | 0.847454 | Binding | 0.276 | 0.904 | 0.500 | 6-33442969-T-C | 1 | 6.20e-7 | -6.959 | Likely Benign | 0.911 | Likely Pathogenic | Ambiguous | 0.269 | Likely Benign | -4.13 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.21 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.5067 | 0.0391 | Weaken | -2 | -3 | -3.6 | -60.10 | ||||||||||||||||||||||||||||||||
| c.2417T>G | F806C 2D  AIThe SynGAP1 missense variant F806C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—predict a pathogenic impact, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while SGM‑Consensus remains likely pathogenic; Foldetta results are unavailable. Based on the predominance of pathogenic predictions and the SGM‑Consensus outcome, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.736850 | Disordered | 0.847454 | Binding | 0.276 | 0.904 | 0.500 | -8.565 | Likely Pathogenic | 0.809 | Likely Pathogenic | Ambiguous | 0.266 | Likely Benign | -4.46 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.11 | Pathogenic | 0.00 | Affected | 0.3071 | 0.1125 | -4 | -2 | -0.3 | -44.04 | ||||||||||||||||||||||||||||||||||||||
| c.2418C>A | F806L 2D AIThe SynGAP1 missense variant F806L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, and ESM1b, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic outcome. 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) is unavailable for this variant. Overall, the balance of evidence—five pathogenic versus three benign predictions, with a consensus pathogenic signal from SGM‑Consensus—suggests that F806L 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. | Likely Pathogenic | SH3-binding motif | 0.736850 | Disordered | 0.847454 | Binding | 0.276 | 0.904 | 0.500 | -3.079 | Likely Benign | 0.941 | Likely Pathogenic | Ambiguous | 0.170 | Likely Benign | -2.96 | Deleterious | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.18 | Pathogenic | 0.32 | Tolerated | 0.2618 | 0.2329 | 2 | 0 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||||
| c.2418C>G | F806L 2D AIThe SynGAP1 missense variant F806L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show discordant results: benign predictions come from REVEL, SIFT, and ESM1b, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus method SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a likely pathogenic verdict (3/4 pathogenic votes). AlphaMissense‑Optimized returns an uncertain result, and no Foldetta stability assessment is available. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion aligns with the SGM‑Consensus prediction; it does not contradict any ClinVar status because no ClinVar entry exists. Thus, the variant is most likely pathogenic, and this assessment is consistent 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 | 0.736850 | Disordered | 0.847454 | Binding | 0.276 | 0.904 | 0.500 | -3.079 | Likely Benign | 0.941 | Likely Pathogenic | Ambiguous | 0.170 | Likely Benign | -2.96 | Deleterious | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.18 | Pathogenic | 0.32 | Tolerated | 0.2618 | 0.2329 | 2 | 0 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||||
| c.2833C>A | H945N 2D AIThe SynGAP1 missense variant H945N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign effect for H945N, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.982235 | Disordered | 0.849210 | Binding | 0.386 | 0.923 | 0.750 | -5.709 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.266 | Likely Benign | -0.29 | Neutral | 0.982 | Probably Damaging | 0.870 | Possibly Damaging | 5.03 | Benign | 0.05 | Affected | 0.2556 | 0.2997 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.2833C>G | H945D 2D AIThe SynGAP1 missense variant H945D 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, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for H945D, 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 | 0.982235 | Disordered | 0.849210 | Binding | 0.386 | 0.923 | 0.750 | -6.572 | Likely Benign | 0.191 | Likely Benign | Likely Benign | 0.396 | Likely Benign | -0.18 | Neutral | 0.982 | Probably Damaging | 0.870 | Possibly Damaging | 5.02 | Benign | 0.04 | Affected | 0.2803 | 0.2275 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2833C>T | H945Y 2D AIThe SynGAP1 missense variant H945Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign effect for H945Y, 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 | 0.982235 | Disordered | 0.849210 | Binding | 0.386 | 0.923 | 0.750 | -6.036 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.335 | Likely Benign | -0.07 | Neutral | 0.982 | Probably Damaging | 0.903 | Possibly Damaging | 5.27 | Benign | 0.05 | Affected | 0.2102 | 0.3912 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.2834A>C | H945P 2D AIThe SynGAP1 missense variant H945P is not reported in ClinVar (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 pathogenic 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 | 0.982235 | Disordered | 0.849210 | Binding | 0.386 | 0.923 | 0.750 | -1.962 | Likely Benign | 0.055 | Likely Benign | Likely Benign | 0.420 | Likely Benign | -0.34 | Neutral | 0.012 | Benign | 0.047 | Benign | 5.04 | Benign | 0.05 | Affected | 0.2730 | 0.3907 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2834A>G | H945R 2D AIThe SynGAP1 missense variant H945R is reported in gnomAD (variant ID 6‑33443386‑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 reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.982235 | Disordered | 0.849210 | Binding | 0.386 | 0.923 | 0.750 | 6-33443386-A-G | 1 | 6.20e-7 | -5.186 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 0.333 | Likely Benign | -0.59 | Neutral | 0.982 | Probably Damaging | 0.903 | Possibly Damaging | 5.05 | Benign | 0.08 | Tolerated | 4.32 | 4 | 0.2764 | 0.3020 | 0 | 2 | -1.3 | 19.05 | ||||||||||||||||||||||||||||||||||
| c.2834A>T | H945L 2D AIThe SynGAP1 missense variant H945L is reported in gnomAD (ID 6‑33443386‑A‑T) 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 (both HumDiv and HumVar models) predict the variant to be pathogenic. High‑accuracy assessments reinforce the benign 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 absence of a pathogenic ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.982235 | Disordered | 0.849210 | Binding | 0.386 | 0.923 | 0.750 | 6-33443386-A-T | 2 | 1.24e-6 | -4.741 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.399 | Likely Benign | 0.16 | Neutral | 0.948 | Possibly Damaging | 0.863 | Possibly Damaging | 5.05 | Benign | 1.00 | Tolerated | 4.32 | 4 | 0.2085 | 0.4526 | -3 | -2 | 7.0 | -23.98 | ||||||||||||||||||||||||||||||||||
| c.2835T>A | H945Q 2D AIThe SynGAP1 missense variant H945Q is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33443387‑T‑A). 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 consensus from 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 for this variant. Overall, the majority of computational 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 | 0.982235 | Disordered | 0.849210 | Binding | 0.386 | 0.923 | 0.750 | Conflicting | 2 | 6-33443387-T-A | 3 | 1.86e-6 | -5.248 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.343 | Likely Benign | -0.36 | Neutral | 0.995 | Probably Damaging | 0.939 | Probably Damaging | 5.03 | Benign | 0.06 | Tolerated | 4.32 | 4 | 0.2671 | 0.3128 | 3 | 0 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||
| c.2835T>G | H945Q 2D AIThe SynGAP1 missense variant H945Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Only two tools, polyPhen‑2 HumDiv and polyPhen‑2 HumVar, predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for H945Q, 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 | 0.982235 | Disordered | 0.849210 | Binding | 0.386 | 0.923 | 0.750 | -5.248 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.343 | Likely Benign | -0.36 | Neutral | 0.995 | Probably Damaging | 0.939 | Probably Damaging | 5.03 | Benign | 0.06 | Tolerated | 4.32 | 4 | 0.2671 | 0.3128 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||
| c.2839G>A | G947R 2D AIThe SynGAP1 missense variant G947R is listed in gnomAD (6-33443391-G-A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Optimized) and pathogenic (SIFT). Two tools remain uncertain (ESM1b, AlphaMissense‑Default). High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign effect, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—does not reach a definitive conclusion (two benign, two uncertain). Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no reported result for this variant. Overall, the preponderance of evidence points to a benign impact, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988695 | Disordered | 0.850554 | Binding | 0.358 | 0.919 | 0.750 | 6-33443391-G-A | 6 | 3.72e-6 | -7.481 | In-Between | 0.343 | Ambiguous | Likely Benign | 0.273 | Likely Benign | -0.60 | Neutral | 0.411 | Benign | 0.140 | Benign | 4.94 | Benign | 0.04 | Affected | 4.32 | 4 | 0.1034 | 0.4733 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||
| c.2839G>C | G947R 2D AIThe SynGAP1 missense variant G947R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta stability analysis is unavailable. Overall, the balance of evidence favors a benign classification, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988695 | Disordered | 0.850554 | Binding | 0.358 | 0.919 | 0.750 | -7.481 | In-Between | 0.343 | Ambiguous | Likely Benign | 0.273 | Likely Benign | -0.60 | Neutral | 0.411 | Benign | 0.140 | Benign | 4.94 | Benign | 0.04 | Affected | 4.32 | 4 | 0.1034 | 0.4733 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.2839G>T | G947W 2D AIThe SynGAP1 missense variant G947W has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988695 | Disordered | 0.850554 | Binding | 0.358 | 0.919 | 0.750 | -10.819 | Likely Pathogenic | 0.285 | Likely Benign | Likely Benign | 0.349 | Likely Benign | -1.21 | Neutral | 0.983 | Probably Damaging | 0.868 | Possibly Damaging | 4.90 | Benign | 0.01 | Affected | 0.0914 | 0.4059 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.2840G>A | G947E 2D AIThe SynGAP1 missense variant G947E is reported in ClinVar as “Not submitted” and is present in gnomAD (variant ID 6-33443392-G-A). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only ESM1b predicts a pathogenic outcome, creating a single discordant signal. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that G947E is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988695 | Disordered | 0.850554 | Binding | 0.358 | 0.919 | 0.750 | 6-33443392-G-A | 1 | 6.20e-7 | -9.574 | Likely Pathogenic | 0.243 | Likely Benign | Likely Benign | 0.302 | Likely Benign | 0.08 | Neutral | 0.126 | Benign | 0.096 | Benign | 4.92 | Benign | 0.10 | Tolerated | 4.32 | 4 | 0.1555 | 0.4259 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| c.2840G>C | G947A 2D AIThe SynGAP1 missense variant G947A is listed in ClinVar (ID 1595137) as Benign and is present in gnomAD (variant ID 6‑33443392‑G‑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 is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign, and Foldetta results are unavailable. Overall, the computational evidence strongly indicates that the variant is most likely benign, and this conclusion is consistent with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988695 | Disordered | 0.850554 | Binding | 0.358 | 0.919 | 0.750 | Benign/Likely benign | 2 | 6-33443392-G-C | 28 | 1.73e-5 | -6.511 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.156 | Likely Benign | -0.41 | Neutral | 0.224 | Benign | 0.131 | Benign | 4.97 | Benign | 0.10 | Tolerated | 4.32 | 4 | 0.3375 | 0.4957 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||
| c.2840G>T | G947V 2D AIThe SynGAP1 missense variant G947V 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign, whereas polyPhen‑2 HumDiv and SIFT predict pathogenicity; ESM1b remains uncertain. High‑accuracy methods reinforce the benign assessment: AlphaMissense‑Optimized scores benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” and Foldetta data are not available. Overall, the preponderance of evidence points to a benign impact for G947V, and this conclusion is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988695 | Disordered | 0.850554 | Binding | 0.358 | 0.919 | 0.750 | -7.171 | In-Between | 0.105 | Likely Benign | Likely Benign | 0.296 | Likely Benign | -1.11 | Neutral | 0.586 | Possibly Damaging | 0.303 | Benign | 4.93 | Benign | 0.01 | Affected | 0.1443 | 0.3507 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.2428C>A | R810S 2D AIThe SynGAP1 R810S missense variant 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 suggests that R810S is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant has not yet been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.486429 | Structured | 0.851848 | Binding | 0.263 | 0.907 | 0.375 | -5.996 | Likely Benign | 0.950 | Likely Pathogenic | Ambiguous | 0.204 | Likely Benign | -3.20 | Deleterious | 0.996 | Probably Damaging | 0.900 | Possibly Damaging | 2.44 | Pathogenic | 0.01 | Affected | 0.3152 | 0.4556 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||
| c.2428C>G | R810G 2D AISynGAP1 missense variant R810G is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: a single benign call from REVEL, and six pathogenic calls from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Two tools (ESM1b and AlphaMissense‑Optimized) give uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized remains uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic, and Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a pathogenic impact for R810G, 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 Pathogenic | SH3-binding motif | 0.486429 | Structured | 0.851848 | Binding | 0.263 | 0.907 | 0.375 | -7.190 | In-Between | 0.828 | Likely Pathogenic | Ambiguous | 0.202 | Likely Benign | -3.57 | Deleterious | 0.996 | Probably Damaging | 0.925 | Probably Damaging | 2.35 | Pathogenic | 0.01 | Affected | 0.3686 | 0.4207 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||
| c.2428C>T | R810C 2D AIThe SynGAP1 missense variant R810C is listed in gnomAD (6‑33442980‑C‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.486429 | Structured | 0.851848 | Binding | 0.263 | 0.907 | 0.375 | 6-33442980-C-T | 2 | 1.24e-6 | -8.925 | Likely Pathogenic | 0.839 | Likely Pathogenic | Ambiguous | 0.245 | Likely Benign | -4.91 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 2.32 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.3517 | 0.4263 | -3 | -4 | 7.0 | -53.05 | |||||||||||||||||||||||||||||||||
| c.2429G>A | R810H 2D AIThe SynGAP1 R810H missense variant is listed in gnomAD (ID 6‑33442981‑G‑A) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas a pathogenic consensus is reached by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as pathogenic, and Foldetta (FoldX‑MD/Rosetta stability analysis) is unavailable. Overall, the majority of tools predict pathogenicity, and the high‑accuracy subset is split, but the pathogenic signal dominates. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.486429 | Structured | 0.851848 | Binding | 0.263 | 0.907 | 0.375 | 6-33442981-G-A | 3 | 1.86e-6 | -6.554 | Likely Benign | 0.550 | Ambiguous | Likely Benign | 0.239 | Likely Benign | -2.80 | Deleterious | 1.000 | Probably Damaging | 0.980 | Probably Damaging | 2.35 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.3149 | 0.2631 | 0 | 2 | 1.3 | -19.05 | ||||||||||||||||||||||||||||||||||
| c.2429G>C | R810P 2D AIThe SynGAP1 missense variant R810P is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized indicates a benign effect, whereas the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple in silico predictors points to a pathogenic impact for R810P. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.486429 | Structured | 0.851848 | Binding | 0.263 | 0.907 | 0.375 | -4.120 | Likely Benign | 0.779 | Likely Pathogenic | Likely Benign | 0.316 | Likely Benign | -4.08 | Deleterious | 1.000 | Probably Damaging | 0.977 | Probably Damaging | 2.33 | Pathogenic | 0.01 | Affected | 0.2307 | 0.5478 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||||
| c.2429G>T | R810L 2D AIThe SynGAP1 R810L missense change is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to REVEL, while the majority of algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic outcome. Uncertain calls come from ESM1b and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta results are unavailable. Overall, the preponderance of evidence from multiple in‑silico predictors points to a pathogenic impact for R810L. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.486429 | Structured | 0.851848 | Binding | 0.263 | 0.907 | 0.375 | -7.172 | In-Between | 0.834 | Likely Pathogenic | Ambiguous | 0.338 | Likely Benign | -4.57 | Deleterious | 0.996 | Probably Damaging | 0.925 | Probably Damaging | 2.35 | Pathogenic | 0.01 | Affected | 0.2019 | 0.5271 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||||||
| c.2830G>A | G944S 2D AIThe SynGAP1 missense variant G944S is listed in ClinVar as a benign alteration (ClinVar ID 833552.0) and is present in the gnomAD database (gnomAD ID 6‑33443382‑G‑A). 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 not available for this variant. Overall, the majority of computational evidence supports a benign classification, which aligns with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.852408 | Binding | 0.360 | 0.923 | 0.750 | Benign | 1 | 6-33443382-G-A | 13 | 8.05e-6 | -5.303 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.223 | Likely Benign | -0.75 | Neutral | 0.007 | Benign | 0.004 | Benign | 3.77 | Benign | 0.00 | Affected | 4.32 | 4 | 0.2471 | 0.5502 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||
| c.2830G>C | G944R 2D AIThe SynGAP1 missense variant G944R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for G944R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.852408 | Binding | 0.360 | 0.923 | 0.750 | -6.577 | Likely Benign | 0.359 | Ambiguous | Likely Benign | 0.459 | Likely Benign | -1.82 | Neutral | 0.639 | Possibly Damaging | 0.299 | Benign | 3.73 | Benign | 0.00 | Affected | 0.1030 | 0.4733 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2830G>T | G944C 2D AIThe SynGAP1 missense variant G944C is listed in ClinVar with no submitted interpretation and is present in gnomAD (variant ID 6‑33443382‑G‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote of the four contributing tools) also indicates Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which remains unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.852408 | Binding | 0.360 | 0.923 | 0.750 | 6-33443382-G-T | 1 | 6.20e-7 | -9.121 | Likely Pathogenic | 0.093 | Likely Benign | Likely Benign | 0.426 | Likely Benign | -1.79 | Neutral | 0.975 | Probably Damaging | 0.848 | Possibly Damaging | 3.70 | Benign | 0.00 | Affected | 4.32 | 4 | 0.1399 | 0.4439 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||
| c.2831G>A | G944D 2D AIThe SynGAP1 missense variant G944D 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 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the majority‑vote SGM‑Consensus also indicates a likely benign outcome. Only SIFT predicts a pathogenic effect, and ESM1b remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign classification. Foldetta stability analysis is not available for this residue. Overall, the preponderance of evidence points to a benign impact, and this assessment does not conflict with the absence of a ClinVar claim. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.852408 | Binding | 0.360 | 0.923 | 0.750 | -7.684 | In-Between | 0.296 | Likely Benign | Likely Benign | 0.421 | Likely Benign | -1.42 | Neutral | 0.224 | Benign | 0.131 | Benign | 3.70 | Benign | 0.00 | Affected | 0.1833 | 0.2826 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2831G>C | G944A 2D AIThe SynGAP1 missense variant G944A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.852408 | Binding | 0.360 | 0.923 | 0.750 | -6.397 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.314 | Likely Benign | -0.61 | Neutral | 0.059 | Benign | 0.042 | Benign | 3.81 | Benign | 0.00 | Affected | 0.3352 | 0.4957 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2831G>T | G944V 2D AIThe SynGAP1 missense variant G944V is catalogued in gnomAD (ID 6‑33443383‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the substitution as benign or likely benign. Only SIFT predicts a pathogenic outcome, while ESM1b remains uncertain. High‑accuracy assessments confirm the benign consensus: AlphaMissense‑Optimized reports a benign effect, and the SGM‑Consensus likewise indicates a likely benign status. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the collective evidence points to a benign variant, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Thus, 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 | 0.977651 | Disordered | 0.852408 | Binding | 0.360 | 0.923 | 0.750 | 6-33443383-G-T | 1 | 6.20e-7 | -7.536 | In-Between | 0.090 | Likely Benign | Likely Benign | 0.446 | Likely Benign | -1.41 | Neutral | 0.126 | Benign | 0.096 | Benign | 3.70 | Benign | 0.00 | Affected | 4.32 | 4 | 0.1455 | 0.3507 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||
| 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.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.2425A>C | S809R 2D AIThe SynGAP1 missense variant S809R is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into three groups: benign predictions from REVEL, PROVEAN, and FATHMM; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; and uncertain predictions from ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward benign. Protein‑folding stability analysis with Foldetta is unavailable. Overall, the balance of evidence, particularly the benign consensus from high‑accuracy tools, suggests the variant is most likely benign, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -7.062 | In-Between | 0.935 | Likely Pathogenic | Ambiguous | 0.085 | Likely Benign | -1.50 | Neutral | 0.784 | Possibly Damaging | 0.472 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.0954 | 0.3702 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2425A>G | S809G 2D AIThe SynGAP1 missense variant S809G is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity 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 (majority vote) is also benign. Foldetta results are not available, so they do not influence the conclusion. Overall, the preponderance of evidence indicates that S809G 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 | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -6.100 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -1.80 | Neutral | 0.270 | Benign | 0.136 | Benign | 2.61 | Benign | 0.02 | Affected | 0.2743 | 0.5369 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||||||
| c.2425A>T | S809C 2D AIThe SynGAP1 missense variant S809C is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM Consensus, which is a majority vote among 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 are unavailable. Overall, the majority of predictions (5 pathogenic vs. 4 benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -8.186 | Likely Pathogenic | 0.221 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -1.99 | Neutral | 0.975 | Probably Damaging | 0.766 | Possibly Damaging | 2.49 | Pathogenic | 0.01 | Affected | 0.1088 | 0.6174 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2426G>A | S809N 2D AIThe SynGAP1 missense variant S809N is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic impact, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for S809N, 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 | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -5.308 | Likely Benign | 0.341 | Ambiguous | Likely Benign | 0.079 | Likely Benign | -1.12 | Neutral | 0.784 | Possibly Damaging | 0.316 | Benign | 2.51 | Benign | 0.04 | Affected | 0.1363 | 0.5028 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||||
| c.2426G>C | S809T 2D AIThe SynGAP1 missense variant S809T 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, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign outcome. Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -3.865 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.076 | Likely Benign | 0.68 | Neutral | 0.003 | Benign | 0.010 | Benign | 2.95 | Benign | 0.82 | Tolerated | 0.1430 | 0.6617 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2426G>T | S809I 2D AIThe SynGAP1 missense variant S809I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Consensus from standard in silico predictors shows a split: six tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Optimized) predict a benign effect, while two (SIFT, AlphaMissense‑Default) predict pathogenicity; ESM1b is uncertain. High‑accuracy assessment further supports a benign outcome: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign classification, and Foldetta data are unavailable. Overall, the preponderance of evidence indicates 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. | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -7.708 | In-Between | 0.632 | Likely Pathogenic | Likely Benign | 0.087 | Likely Benign | -1.93 | Neutral | 0.065 | Benign | 0.022 | Benign | 2.50 | Benign | 0.01 | Affected | 0.1039 | 0.5984 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2427C>A | S809R 2D AIThe SynGAP1 missense variant S809R is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into three groups: benign predictions from REVEL, PROVEAN, and FATHMM; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; and uncertain predictions from ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward benign. Protein‑folding stability analysis with Foldetta is unavailable. Overall, the balance of evidence, particularly the benign consensus from high‑accuracy tools, suggests the variant is most likely benign, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -7.062 | In-Between | 0.935 | Likely Pathogenic | Ambiguous | 0.091 | Likely Benign | -1.50 | Neutral | 0.784 | Possibly Damaging | 0.472 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.0954 | 0.3702 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2427C>G | S809R 2D AIThe SynGAP1 missense variant S809R is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into three groups: benign predictions from REVEL, PROVEAN, and FATHMM; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; and uncertain predictions from ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward benign. Protein‑folding stability analysis with Foldetta is unavailable. Overall, the balance of evidence, particularly the benign consensus from high‑accuracy tools, suggests the variant is most likely benign, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -7.062 | In-Between | 0.935 | Likely Pathogenic | Ambiguous | 0.091 | Likely Benign | -1.50 | Neutral | 0.784 | Possibly Damaging | 0.472 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.0954 | 0.3702 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2419T>A | Y807N 2D  AIThe SynGAP1 missense variant Y807N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL and AlphaMissense‑Optimized, whereas pathogenic predictions are returned by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score, which is labeled Likely Pathogenic. ESM1b is uncertain. High‑accuracy methods give a clearer picture: AlphaMissense‑Optimized predicts a benign effect, while the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates pathogenicity. Foldetta, a protein‑folding stability approach that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions lean toward pathogenicity, and this is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.699094 | Disordered | 0.853760 | Binding | 0.336 | 0.901 | 0.500 | -7.795 | In-Between | 0.591 | Likely Pathogenic | Likely Benign | 0.154 | Likely Benign | -4.01 | Deleterious | 0.934 | Possibly Damaging | 0.773 | Possibly Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.2274 | 0.0704 | -2 | -2 | -2.2 | -49.07 | ||||||||||||||||||||||||||||||||||||||
| c.2419T>C | Y807H 2D  AIThe SynGAP1 missense variant Y807H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that indicate a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as pathogenic. AlphaMissense‑Optimized remains benign, while Foldetta results are unavailable. Overall, the majority of high‑accuracy and consensus predictors (five out of six) suggest a pathogenic impact, whereas only three predict benign. Consequently, the variant is most likely pathogenic based on current computational evidence, 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. | SH3-binding motif | 0.699094 | Disordered | 0.853760 | Binding | 0.336 | 0.901 | 0.500 | -5.879 | Likely Benign | 0.413 | Ambiguous | Likely Benign | 0.152 | Likely Benign | -2.74 | Deleterious | 0.989 | Probably Damaging | 0.913 | Probably Damaging | 2.44 | Pathogenic | 0.00 | Affected | 0.2530 | 0.0704 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||||||||||||
| c.2419T>G | Y807D 2D  AIThe SynGAP1 missense variant Y807D is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect are limited to REVEL, while the majority of algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Uncertain calls come from ESM1b and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for Y807D, 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 Pathogenic | SH3-binding motif | 0.699094 | Disordered | 0.853760 | Binding | 0.336 | 0.901 | 0.500 | -7.598 | In-Between | 0.862 | Likely Pathogenic | Ambiguous | 0.186 | Likely Benign | -4.40 | Deleterious | 0.966 | Probably Damaging | 0.773 | Possibly Damaging | 2.42 | Pathogenic | 0.00 | Affected | 0.3944 | 0.0704 | -4 | -3 | -2.2 | -48.09 | ||||||||||||||||||||||||||||||||||||||
| c.2420A>C | Y807S 2D  AIThe SynGAP1 Y807S variant 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b, while those that predict pathogenicity are PROVEAN, SIFT, and FATHMM. AlphaMissense‑Default is uncertain, whereas AlphaMissense‑Optimized predicts benign. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, leans toward pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of conventional tools (four benign vs. three pathogenic) suggest a benign effect, and the high‑accuracy AlphaMissense‑Optimized also predicts benign, while the SGM Consensus predicts pathogenic. Based on the balance of evidence, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar reporting. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.699094 | Disordered | 0.853760 | Binding | 0.336 | 0.901 | 0.500 | -5.517 | Likely Benign | 0.384 | Ambiguous | Likely Benign | 0.093 | Likely Benign | -3.90 | Deleterious | 0.136 | Benign | 0.067 | Benign | 2.44 | Pathogenic | 0.01 | Affected | 0.4561 | 0.1884 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2420A>G | Y807C 2D  AIThe SynGAP1 missense variant Y807C is listed in ClinVar with an “Uncertain” status (ClinVar ID 2119812.0) and is present in gnomAD (ID 6‑33442972‑A‑G). Prediction tools that agree on a benign effect include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (five pathogenic vs. three benign) and the SGM Consensus support a pathogenic interpretation, whereas AlphaMissense‑Optimized alone suggests benign. The variant is most likely pathogenic based on the collective evidence, and this conclusion is not contradicted by the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.699094 | Disordered | 0.853760 | Binding | 0.336 | 0.901 | 0.500 | Uncertain | 1 | 6-33442972-A-G | 1 | 6.20e-7 | -7.228 | In-Between | 0.204 | Likely Benign | Likely Benign | 0.243 | Likely Benign | -3.89 | Deleterious | 0.997 | Probably Damaging | 0.934 | Probably Damaging | 2.42 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.3101 | 0.1907 | 0 | -2 | 3.8 | -60.04 | ||||||||||||||||||||||||||||||||
| c.2420A>T | Y807F 2D  AIThe SynGAP1 missense variant Y807F is listed in ClinVar (ID 1491782.0) with an “Uncertain” status and is not reported in gnomAD. All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. No tool in the set predicts pathogenicity. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the four high‑accuracy predictors) is benign. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, has no available result for this variant. Overall, the computational evidence strongly supports 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 | SH3-binding motif | 0.699094 | Disordered | 0.853760 | Binding | 0.336 | 0.901 | 0.500 | Uncertain | 1 | -3.667 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.057 | Likely Benign | 0.14 | Neutral | 0.012 | Benign | 0.022 | Benign | 2.92 | Benign | 0.98 | Tolerated | 3.77 | 5 | 0.2485 | 0.2500 | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||||||||||
| c.2332A>C | N778H 2D  AIThe SynGAP1 missense variant N778H is not reported 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, 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 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 Benign | 0.494003 | Structured | 0.853922 | Binding | 0.288 | 0.887 | 0.500 | -4.761 | Likely Benign | 0.172 | Likely Benign | Likely Benign | 0.100 | Likely Benign | -1.62 | Neutral | 0.991 | Probably Damaging | 0.980 | Probably Damaging | 4.17 | Benign | 0.04 | Affected | 0.1400 | 0.7220 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||||||
| c.2332A>G | N778D 2D  AIThe SynGAP1 missense variant N778D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the 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 | 0.494003 | Structured | 0.853922 | Binding | 0.288 | 0.887 | 0.500 | -4.838 | Likely Benign | 0.446 | Ambiguous | Likely Benign | 0.093 | Likely Benign | -0.86 | Neutral | 0.843 | Possibly Damaging | 0.893 | Possibly Damaging | 4.21 | Benign | 0.15 | Tolerated | 0.1896 | 0.4528 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2332A>T | N778Y 2D  AIThe SynGAP1 missense variant N778Y is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster into two groups: benign (REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized) and pathogenic (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT). AlphaMissense‑Default is uncertain, while the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Taken together, the preponderance of evidence from both general and high‑accuracy predictors points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.494003 | Structured | 0.853922 | Binding | 0.288 | 0.887 | 0.500 | -5.723 | Likely Benign | 0.421 | Ambiguous | Likely Benign | 0.175 | Likely Benign | -2.48 | Neutral | 0.991 | Probably Damaging | 0.980 | Probably Damaging | 4.16 | Benign | 0.02 | Affected | 0.0589 | 0.6139 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||||||||||||
| c.2333A>C | N778T 2D  AIThe SynGAP1 missense variant N778T is not reported 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 prediction is available, so it does not influence the assessment. Overall, the majority of evidence indicates that the variant is most likely benign, and this conclusion 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 | 0.494003 | Structured | 0.853922 | Binding | 0.288 | 0.887 | 0.500 | -3.820 | Likely Benign | 0.222 | Likely Benign | Likely Benign | 0.110 | Likely Benign | -1.52 | Neutral | 0.925 | Possibly Damaging | 0.932 | Probably Damaging | 4.23 | Benign | 0.09 | Tolerated | 0.1441 | 0.7395 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||||||||||
| c.2333A>G | N778S 2D  AIThe SynGAP1 missense variant N778S is reported in gnomAD (ID 6‑33442491‑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 two tools—polyPhen‑2 HumDiv and HumVar—predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is 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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.494003 | Structured | 0.853922 | Binding | 0.288 | 0.887 | 0.500 | 6-33442491-A-G | 1 | 1.28e-6 | -2.711 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.137 | Likely Benign | -0.61 | Neutral | 0.843 | Possibly Damaging | 0.893 | Possibly Damaging | 4.32 | Benign | 0.86 | Tolerated | 3.64 | 6 | 0.4285 | 0.6890 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||||||||||
| c.2333A>T | N778I 2D  AIThe SynGAP1 missense variant N778I is reported in gnomAD (ID 6‑33442491‑A‑T) but has no ClinVar entry. 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, 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 (majority of the four high‑accuracy predictors) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, 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 | 0.494003 | Structured | 0.853922 | Binding | 0.288 | 0.887 | 0.500 | 6-33442491-A-T | -6.659 | Likely Benign | 0.622 | Likely Pathogenic | Likely Benign | 0.150 | Likely Benign | -2.48 | Neutral | 0.991 | Probably Damaging | 0.980 | Probably Damaging | 4.17 | Benign | 0.02 | Affected | 3.64 | 6 | 0.0628 | 0.6128 | -3 | -2 | 8.0 | -0.94 | ||||||||||||||||||||||||||||||||||||
| c.2334C>A | N778K 2D  AIThe SynGAP1 missense variant N778K is catalogued in gnomAD (ID 6‑33442492‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM; pathogenic predictions from PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome, reflecting the majority of benign calls. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain, and Foldetta data are not available. Overall, the majority of evidence points toward a benign effect, and this is consistent with the lack of a ClinVar pathogenic classification. Therefore, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.494003 | Structured | 0.853922 | Binding | 0.288 | 0.887 | 0.500 | 6-33442492-C-A | -6.768 | Likely Benign | 0.798 | Likely Pathogenic | Ambiguous | 0.113 | Likely Benign | -1.57 | Neutral | 0.925 | Possibly Damaging | 0.932 | Probably Damaging | 4.27 | Benign | 0.18 | Tolerated | 3.64 | 6 | 0.2037 | 0.5883 | 0 | 1 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||||
| c.2334C>G | N778K 2D AIThe SynGAP1 missense variant N778K has no ClinVar record and is not listed in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The 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 returns an uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available output for this variant. Overall, the preponderance of evidence points to a benign effect. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.494003 | Structured | 0.853922 | Binding | 0.288 | 0.887 | 0.500 | -6.768 | Likely Benign | 0.798 | Likely Pathogenic | Ambiguous | 0.114 | Likely Benign | -1.57 | Neutral | 0.925 | Possibly Damaging | 0.932 | Probably Damaging | 4.27 | Benign | 0.18 | Tolerated | 3.64 | 6 | 0.2037 | 0.5883 | 0 | 1 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||
| c.3490C>A | L1164M 2D AIThe SynGAP1 missense variant L1164M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also leans benign. No Foldetta (FoldX‑MD/ Rosetta stability) result is available, so it does not influence the interpretation. Overall, the majority of computational 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 | 0.517562 | Disordered | 0.853935 | Binding | 0.325 | 0.815 | 0.375 | -5.493 | Likely Benign | 0.757 | Likely Pathogenic | Likely Benign | 0.349 | Likely Benign | -0.29 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 5.34 | Benign | 0.13 | Tolerated | 0.0847 | 0.3378 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3490C>G | L1164V 2D AIThe SynGAP1 missense variant L1164V has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and no Foldetta stability data are available. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.853935 | Binding | 0.325 | 0.815 | 0.375 | -4.911 | Likely Benign | 0.797 | Likely Pathogenic | Ambiguous | 0.330 | Likely Benign | -0.88 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 5.54 | Benign | 0.14 | Tolerated | 0.1456 | 0.2617 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3491T>A | L1164Q 2D AIThe SynGAP1 missense variant L1164Q has no ClinVar record and is not present in gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign status. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, whereas the SGM‑Consensus remains benign; Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not conflict with ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.853935 | Binding | 0.325 | 0.815 | 0.375 | -5.374 | Likely Benign | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.497 | Likely Benign | -0.95 | Neutral | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 5.32 | Benign | 0.18 | Tolerated | 0.1171 | 0.1181 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3491T>C | L1164P 2D AIThe SynGAP1 missense variant L1164P has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic impact are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the majority of tools (seven pathogenic vs. three benign) predict a deleterious effect, indicating that the variant is most likely pathogenic. This prediction does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.853935 | Binding | 0.325 | 0.815 | 0.375 | -3.928 | Likely Benign | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.573 | Likely Pathogenic | -2.16 | Neutral | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 5.41 | Benign | 0.04 | Affected | 0.3173 | 0.1414 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3491T>G | L1164R 2D AIThe SynGAP1 missense variant L1164R has no ClinVar entry and is absent from gnomAD, so its population frequency is unknown. Functional prediction tools show mixed results: benign calls come from PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls come from REVEL, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, and AlphaMissense‑Optimized. Grouping by consensus, four tools predict benign and five predict pathogenic. High‑accuracy methods give a more nuanced view: the SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign outcome; AlphaMissense‑Optimized independently predicts Pathogenic; Foldetta’s stability assessment is unavailable. Overall, the majority of standard predictors lean toward pathogenicity, but the SGM Consensus and several benign‑oriented tools counterbalance this. Given the lack of ClinVar annotation, there is no contradiction. The variant is most likely pathogenic based on the preponderance of predictions, though the SGM Consensus suggests a benign interpretation, indicating uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.853935 | Binding | 0.325 | 0.815 | 0.375 | -4.390 | Likely Benign | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.539 | Likely Pathogenic | -1.65 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 5.33 | Benign | 0.08 | Tolerated | 0.1396 | 0.0623 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3391C>A | P1131T 2D AIThe SynGAP1 missense variant P1131T is not 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 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. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.855155 | Binding | 0.360 | 0.899 | 0.750 | -4.766 | Likely Benign | 0.219 | Likely Benign | Likely Benign | 0.313 | Likely Benign | -2.93 | Deleterious | 0.245 | Benign | 0.096 | Benign | 5.30 | Benign | 0.00 | Affected | 0.1353 | 0.6315 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3391C>G | P1131A 2D AIThe SynGAP1 missense variant P1131A 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 consistent with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.855155 | Binding | 0.360 | 0.899 | 0.750 | -4.785 | Likely Benign | 0.171 | Likely Benign | Likely Benign | 0.207 | Likely Benign | -2.88 | Deleterious | 0.009 | Benign | 0.008 | Benign | 5.36 | Benign | 0.00 | Affected | 0.2977 | 0.5501 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3391C>T | P1131S 2D AIThe SynGAP1 missense variant P1131S is reported in gnomAD (variant ID 6‑33443943‑C‑T) 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 substitution as benign. In contrast, PROVEAN 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 further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, and this is not contradictory to ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.855155 | Binding | 0.360 | 0.899 | 0.750 | 6-33443943-C-T | 1 | 6.72e-7 | -4.089 | Likely Benign | 0.246 | Likely Benign | Likely Benign | 0.209 | Likely Benign | -2.62 | Deleterious | 0.025 | Benign | 0.015 | Benign | 5.54 | Benign | 0.00 | Affected | 4.32 | 4 | 0.2936 | 0.5936 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3392C>A | P1131H 2D AIThe SynGAP1 missense variant P1131H is not 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. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the balance of evidence leans toward a benign classification, 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. | 0.919029 | Disordered | 0.855155 | Binding | 0.360 | 0.899 | 0.750 | -5.207 | Likely Benign | 0.454 | Ambiguous | Likely Benign | 0.357 | Likely Benign | -3.50 | Deleterious | 0.971 | Probably Damaging | 0.750 | Possibly Damaging | 5.24 | Benign | 0.00 | Affected | 0.1519 | 0.5546 | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||||||
| c.3392C>G | P1131R 2D AIThe SynGAP1 P1131R missense variant has no ClinVar record and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta data are unavailable. With five benign versus four pathogenic calls and a benign result from the most accurate tool, the variant is most likely benign. This assessment does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.919029 | Disordered | 0.855155 | Binding | 0.360 | 0.899 | 0.750 | -3.792 | Likely Benign | 0.702 | Likely Pathogenic | Likely Benign | 0.416 | Likely Benign | -2.58 | Deleterious | 0.918 | Possibly Damaging | 0.420 | Benign | 5.26 | Benign | 0.00 | Affected | 0.1252 | 0.4010 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3392C>T | P1131L 2D AIThe SynGAP1 missense variant P1131L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN and SIFT, while AlphaMissense‑Default remains uncertain. The high‑accuracy AlphaMissense‑Optimized tool classifies the variant as benign. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also yields a benign prediction (2 benign vs. 1 pathogenic, with one uncertain). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.919029 | Disordered | 0.855155 | Binding | 0.360 | 0.899 | 0.750 | -5.267 | Likely Benign | 0.420 | Ambiguous | Likely Benign | 0.293 | Likely Benign | -3.62 | Deleterious | 0.002 | Benign | 0.005 | Benign | 5.26 | Benign | 0.00 | Affected | 0.2043 | 0.6998 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3463G>A | V1155M 2D AISynGAP1 missense variant V1155M is not reported in ClinVar and is present in gnomAD (ID 6‑33444498‑G‑A). Prediction tools that agree on benign impact include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, 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 slightly favors a benign interpretation, with no conflict with the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.855718 | Binding | 0.335 | 0.857 | 0.500 | 6-33444498-G-A | 1 | 6.20e-7 | -3.818 | Likely Benign | 0.915 | Likely Pathogenic | Ambiguous | 0.249 | Likely Benign | -1.19 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.57 | Benign | 0.02 | Affected | 3.77 | 5 | 0.0779 | 0.4079 | 1 | 2 | -2.3 | 32.06 | ||||||||||||||||||||||||||||||||||
| c.3463G>C | V1155L 2D AIThe SynGAP1 missense variant V1155L is not reported in ClinVar and has no gnomAD entry. Consensus from multiple in silico predictors shows a split: benign calls come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar) and both AlphaMissense models. When predictions are grouped by agreement, the benign set includes five tools and the pathogenic set includes four. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts pathogenicity, whereas the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence, especially from the high‑accuracy AlphaMissense‑Optimized and the SGM‑Consensus, suggests the variant 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 | 0.750527 | Disordered | 0.855718 | Binding | 0.335 | 0.857 | 0.500 | -2.823 | Likely Benign | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.229 | Likely Benign | -1.26 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.63 | Benign | 0.09 | Tolerated | 0.0951 | 0.4175 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3463G>T | V1155L 2D AIThe SynGAP1 missense variant V1155L is not reported in ClinVar and has no gnomAD entry. Consensus from multiple in silico predictors shows a split: benign calls come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar) and both AlphaMissense models. When predictions are grouped by agreement, the benign set includes five tools and the pathogenic set includes four. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts pathogenicity, whereas the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence, especially from the high‑accuracy AlphaMissense‑Optimized and the SGM‑Consensus, suggests the variant 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 | 0.750527 | Disordered | 0.855718 | Binding | 0.335 | 0.857 | 0.500 | -2.823 | Likely Benign | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.229 | Likely Benign | -1.26 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.63 | Benign | 0.09 | Tolerated | 0.0951 | 0.4175 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3464T>A | V1155E 2D AIThe SynGAP1 missense variant V1155E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments highlight a discrepancy: AlphaMissense‑Optimized predicts pathogenic, whereas the SGM‑Consensus indicates likely benign; Foldetta stability analysis is unavailable. Consequently, the evidence is evenly split between benign and pathogenic interpretations, and no ClinVar entry contradicts these findings. The variant’s clinical significance remains uncertain, with no definitive leaning toward benign or pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.855718 | Binding | 0.335 | 0.857 | 0.500 | -3.175 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.204 | Likely Benign | -2.01 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.58 | Benign | 0.02 | Affected | 0.0973 | 0.1727 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||||||||||||
| c.3464T>C | V1155A 2D AIThe SynGAP1 missense variant V1155A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.855718 | Binding | 0.335 | 0.857 | 0.500 | -2.019 | Likely Benign | 0.941 | Likely Pathogenic | Ambiguous | 0.224 | Likely Benign | 0.77 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 3.15 | Benign | 1.00 | Tolerated | 0.3070 | 0.1859 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| c.3464T>G | V1155G 2D AIThe SynGAP1 missense variant V1155G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give mixed results: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (benign), FATHMM (benign), and PROVEAN (benign), reports a benign outcome; Foldetta’s stability assessment is unavailable. Overall, the majority of conventional tools lean toward pathogenicity, whereas the high‑accuracy consensus leans benign, leaving the functional impact uncertain. The variant is most likely pathogenic based on the prevailing predictions, 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. | 0.750527 | Disordered | 0.855718 | Binding | 0.335 | 0.857 | 0.500 | -3.018 | Likely Benign | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.209 | Likely Benign | -1.91 | Neutral | 0.997 | Probably Damaging | 0.999 | Probably Damaging | 2.59 | Benign | 0.05 | Affected | 0.2211 | 0.2374 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2272T>A | Y758N 2D AIThe SynGAP1 missense variant Y758N 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 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 | 0.517562 | Disordered | 0.856063 | Binding | 0.289 | 0.871 | 0.375 | -3.316 | Likely Benign | 0.234 | Likely Benign | Likely Benign | 0.100 | Likely Benign | -1.32 | Neutral | 0.837 | Possibly Damaging | 0.631 | Possibly Damaging | 2.72 | Benign | 0.02 | Affected | 0.2467 | 0.0331 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||||||||||||
| c.2272T>C | Y758H 2D AIThe SynGAP1 missense variant Y758H 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 assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.856063 | Binding | 0.289 | 0.871 | 0.375 | -3.194 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.92 | Neutral | 0.064 | Benign | 0.031 | Benign | 2.71 | Benign | 0.02 | Affected | 0.2519 | 0.0331 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||||||||||||
| c.2272T>G | Y758D 2D AIThe SynGAP1 missense variant Y758D is not reported 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—including the high‑accuracy tools—points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.856063 | Binding | 0.289 | 0.871 | 0.375 | -3.688 | Likely Benign | 0.481 | Ambiguous | Likely Benign | 0.160 | Likely Benign | -1.89 | Neutral | 0.973 | Probably Damaging | 0.796 | Possibly Damaging | 2.71 | Benign | 0.02 | Affected | 0.4647 | 0.0331 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||||||||||||
| c.2273A>C | Y758S 2D AIThe SynGAP1 missense variant Y758S is reported in gnomAD (variant ID 6‑33441738‑A‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict it to be pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority‑vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the preponderance of evidence points to a benign impact, and this assessment does not contradict any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.856063 | Binding | 0.289 | 0.871 | 0.375 | 6-33441738-A-C | 1 | 6.20e-7 | -1.912 | Likely Benign | 0.215 | Likely Benign | Likely Benign | 0.110 | Likely Benign | -0.54 | Neutral | 0.912 | Possibly Damaging | 0.629 | Possibly Damaging | 2.75 | Benign | 0.06 | Tolerated | 3.99 | 5 | 0.5377 | 0.1663 | Weaken | -2 | -3 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||
| c.2273A>G | Y758C 2D AIThe SynGAP1 missense variant Y758C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.856063 | Binding | 0.289 | 0.871 | 0.375 | -5.256 | Likely Benign | 0.123 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -1.91 | Neutral | 0.998 | Probably Damaging | 0.921 | Probably Damaging | 2.71 | Benign | 0.03 | Affected | 0.3375 | 0.1922 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||||||||||||
| c.2273A>T | Y758F 2D AIThe SynGAP1 missense variant Y758F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.856063 | Binding | 0.289 | 0.871 | 0.375 | -1.431 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.112 | Likely Benign | -0.79 | Neutral | 0.679 | Possibly Damaging | 0.371 | Benign | 2.75 | Benign | 1.00 | Tolerated | 0.2441 | 0.2835 | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2422G>A | V808I 2D AIThe SynGAP1 missense variant V808I 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, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Pathogenic predictions come from polyPhen‑2 HumDiv, SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign and the SGM‑Consensus (majority vote) 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 annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.699094 | Disordered | 0.856438 | Binding | 0.289 | 0.903 | 0.500 | -4.190 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -0.67 | Neutral | 0.659 | Possibly Damaging | 0.191 | Benign | 2.33 | Pathogenic | 0.00 | Affected | 0.0935 | 0.4282 | 4 | 3 | 0.3 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2422G>C | V808L 2D AIThe SynGAP1 missense variant V808L is not reported 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, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. 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) 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 for V808L, 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 | 0.699094 | Disordered | 0.856438 | Binding | 0.289 | 0.903 | 0.500 | -4.723 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.188 | Likely Benign | -1.82 | Neutral | 0.911 | Possibly Damaging | 0.621 | Possibly Damaging | 2.33 | Pathogenic | 0.00 | Affected | 0.1166 | 0.4745 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2422G>T | V808L 2D AIThe SynGAP1 missense variant V808L is not reported 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, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. 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) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.699094 | Disordered | 0.856438 | Binding | 0.289 | 0.903 | 0.500 | -4.723 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.188 | Likely Benign | -1.82 | Neutral | 0.911 | Possibly Damaging | 0.621 | Possibly Damaging | 2.33 | Pathogenic | 0.00 | Affected | 0.1166 | 0.4745 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2423T>A | V808E 2D AIThe SynGAP1 missense variant V808E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: the single benign prediction comes from REVEL, while the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized returns an uncertain result, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels the variant as Likely Pathogenic, and Foldetta data are not available. Based on the preponderance of pathogenic predictions and the SGM‑Consensus outcome, the variant is most likely pathogenic; this assessment does not contradict any ClinVar status, as none exists for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.699094 | Disordered | 0.856438 | Binding | 0.289 | 0.903 | 0.500 | -9.078 | Likely Pathogenic | 0.888 | Likely Pathogenic | Ambiguous | 0.307 | Likely Benign | -2.84 | Deleterious | 0.999 | Probably Damaging | 0.958 | Probably Damaging | 2.28 | Pathogenic | 0.00 | Affected | 0.1129 | 0.2787 | -2 | -2 | -7.7 | 29.98 | ||||||||||||||||||||||||||||||||||||||
| c.2423T>C | V808A 2D AIThe SynGAP1 missense variant V808A is not reported 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 remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign verdict, while Foldetta results are unavailable. Taken together, the majority of evidence points to a benign impact, 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. | SH3-binding motif | 0.699094 | Disordered | 0.856438 | Binding | 0.289 | 0.903 | 0.500 | -5.091 | Likely Benign | 0.541 | Ambiguous | Likely Benign | 0.177 | Likely Benign | -1.96 | Neutral | 0.953 | Possibly Damaging | 0.621 | Possibly Damaging | 2.31 | Pathogenic | 0.00 | Affected | 0.2748 | 0.2809 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| c.2423T>G | V808G 2D AIThe SynGAP1 V808G missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, 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 results are unavailable. Overall, the majority of individual predictors (five benign vs. three pathogenic) support a benign classification, and this is not contradicted by any ClinVar annotation. Thus, based on the available predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.699094 | Disordered | 0.856438 | Binding | 0.289 | 0.903 | 0.500 | -6.635 | Likely Benign | 0.460 | Ambiguous | Likely Benign | 0.268 | Likely Benign | -2.94 | Deleterious | 0.069 | Benign | 0.135 | Benign | 2.27 | Pathogenic | 0.00 | Affected | 0.1925 | 0.3336 | -1 | -3 | -4.6 | -42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3487C>A | H1163N 2D AIThe SynGAP1 missense variant H1163N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for H1163N, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.858469 | Binding | 0.328 | 0.825 | 0.375 | -3.219 | Likely Benign | 0.643 | Likely Pathogenic | Likely Benign | 0.280 | Likely Benign | -1.70 | Neutral | 0.991 | Probably Damaging | 0.988 | Probably Damaging | 5.47 | Benign | 0.17 | Tolerated | 0.1588 | 0.2759 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3487C>G | H1163D 2D AISynGAP1 missense variant H1163D 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, SIFT, ESM1b, and FATHMM, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized rates the variant as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a tie and is therefore unavailable, and Foldetta folding‑stability analysis is not provided. With an equal number of benign and pathogenic predictions and no decisive high‑accuracy evidence, the variant remains ambiguous. Thus, it is most likely neither clearly benign nor pathogenic, and this uncertainty aligns with its ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.509769 | Disordered | 0.858469 | Binding | 0.328 | 0.825 | 0.375 | Uncertain | 1 | -2.107 | Likely Benign | 0.949 | Likely Pathogenic | Ambiguous | 0.476 | Likely Benign | -2.60 | Deleterious | 0.991 | Probably Damaging | 0.991 | Probably Damaging | 5.44 | Benign | 0.31 | Tolerated | 3.88 | 3 | 0.2145 | 0.1986 | 1 | -1 | -0.3 | -22.05 | ||||||||||||||||||||||||||||||||||||
| c.3487C>T | H1163Y 2D AIThe SynGAP1 missense variant H1163Y is not reported 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 classifying the variant as benign and the SGM‑Consensus also indicating a likely benign outcome; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). 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 | 0.509769 | Disordered | 0.858469 | Binding | 0.328 | 0.825 | 0.375 | -4.051 | Likely Benign | 0.688 | Likely Pathogenic | Likely Benign | 0.390 | Likely Benign | -1.81 | Neutral | 0.991 | Probably Damaging | 0.988 | Probably Damaging | 5.40 | Benign | 0.08 | Tolerated | 0.0845 | 0.4487 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.3488A>C | H1163P 2D AIThe SynGAP1 missense variant H1163P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are SIFT, ESM1b, and FATHMM, while those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie (2 pathogenic vs. 2 benign), and Foldetta results are unavailable. Overall, more tools predict pathogenicity than benignity (5 vs. 3), and there is no ClinVar record to contradict this assessment. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.509769 | Disordered | 0.858469 | Binding | 0.328 | 0.825 | 0.375 | -2.023 | Likely Benign | 0.815 | Likely Pathogenic | Ambiguous | 0.578 | Likely Pathogenic | -3.19 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 5.39 | Benign | 0.10 | Tolerated | 0.2015 | 0.3900 | 0 | -2 | 1.6 | -40.02 | ||||||||||||||||||||||||||||||||||||||||
| c.3488A>G | H1163R 2D AIThe SynGAP1 missense variant H1163R is not reported 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 | 0.509769 | Disordered | 0.858469 | Binding | 0.328 | 0.825 | 0.375 | -2.505 | Likely Benign | 0.942 | Likely Pathogenic | Ambiguous | 0.472 | Likely Benign | -2.08 | Neutral | 0.991 | Probably Damaging | 0.991 | Probably Damaging | 5.43 | Benign | 0.27 | Tolerated | 0.1863 | 0.2402 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.3488A>T | H1163L 2D AIThe SynGAP1 missense variant H1163L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign) and Foldetta results are unavailable. Overall, the majority of predictions (5 pathogenic vs. 4 benign) lean toward a pathogenic impact. There is no ClinVar entry to contradict this assessment, so the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.509769 | Disordered | 0.858469 | Binding | 0.328 | 0.825 | 0.375 | -2.401 | Likely Benign | 0.707 | Likely Pathogenic | Likely Benign | 0.568 | Likely Pathogenic | -3.15 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.55 | Benign | 0.10 | Tolerated | 0.0938 | 0.5356 | -2 | -3 | 7.0 | -23.98 | ||||||||||||||||||||||||||||||||||||||||
| c.3489C>A | H1163Q 2D AIThe SynGAP1 missense variant H1163Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for H1163Q. 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 | 0.509769 | Disordered | 0.858469 | Binding | 0.328 | 0.825 | 0.375 | -2.970 | Likely Benign | 0.899 | Likely Pathogenic | Ambiguous | 0.414 | Likely Benign | -1.41 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.43 | Benign | 0.58 | Tolerated | 0.1445 | 0.3424 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3489C>G | H1163Q 2D AIThe SynGAP1 missense variant H1163Q is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. AlphaMissense‑Optimized is uncertain, and no Foldetta (FoldX‑MD/Rosetta stability) result is available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar reporting and gnomAD presence, 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 | 0.509769 | Disordered | 0.858469 | Binding | 0.328 | 0.825 | 0.375 | -2.970 | Likely Benign | 0.899 | Likely Pathogenic | Ambiguous | 0.414 | Likely Benign | -1.41 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.43 | Benign | 0.58 | Tolerated | 0.1445 | 0.3424 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3484C>A | P1162T 2D AIThe SynGAP1 missense variant P1162T is not reported 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 the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.858809 | Binding | 0.366 | 0.823 | 0.375 | -3.466 | Likely Benign | 0.879 | Likely Pathogenic | Ambiguous | 0.171 | Likely Benign | -2.15 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.71 | Benign | 0.22 | Tolerated | 0.1395 | 0.6097 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3484C>G | P1162A 2D AIThe SynGAP1 missense variant P1162A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.858809 | Binding | 0.366 | 0.823 | 0.375 | -2.594 | Likely Benign | 0.878 | Likely Pathogenic | Ambiguous | 0.169 | Likely Benign | -2.33 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.74 | Benign | 0.41 | Tolerated | 0.3437 | 0.5655 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3484C>T | P1162S 2D AIThe SynGAP1 missense variant P1162S is listed in ClinVar (ID 2287942.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM. 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, reports a “Likely Benign” classification. AlphaMissense‑Optimized is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the majority of high‑accuracy and consensus predictions lean toward a benign impact. Thus, the variant is most likely benign, which is consistent with its ClinVar “Uncertain” designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.858809 | Binding | 0.366 | 0.823 | 0.375 | Uncertain | 1 | -2.118 | Likely Benign | 0.913 | Likely Pathogenic | Ambiguous | 0.215 | Likely Benign | -1.93 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.73 | Benign | 0.55 | Tolerated | 3.88 | 3 | 0.3386 | 0.6055 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||
| c.3485C>A | P1162H 2D AIThe SynGAP1 missense variant P1162H is not reported 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as Pathogenic, whereas the SGM‑Consensus (majority vote) indicates Likely Benign; Foldetta results are unavailable. Overall, the majority of tools (six benign vs. four pathogenic) lean toward a benign interpretation, but the high‑accuracy AlphaMissense‑Optimized prediction conflicts with the consensus. Because ClinVar contains no entry, there is no contradiction with clinical database status. Based on the collective predictions, the variant is most likely benign, though the AlphaMissense‑Optimized result suggests caution. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.858809 | Binding | 0.366 | 0.823 | 0.375 | -3.733 | Likely Benign | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.168 | Likely Benign | -2.46 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.67 | Benign | 0.17 | Tolerated | 0.1481 | 0.5001 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3485C>G | P1162R 2D AIThe SynGAP1 missense variant P1162R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of predictions (5 pathogenic vs 4 benign) and the pathogenic call from AlphaMissense‑Optimized suggest the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.599170 | Disordered | 0.858809 | Binding | 0.366 | 0.823 | 0.375 | -2.657 | Likely Benign | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.208 | Likely Benign | -2.68 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.70 | Benign | 0.14 | Tolerated | 0.1269 | 0.3439 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3485C>T | P1162L 2D AIThe SynGAP1 missense variant P1162L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence (five pathogenic vs. four benign predictions) indicates that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.599170 | Disordered | 0.858809 | Binding | 0.366 | 0.823 | 0.375 | -3.370 | Likely Benign | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.209 | Likely Benign | -3.48 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.68 | Benign | 0.06 | Tolerated | 0.2153 | 0.7372 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2827G>A | G943S 2D AIThe SynGAP1 missense variant G943S 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. 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 | 0.973328 | Disordered | 0.860437 | Binding | 0.372 | 0.910 | 0.750 | -5.785 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.295 | Likely Benign | 0.34 | Neutral | 0.059 | Benign | 0.039 | Benign | 2.88 | Benign | 0.51 | Tolerated | 0.2482 | 0.5502 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2827G>C | G943R 2D AIThe SynGAP1 missense variant G943R is reported in gnomAD (variant ID 6-33443379‑G‑C) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity; only ESM1b is uncertain. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions strongly supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.973328 | Disordered | 0.860437 | Binding | 0.372 | 0.910 | 0.750 | 6-33443379-G-C | 1 | 6.20e-7 | -7.159 | In-Between | 0.335 | Likely Benign | Likely Benign | 0.308 | Likely Benign | 1.00 | Neutral | 0.411 | Benign | 0.062 | Benign | 2.86 | Benign | 0.94 | Tolerated | 4.32 | 4 | 0.0976 | 0.4933 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||
| c.2827G>T | G943C 2D AIThe SynGAP1 missense variant G943C is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which itself is “Likely Benign”). In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b all predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence—including the consensus and high‑accuracy tools—points to a benign impact. Thus, 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 | 0.973328 | Disordered | 0.860437 | Binding | 0.372 | 0.910 | 0.750 | -9.822 | Likely Pathogenic | 0.108 | Likely Benign | Likely Benign | 0.356 | Likely Benign | -0.94 | Neutral | 0.938 | Possibly Damaging | 0.649 | Possibly Damaging | 2.84 | Benign | 0.10 | Tolerated | 0.1425 | 0.4439 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.2828G>A | G943D 2D AIThe SynGAP1 missense variant G943D is not reported in ClinVar and is absent from gnomAD. In silico predictors 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) reports “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. Taken together, the overwhelming majority of predictions indicate a benign effect, and this conclusion does not contradict any ClinVar status (none is assigned). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.973328 | Disordered | 0.860437 | Binding | 0.372 | 0.910 | 0.750 | -7.951 | In-Between | 0.304 | Likely Benign | Likely Benign | 0.296 | Likely Benign | -0.28 | Neutral | 0.224 | Benign | 0.113 | Benign | 2.85 | Benign | 0.11 | Tolerated | 0.1904 | 0.2826 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2828G>C | G943A 2D AIThe SynGAP1 missense variant G943A is reported in gnomAD (ID 6‑33443380‑G‑C) but has no ClinVar entry. All available in silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments 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 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 | 0.973328 | Disordered | 0.860437 | Binding | 0.372 | 0.910 | 0.750 | 6-33443380-G-C | 3 | 1.86e-6 | -6.684 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.274 | Likely Benign | 0.10 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.87 | Benign | 0.89 | Tolerated | 4.32 | 4 | 0.3415 | 0.4957 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2828G>T | G943V 2D AIThe SynGAP1 missense variant G943V 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. The only tool with an uncertain outcome is ESM1b, which does not alter the overall consensus. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign classification. High‑accuracy predictors corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are not available. Taken together, the evidence overwhelmingly supports a benign interpretation, and there is no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.973328 | Disordered | 0.860437 | Binding | 0.372 | 0.910 | 0.750 | -7.658 | In-Between | 0.092 | Likely Benign | Likely Benign | 0.265 | Likely Benign | -0.43 | Neutral | 0.224 | Benign | 0.062 | Benign | 2.85 | Benign | 0.16 | Tolerated | 0.1399 | 0.3507 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3478A>C | N1160H 2D AIThe SynGAP1 missense variant N1160H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default all indicate 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 for this variant. Overall, the preponderance of evidence from multiple in silico predictors points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.585406 | Disordered | 0.861611 | Binding | 0.361 | 0.836 | 0.375 | -3.704 | Likely Benign | 0.848 | Likely Pathogenic | Ambiguous | 0.262 | Likely Benign | -3.44 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.79 | Pathogenic | 0.02 | Affected | 0.1152 | 0.6583 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3478A>G | N1160D 2D AIThe SynGAP1 missense variant at position N1160D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and ESM1b, whereas a majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.585406 | Disordered | 0.861611 | Binding | 0.361 | 0.836 | 0.375 | -3.222 | Likely Benign | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.225 | Likely Benign | -3.22 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.84 | Pathogenic | 0.08 | Tolerated | 0.1618 | 0.3920 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3478A>T | N1160Y 2D AIThe SynGAP1 missense variant N1160Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic.” No Foldetta stability prediction is available. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.585406 | Disordered | 0.861611 | Binding | 0.361 | 0.836 | 0.375 | -4.074 | Likely Benign | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.421 | Likely Benign | -4.90 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.79 | Pathogenic | 0.01 | Affected | 0.0591 | 0.5681 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||||||||||||
| c.3479A>C | N1160T 2D AIThe SynGAP1 missense variant N1160T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, SIFT, and ESM1b, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any existing ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.585406 | Disordered | 0.861611 | Binding | 0.361 | 0.836 | 0.375 | -3.017 | Likely Benign | 0.889 | Likely Pathogenic | Ambiguous | 0.229 | Likely Benign | -3.61 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.81 | Pathogenic | 0.63 | Tolerated | 0.1147 | 0.6759 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||||||||||
| c.3479A>G | N1160S 2D AIThe SynGAP1 missense variant N1160S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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, has no available result for this variant. Overall, the variant is most likely pathogenic based on the high‑accuracy consensus, and this assessment does not contradict ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.585406 | Disordered | 0.861611 | Binding | 0.361 | 0.836 | 0.375 | -1.880 | Likely Benign | 0.550 | Ambiguous | Likely Benign | 0.228 | Likely Benign | -3.26 | Deleterious | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 1.83 | Pathogenic | 0.15 | Tolerated | 0.3459 | 0.6304 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3479A>T | N1160I 2D AIThe SynGAP1 missense variant N1160I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence from multiple in silico tools indicates that the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.585406 | Disordered | 0.861611 | Binding | 0.361 | 0.836 | 0.375 | -4.996 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.440 | Likely Benign | -5.35 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.79 | Pathogenic | 0.01 | Affected | 0.0618 | 0.5903 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3480C>A | N1160K 2D AIThe SynGAP1 missense variant N1160K is not reported in ClinVar and is absent from 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, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. No Foldetta stability analysis is available for this residue. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.585406 | Disordered | 0.861611 | Binding | 0.361 | 0.836 | 0.375 | -3.768 | Likely Benign | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.188 | Likely Benign | -3.92 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 1.83 | Pathogenic | 0.04 | Affected | 0.1919 | 0.5017 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3480C>G | N1160K 2D AIThe SynGAP1 missense variant N1160K is not reported in ClinVar and is absent from 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, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. No Foldetta stability analysis is available for this residue. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.585406 | Disordered | 0.861611 | Binding | 0.361 | 0.836 | 0.375 | -3.768 | Likely Benign | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.189 | Likely Benign | -3.92 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 1.83 | Pathogenic | 0.04 | Affected | 0.1919 | 0.5017 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2842G>A | G948S 2D AIThe SynGAP1 missense variant G948S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess sequence conservation and structural impact uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this benign assessment: 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 predictor, has no available result for this variant. Overall, the collective evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988505 | Disordered | 0.862121 | Binding | 0.365 | 0.919 | 0.750 | -4.760 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.177 | Likely Benign | 1.09 | Neutral | 0.068 | Benign | 0.026 | Benign | 4.57 | Benign | 1.00 | Tolerated | 0.2466 | 0.5502 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2842G>C | G948R 2D AIThe SynGAP1 missense variant G948R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988505 | Disordered | 0.862121 | Binding | 0.365 | 0.919 | 0.750 | -6.782 | Likely Benign | 0.315 | Likely Benign | Likely Benign | 0.266 | Likely Benign | -0.60 | Neutral | 0.818 | Possibly Damaging | 0.435 | Benign | 4.58 | Benign | 0.04 | Affected | 0.1069 | 0.4933 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2842G>T | G948C 2D AIThe SynGAP1 missense variant G948C is not reported 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 high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the majority of evidence points to a benign impact. The predictions do not contradict ClinVar status, as no ClinVar assertion exists for this variant. Thus, based on the available computational predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988505 | Disordered | 0.862121 | Binding | 0.365 | 0.919 | 0.750 | -10.254 | Likely Pathogenic | 0.102 | Likely Benign | Likely Benign | 0.247 | Likely Benign | -0.77 | Neutral | 0.997 | Probably Damaging | 0.840 | Possibly Damaging | 4.50 | Benign | 0.04 | Affected | 0.1422 | 0.4439 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.2843G>A | G948D 2D AIThe SynGAP1 missense variant G948D 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv 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, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988505 | Disordered | 0.862121 | Binding | 0.365 | 0.919 | 0.750 | -8.423 | Likely Pathogenic | 0.267 | Likely Benign | Likely Benign | 0.279 | Likely Benign | 0.15 | Neutral | 0.818 | Possibly Damaging | 0.266 | Benign | 4.55 | Benign | 0.11 | Tolerated | 0.1871 | 0.2826 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2843G>C | G948A 2D AIThe SynGAP1 missense variant G948A 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 | 0.988505 | Disordered | 0.862121 | Binding | 0.365 | 0.919 | 0.750 | -5.627 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.189 | Likely Benign | 0.04 | Neutral | 0.288 | Benign | 0.103 | Benign | 4.64 | Benign | 0.39 | Tolerated | 0.3350 | 0.4957 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2843G>T | G948V 2D AIThe SynGAP1 missense variant G948V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. Foldetta, a protein‑folding stability method 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 G948V 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 | 0.988505 | Disordered | 0.862121 | Binding | 0.365 | 0.919 | 0.750 | -6.541 | Likely Benign | 0.102 | Likely Benign | Likely Benign | 0.256 | Likely Benign | -0.48 | Neutral | 0.901 | Possibly Damaging | 0.435 | Benign | 4.52 | Benign | 0.06 | Tolerated | 0.1464 | 0.3507 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3871C>A | L1291M 2D AIThe SynGAP1 missense variant L1291M is reported in gnomAD (ID 6‑33447919‑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 classify the change as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT each predict a pathogenic impact. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the four benign predictors) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that 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 | 0.827927 | Disordered | 0.863458 | Binding | 0.579 | 0.797 | 0.625 | 6-33447919-C-A | -5.625 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.93 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 2.53 | Benign | 0.03 | Affected | 3.77 | 5 | 0.0767 | 0.2973 | 2 | 4 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||
| c.3871C>G | L1291V 2D AIThe SynGAP1 missense variant L1291V 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, so the pathogenic prediction group is empty. High‑accuracy assessments corroborate this benign consensus: 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 prediction aligns 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 | 0.863458 | Binding | 0.579 | 0.797 | 0.625 | -4.583 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.028 | Likely Benign | 0.28 | Neutral | 0.149 | Benign | 0.064 | Benign | 2.61 | Benign | 0.07 | Tolerated | 0.1435 | 0.2946 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3872T>A | L1291Q 2D AISynGAP1 missense variant L1291Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is equivocal (two benign, two pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence is split, with an equal number of benign and pathogenic calls and no decisive high‑accuracy consensus. Consequently, the variant’s likely effect remains uncertain; it is not contradicted by any ClinVar annotation. 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 | -4.450 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.290 | Likely Benign | -4.18 | Deleterious | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.49 | Pathogenic | 0.01 | Affected | 0.1052 | 0.1049 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||||||||
| 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.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.2749C>A | P917T 2D AIThe SynGAP1 missense variant P917T 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 | 0.599170 | Disordered | 0.863949 | Binding | 0.314 | 0.862 | 0.375 | -4.012 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -1.68 | Neutral | 0.139 | Benign | 0.088 | Benign | 2.69 | Benign | 0.00 | Affected | 0.1445 | 0.5711 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2749C>G | P917A 2D AIThe SynGAP1 missense variant P917A is not reported in ClinVar and is present in gnomAD (ID 6‑33443301‑C‑G). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all classify the change as benign or likely benign. Only SIFT predicts a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the collective predictions point to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for P917A. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.863949 | Binding | 0.314 | 0.862 | 0.375 | 6-33443301-C-G | 1 | 6.20e-7 | -3.681 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -1.33 | Neutral | 0.065 | Benign | 0.037 | Benign | 2.72 | Benign | 0.00 | Affected | 3.77 | 5 | 0.3458 | 0.4772 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.2749C>T | P917S 2D AIThe SynGAP1 missense variant P917S is catalogued in gnomAD (ID 6‑33443301‑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 report benign. Only SIFT predicts pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: 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 reported result for this variant, so it provides no additional evidence. Overall, the preponderance of predictions indicates that P917S is most likely benign, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.863949 | Binding | 0.314 | 0.862 | 0.375 | 6-33443301-C-T | 1 | 6.20e-7 | -3.562 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -0.54 | Neutral | 0.003 | Benign | 0.002 | Benign | 2.70 | Benign | 0.00 | Affected | 3.77 | 5 | 0.3478 | 0.5121 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.2750C>A | P917H 2D AIThe SynGAP1 missense variant P917H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence—including the high‑accuracy tools—points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.863949 | Binding | 0.314 | 0.862 | 0.375 | -5.395 | Likely Benign | 0.182 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -2.00 | Neutral | 0.975 | Probably Damaging | 0.766 | Possibly Damaging | 2.65 | Benign | 0.00 | Affected | 0.1584 | 0.4410 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2750C>G | P917R 2D AIThe SynGAP1 missense variant P917R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (gnomAD ID 6‑33443302‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also as benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.863949 | Binding | 0.314 | 0.862 | 0.375 | Uncertain | 1 | 6-33443302-C-G | 5 | 3.10e-6 | -4.475 | Likely Benign | 0.363 | Ambiguous | Likely Benign | 0.142 | Likely Benign | -1.70 | Neutral | 0.642 | Possibly Damaging | 0.316 | Benign | 2.68 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1270 | 0.3012 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||
| c.2750C>T | P917L 2D AIThe SynGAP1 missense variant P917L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the 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 | 0.599170 | Disordered | 0.863949 | Binding | 0.314 | 0.862 | 0.375 | -3.369 | Likely Benign | 0.172 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -2.35 | Neutral | 0.425 | Benign | 0.233 | Benign | 2.75 | Benign | 0.00 | Affected | 0.2001 | 0.6351 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3481A>C | M1161L 2D AIThe SynGAP1 missense variant M1161L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool rates the variant as uncertain, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Consequently, the available computational evidence is conflicting, with an equal number of benign and pathogenic predictions and no definitive high‑accuracy support. The variant is most likely of uncertain significance; this lack of consensus is consistent with its absence from ClinVar and gnomAD. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.580690 | Disordered | 0.864109 | Binding | 0.372 | 0.830 | 0.375 | -2.129 | Likely Benign | 0.862 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | -1.59 | Neutral | 0.699 | Possibly Damaging | 0.833 | Possibly Damaging | 2.38 | Pathogenic | 0.48 | Tolerated | 0.1614 | 0.4244 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3481A>G | M1161V 2D AISynGAP1 missense variant M1161V is not reported in ClinVar and is present in gnomAD (ID 6‑33444516‑A‑G). Functional prediction tools cluster into two groups: benign predictions from REVEL, PROVEAN, SIFT, and ESM1b; pathogenic predictions from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta data are unavailable. Consequently, the evidence does not favor either outcome. The variant is most likely neither clearly benign nor pathogenic based on current predictions, and this lack of consensus does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.580690 | Disordered | 0.864109 | Binding | 0.372 | 0.830 | 0.375 | 6-33444516-A-G | 2 | 1.24e-6 | -3.060 | Likely Benign | 0.915 | Likely Pathogenic | Ambiguous | 0.150 | Likely Benign | -1.85 | Neutral | 0.843 | Possibly Damaging | 0.926 | Probably Damaging | 2.27 | Pathogenic | 0.22 | Tolerated | 3.77 | 5 | 0.3422 | 0.3292 | 1 | 2 | 2.3 | -32.06 | |||||||||||||||||||||||||||||||||||
| c.3481A>T | M1161L 2D AISynGAP1 missense variant M1161L is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it yields a 2‑to‑2 split. High‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain, and both the SGM Consensus and Foldetta (which would combine FoldX‑MD and Rosetta outputs) are unavailable. Consequently, the overall computational evidence does not strongly favor either outcome. The variant is most likely inconclusive in pathogenicity prediction, and this does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.580690 | Disordered | 0.864109 | Binding | 0.372 | 0.830 | 0.375 | -2.129 | Likely Benign | 0.862 | Likely Pathogenic | Ambiguous | 0.156 | Likely Benign | -1.59 | Neutral | 0.699 | Possibly Damaging | 0.833 | Possibly Damaging | 2.38 | Pathogenic | 0.48 | Tolerated | 0.1614 | 0.4244 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3482T>A | M1161K 2D AIThe SynGAP1 missense variant M1161K 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, SIFT, and ESM1b, whereas tools that predict a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic and the SGM‑Consensus labeling it as Likely Pathogenic; Foldetta results are unavailable. Overall, the majority of computational predictions support a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.580690 | Disordered | 0.864109 | Binding | 0.372 | 0.830 | 0.375 | -3.005 | Likely Benign | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.236 | Likely Benign | -2.91 | Deleterious | 0.968 | Probably Damaging | 0.969 | Probably Damaging | 2.19 | Pathogenic | 0.17 | Tolerated | 0.1629 | 0.0828 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||||||
| c.3482T>C | M1161T 2D AIThe SynGAP1 missense variant M1161T is listed in gnomAD (ID 6‑33444517‑T‑C) but has no ClinVar entry. Functional prediction tools fall into two groups: benign predictions come from REVEL, SIFT, and ESM1b, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.580690 | Disordered | 0.864109 | Binding | 0.372 | 0.830 | 0.375 | 6-33444517-T-C | 1 | 6.20e-7 | -2.620 | Likely Benign | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.148 | Likely Benign | -2.75 | Deleterious | 0.968 | Probably Damaging | 0.954 | Probably Damaging | 2.19 | Pathogenic | 0.27 | Tolerated | 3.77 | 5 | 0.2218 | 0.1786 | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||||||||||||||||
| c.3482T>G | M1161R 2D AIThe SynGAP1 missense variant M1161R 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, SIFT, and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN)—predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus as likely pathogenic; Foldetta results are unavailable. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.580690 | Disordered | 0.864109 | Binding | 0.372 | 0.830 | 0.375 | -2.653 | Likely Benign | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.220 | Likely Benign | -2.97 | Deleterious | 0.968 | Probably Damaging | 0.978 | Probably Damaging | 2.18 | Pathogenic | 0.13 | Tolerated | 0.1689 | 0.0809 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||||||
| c.3483G>A | M1161I 2D AIThe SynGAP1 missense variant M1161I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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 evidence (five pathogenic vs. four benign predictions) indicates that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.580690 | Disordered | 0.864109 | Binding | 0.372 | 0.830 | 0.375 | -3.124 | Likely Benign | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.155 | Likely Benign | -1.92 | Neutral | 0.925 | Possibly Damaging | 0.954 | Probably Damaging | 2.27 | Pathogenic | 0.25 | Tolerated | 3.77 | 5 | 0.1437 | 0.3190 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3483G>C | M1161I 2D AIThe SynGAP1 missense variant M1161I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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 predictions (five pathogenic vs. four benign) indicate that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.580690 | Disordered | 0.864109 | Binding | 0.372 | 0.830 | 0.375 | -3.124 | Likely Benign | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.155 | Likely Benign | -1.92 | Neutral | 0.925 | Possibly Damaging | 0.954 | Probably Damaging | 2.27 | Pathogenic | 0.25 | Tolerated | 3.77 | 5 | 0.1437 | 0.3190 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3483G>T | M1161I 2D AIThe SynGAP1 missense variant M1161I is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33444518‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, whereas polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic outcome. 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, there are five pathogenic predictions versus four benign ones, tipping the balance toward a likely pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.580690 | Disordered | 0.864109 | Binding | 0.372 | 0.830 | 0.375 | 6-33444518-G-T | 1 | 6.20e-7 | -3.124 | Likely Benign | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.155 | Likely Benign | -1.92 | Neutral | 0.925 | Possibly Damaging | 0.954 | Probably Damaging | 2.27 | Pathogenic | 0.25 | Tolerated | 3.77 | 5 | 0.1437 | 0.3190 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||
| 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.3475T>A | S1159T 2D AIThe SynGAP1 missense variant S1159T is not reported 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 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 | 0.626927 | Disordered | 0.867068 | Binding | 0.343 | 0.846 | 0.375 | -4.057 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.59 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.68 | Benign | 0.28 | Tolerated | 0.1114 | 0.5715 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3475T>C | S1159P 2D AIThe SynGAP1 missense variant S1159P is not reported in ClinVar and has no gnomAD entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus score, which is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (majority vote) is benign. No Foldetta stability prediction is available for this residue. 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 | 0.626927 | Disordered | 0.867068 | Binding | 0.343 | 0.846 | 0.375 | -3.656 | Likely Benign | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.188 | Likely Benign | -2.06 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.64 | Benign | 0.14 | Tolerated | 0.1807 | 0.5111 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3475T>G | S1159A 2D AIThe SynGAP1 missense variant S1159A 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 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 reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.626927 | Disordered | 0.867068 | Binding | 0.343 | 0.846 | 0.375 | -3.653 | Likely Benign | 0.327 | Likely Benign | Likely Benign | 0.095 | Likely Benign | -0.46 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.71 | Benign | 0.44 | Tolerated | 0.4754 | 0.4541 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3476C>A | S1159Y 2D AIThe SynGAP1 missense variant S1159Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the majority of evidence (six benign predictions versus five pathogenic, plus a benign consensus) points to a likely benign impact for S1159Y. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.626927 | Disordered | 0.867068 | Binding | 0.343 | 0.846 | 0.375 | -5.665 | Likely Benign | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.195 | Likely Benign | -1.57 | Neutral | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 2.65 | Benign | 0.07 | Tolerated | 0.0567 | 0.4923 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.3476C>G | S1159C 2D AIThe SynGAP1 missense variant S1159C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. 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 | 0.626927 | Disordered | 0.867068 | Binding | 0.343 | 0.846 | 0.375 | -6.650 | Likely Benign | 0.591 | Likely Pathogenic | Likely Benign | 0.172 | Likely Benign | -1.22 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.63 | Benign | 0.06 | Tolerated | 0.0807 | 0.5668 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.3476C>T | S1159F 2D AIThe SynGAP1 missense variant S1159F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) remains benign; Foldetta stability analysis is unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.626927 | Disordered | 0.867068 | Binding | 0.343 | 0.846 | 0.375 | -5.627 | Likely Benign | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.181 | Likely Benign | -1.11 | Neutral | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 2.66 | Benign | 0.20 | Tolerated | 0.0527 | 0.5211 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.3166G>A | G1056S 2D AIThe SynGAP1 missense variant G1056S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988291 | Disordered | 0.868632 | Binding | 0.402 | 0.935 | 0.875 | -5.252 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.339 | Likely Benign | -0.28 | Neutral | 0.451 | Benign | 0.149 | Benign | 1.87 | Pathogenic | 0.55 | Tolerated | 0.2497 | 0.5702 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3166G>C | G1056R 2D AIThe SynGAP1 missense variant G1056R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM, while AlphaMissense‑Default remains uncertain. High‑accuracy assessment shows AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) favors a pathogenic outcome, and Foldetta data are unavailable. Overall, the majority of conventional predictors indicate a benign impact, whereas the SGM Consensus suggests pathogenicity. Given the preponderance of benign predictions and the lack of ClinVar evidence, the variant is most likely benign, and this assessment does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988291 | Disordered | 0.868632 | Binding | 0.402 | 0.935 | 0.875 | -9.358 | Likely Pathogenic | 0.390 | Ambiguous | Likely Benign | 0.410 | Likely Benign | 0.12 | Neutral | 0.011 | Benign | 0.010 | Benign | 1.83 | Pathogenic | 0.13 | Tolerated | 0.1127 | 0.4533 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3166G>T | G1056C 2D AIThe SynGAP1 missense variant G1056C is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign impact. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988291 | Disordered | 0.868632 | Binding | 0.402 | 0.935 | 0.875 | -9.974 | Likely Pathogenic | 0.122 | Likely Benign | Likely Benign | 0.432 | Likely Benign | -0.70 | Neutral | 0.994 | Probably Damaging | 0.777 | Possibly Damaging | 1.83 | Pathogenic | 0.06 | Tolerated | 0.1414 | 0.4439 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||||||
| c.3167G>A | G1056D 2D AIThe SynGAP1 missense variant G1056D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs. 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence (six benign vs. three pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988291 | Disordered | 0.868632 | Binding | 0.402 | 0.935 | 0.875 | -10.352 | Likely Pathogenic | 0.328 | Likely Benign | Likely Benign | 0.380 | Likely Benign | 0.09 | Neutral | 0.666 | Possibly Damaging | 0.193 | Benign | 1.83 | Pathogenic | 0.92 | Tolerated | 0.1912 | 0.2626 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3167G>C | G1056A 2D AIThe SynGAP1 missense variant G1056A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign consensus (2 benign vs. 1 pathogenic, with one uncertain). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988291 | Disordered | 0.868632 | Binding | 0.402 | 0.935 | 0.875 | -7.458 | In-Between | 0.086 | Likely Benign | Likely Benign | 0.325 | Likely Benign | -0.25 | Neutral | 0.264 | Benign | 0.097 | Benign | 1.85 | Pathogenic | 0.49 | Tolerated | 0.3325 | 0.4957 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3167G>T | G1056V 2D AIThe SynGAP1 missense variant G1056V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence (7 benign vs 2 pathogenic) supports a benign classification. This consensus does not contradict ClinVar status, which has no entry for this variant. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988291 | Disordered | 0.868632 | Binding | 0.402 | 0.935 | 0.875 | -8.130 | Likely Pathogenic | 0.097 | Likely Benign | Likely Benign | 0.448 | Likely Benign | -0.24 | Neutral | 0.292 | Benign | 0.110 | Benign | 1.83 | Pathogenic | 0.08 | Tolerated | 0.1488 | 0.3507 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3169A>C | S1057R 2D AIThe SynGAP1 missense variant S1057R is catalogued in gnomAD (ID 6‑33443721‑A‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988291 | Disordered | 0.869507 | Binding | 0.413 | 0.927 | 0.875 | 6-33443721-A-C | -6.648 | Likely Benign | 0.379 | Ambiguous | Likely Benign | 0.221 | Likely Benign | -0.24 | Neutral | 0.677 | Possibly Damaging | 0.168 | Benign | 5.30 | Benign | 0.21 | Tolerated | 3.77 | 5 | 0.1584 | 0.3620 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| c.3169A>G | S1057G 2D AIThe SynGAP1 missense variant S1057G is reported in gnomAD (ID 6‑33443721‑A‑G) but has no ClinVar entry. All evaluated in‑silico predictors uniformly classify the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988291 | Disordered | 0.869507 | Binding | 0.413 | 0.927 | 0.875 | 6-33443721-A-G | 1 | 7.20e-7 | -1.005 | Likely Benign | 0.049 | Likely Benign | Likely Benign | 0.211 | Likely Benign | -0.47 | Neutral | 0.421 | Benign | 0.111 | Benign | 5.76 | Benign | 0.52 | Tolerated | 3.77 | 5 | 0.2654 | 0.4846 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||
| c.3169A>T | S1057C 2D AIThe SynGAP1 missense variant S1057C is reported in gnomAD (ID 6‑33443721‑A‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Two tools, polyPhen‑2 HumDiv and polyPhen‑2 HumVar, predict a pathogenic impact, while ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988291 | Disordered | 0.869507 | Binding | 0.413 | 0.927 | 0.875 | 6-33443721-A-T | -7.529 | In-Between | 0.100 | Likely Benign | Likely Benign | 0.258 | Likely Benign | -0.64 | Neutral | 0.977 | Probably Damaging | 0.683 | Possibly Damaging | 5.23 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.1856 | 0.6106 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||
| c.3170G>A | S1057N 2D AIThe SynGAP1 missense variant S1057N is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All available in‑silico predictors classify the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” No tool predicts pathogenicity. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, and this is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988291 | Disordered | 0.869507 | Binding | 0.413 | 0.927 | 0.875 | Uncertain | 1 | -6.386 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.218 | Likely Benign | -0.41 | Neutral | 0.451 | Benign | 0.129 | Benign | 5.25 | Benign | 0.28 | Tolerated | 0.2232 | 0.4605 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||
| c.3170G>C | S1057T 2D AIThe SynGAP1 missense variant S1057T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods indicates that the variant is most likely benign, and this assessment is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988291 | Disordered | 0.869507 | Binding | 0.413 | 0.927 | 0.875 | -6.375 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.241 | Likely Benign | -0.18 | Neutral | 0.625 | Possibly Damaging | 0.170 | Benign | 5.26 | Benign | 0.60 | Tolerated | 0.2289 | 0.5976 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3170G>T | S1057I 2D AIThe SynGAP1 missense variant S1057I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to the variant being most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988291 | Disordered | 0.869507 | Binding | 0.413 | 0.927 | 0.875 | -6.887 | Likely Benign | 0.186 | Likely Benign | Likely Benign | 0.259 | Likely Benign | -0.87 | Neutral | 0.925 | Possibly Damaging | 0.238 | Benign | 5.24 | Benign | 0.07 | Tolerated | 0.1802 | 0.4980 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.3171C>A | S1057R 2D AIThe SynGAP1 missense variant S1057R is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign. Only polyPhen‑2 HumDiv flags it as pathogenic, while AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988291 | Disordered | 0.869507 | Binding | 0.413 | 0.927 | 0.875 | -6.648 | Likely Benign | 0.379 | Ambiguous | Likely Benign | 0.272 | Likely Benign | -0.24 | Neutral | 0.677 | Possibly Damaging | 0.168 | Benign | 5.30 | Benign | 0.21 | Tolerated | 3.77 | 5 | 0.1584 | 0.3620 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.3171C>G | S1057R 2D AIThe SynGAP1 missense variant S1057R is catalogued in gnomAD (ID 6‑33443723‑C‑G) but has no ClinVar submission. Functional prediction tools largely converge on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all report benign or tolerated. Only polyPhen‑2 HumDiv flags it as pathogenic, while AlphaMissense‑Default remains uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus confirms a benign likelihood; Foldetta data are unavailable, so no stability evidence is provided. Taken together, the preponderance of evidence indicates the variant is most likely benign, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988291 | Disordered | 0.869507 | Binding | 0.413 | 0.927 | 0.875 | 6-33443723-C-G | -6.648 | Likely Benign | 0.379 | Ambiguous | Likely Benign | 0.272 | Likely Benign | -0.24 | Neutral | 0.677 | Possibly Damaging | 0.168 | Benign | 5.30 | Benign | 0.21 | Tolerated | 3.77 | 5 | 0.1584 | 0.3620 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| c.3466G>A | A1156T 2D AIThe SynGAP1 missense variant A1156T is not 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 outcome: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence from multiple in silico tools points to a pathogenic effect for A1156T, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.720929 | Disordered | 0.871395 | Binding | 0.294 | 0.861 | 0.500 | -3.732 | Likely Benign | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.285 | Likely Benign | -2.99 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 1.63 | Pathogenic | 0.00 | Affected | 0.1366 | 0.7442 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3466G>C | A1156P 2D AIThe SynGAP1 missense variant A1156P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are REVEL and ESM1b, whereas the remaining tools—SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic.” No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence indicates that A1156P is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.720929 | Disordered | 0.871395 | Binding | 0.294 | 0.861 | 0.500 | -2.847 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.405 | Likely Benign | -3.49 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.59 | Pathogenic | 0.00 | Affected | 0.1718 | 0.5104 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3466G>T | A1156S 2D AIThe SynGAP1 missense variant A1156S is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33444501‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑to‑2 split. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of available predictions (five pathogenic vs. three benign) lean toward pathogenicity. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.720929 | Disordered | 0.871395 | Binding | 0.294 | 0.861 | 0.500 | 6-33444501-G-T | 1 | 6.20e-7 | -2.052 | Likely Benign | 0.798 | Likely Pathogenic | Ambiguous | 0.197 | Likely Benign | -2.23 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.65 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2594 | 0.6154 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||
| c.3467C>A | A1156D 2D AIThe SynGAP1 missense variant A1156D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence indicates that A1156D is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.720929 | Disordered | 0.871395 | Binding | 0.294 | 0.861 | 0.500 | -3.497 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.350 | Likely Benign | -4.45 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.59 | Pathogenic | 0.00 | Affected | 0.1662 | 0.2058 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.3467C>G | A1156G 2D AIThe SynGAP1 missense variant A1156G is not reported in ClinVar and has no allele in gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the change as pathogenic, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also reports a likely pathogenic outcome. Foldetta results are unavailable for this variant. Overall, the consensus of the available predictions indicates that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.720929 | Disordered | 0.871395 | Binding | 0.294 | 0.861 | 0.500 | -3.728 | Likely Benign | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.230 | Likely Benign | -3.02 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.62 | Pathogenic | 0.00 | Affected | 0.2214 | 0.4461 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3467C>T | A1156V 2D AIThe SynGAP1 missense variant A1156V has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect are REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labeling it “Likely Pathogenic”; Foldetta results are unavailable. Based on the aggregate predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.720929 | Disordered | 0.871395 | Binding | 0.294 | 0.861 | 0.500 | -5.087 | Likely Benign | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.270 | Likely Benign | -2.99 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.62 | Pathogenic | 0.00 | Affected | 0.1062 | 0.6202 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.3163G>A | G1055R 2D AIThe SynGAP1 missense variant G1055R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.982235 | Disordered | 0.872113 | Binding | 0.379 | 0.935 | 0.875 | -8.778 | Likely Pathogenic | 0.375 | Ambiguous | Likely Benign | 0.275 | Likely Benign | -0.09 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 3.31 | Benign | 0.08 | Tolerated | 0.1013 | 0.4733 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3163G>C | G1055R 2D AIThe SynGAP1 missense variant G1055R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. AlphaMissense‑Default is uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign outcome (2 benign vs. 1 pathogenic, 1 uncertain). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.982235 | Disordered | 0.872113 | Binding | 0.379 | 0.935 | 0.875 | -8.778 | Likely Pathogenic | 0.375 | Ambiguous | Likely Benign | 0.275 | Likely Benign | -0.09 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 3.31 | Benign | 0.08 | Tolerated | 0.1013 | 0.4733 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3163G>T | G1055W 2D AIThe SynGAP1 missense variant G1055W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.982235 | Disordered | 0.872113 | Binding | 0.379 | 0.935 | 0.875 | -11.436 | Likely Pathogenic | 0.317 | Likely Benign | Likely Benign | 0.367 | Likely Benign | -0.77 | Neutral | 0.997 | Probably Damaging | 0.946 | Probably Damaging | 3.28 | Benign | 0.01 | Affected | 0.0899 | 0.4246 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3164G>A | G1055E 2D AIThe SynGAP1 missense variant G1055E is catalogued in gnomAD (variant ID 6‑33443716‑G‑A) but has no ClinVar entry. In silico prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a benign effect. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.982235 | Disordered | 0.872113 | Binding | 0.379 | 0.935 | 0.875 | 6-33443716-G-A | 1 | 6.21e-7 | -10.951 | Likely Pathogenic | 0.290 | Likely Benign | Likely Benign | 0.320 | Likely Benign | -0.03 | Neutral | 0.901 | Possibly Damaging | 0.456 | Possibly Damaging | 3.30 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.1525 | 0.4459 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| c.3164G>C | G1055A 2D AIThe SynGAP1 missense variant G1055A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumDiv indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus also reports Likely Benign; Foldetta results are unavailable. Overall, the consensus of the available predictions points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.982235 | Disordered | 0.872113 | Binding | 0.379 | 0.935 | 0.875 | -6.835 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.244 | Likely Benign | 0.15 | Neutral | 0.649 | Possibly Damaging | 0.148 | Benign | 3.30 | Benign | 1.00 | Tolerated | 0.3350 | 0.5144 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3164G>T | G1055V 2D AIThe SynGAP1 missense variant G1055V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while ESM1b remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.982235 | Disordered | 0.872113 | Binding | 0.379 | 0.935 | 0.875 | -7.434 | In-Between | 0.114 | Likely Benign | Likely Benign | 0.399 | Likely Benign | 0.26 | Neutral | 0.818 | Possibly Damaging | 0.222 | Benign | 3.28 | Benign | 0.17 | Tolerated | 0.1399 | 0.3694 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| 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.2845G>A | G949S 2D AIThe SynGAP1 missense variant G949S is listed in ClinVar as a benign alteration (ClinVar ID 212352.0) and is present in the gnomAD database (6‑33443397‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar classification and indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988861 | Disordered | 0.874971 | Binding | 0.365 | 0.923 | 0.750 | Benign/Likely benign | 4 | 6-33443397-G-A | 122 | 7.56e-5 | -5.693 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.321 | Likely Benign | 0.30 | Neutral | 0.611 | Possibly Damaging | 0.102 | Benign | 2.23 | Pathogenic | 0.00 | Affected | 4.32 | 4 | 0.2528 | 0.5159 | 1 | 0 | -0.4 | 30.03 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.2845G>C | G949R 2D AIThe SynGAP1 missense variant G949R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Consensus from standard in silico predictors shows a split: benign calls come from REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic calls come from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; ESM1b is uncertain. High‑accuracy assessment further supports a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign outcome, and Foldetta data are unavailable. Overall, the preponderance of evidence indicates the variant is most likely benign, and this conclusion does not conflict with any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988861 | Disordered | 0.874971 | Binding | 0.365 | 0.923 | 0.750 | -7.650 | In-Between | 0.301 | Likely Benign | Likely Benign | 0.317 | Likely Benign | -0.14 | Neutral | 0.997 | Probably Damaging | 0.934 | Probably Damaging | 2.21 | Pathogenic | 0.01 | Affected | 0.1095 | 0.4569 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.2845G>T | G949C 2D AIThe SynGAP1 missense variant G949C is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs. 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 available predictions (five pathogenic vs. four benign) indicate that 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. | 0.988861 | Disordered | 0.874971 | Binding | 0.365 | 0.923 | 0.750 | -10.580 | Likely Pathogenic | 0.091 | Likely Benign | Likely Benign | 0.345 | Likely Benign | -1.02 | Neutral | 1.000 | Probably Damaging | 0.975 | Probably Damaging | 2.21 | Pathogenic | 0.01 | Affected | 0.1480 | 0.4097 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||||||
| c.2846G>A | G949D 2D AIThe SynGAP1 missense variant G949D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. 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 high‑confidence predictors (5 pathogenic vs. 4 benign) indicate 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. | 0.988861 | Disordered | 0.874971 | Binding | 0.365 | 0.923 | 0.750 | -8.692 | Likely Pathogenic | 0.239 | Likely Benign | Likely Benign | 0.316 | Likely Benign | 0.25 | Neutral | 0.945 | Possibly Damaging | 0.753 | Possibly Damaging | 2.21 | Pathogenic | 0.02 | Affected | 0.1927 | 0.2826 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2846G>C | G949A 2D AIThe SynGAP1 missense variant G949A is not reported in ClinVar (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, is “Likely Benign” (3 benign vs. 1 pathogenic votes). High‑accuracy methods confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the 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 | 0.988861 | Disordered | 0.874971 | Binding | 0.365 | 0.923 | 0.750 | -6.838 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.274 | Likely Benign | -0.08 | Neutral | 0.779 | Possibly Damaging | 0.425 | Benign | 2.28 | Pathogenic | 0.08 | Tolerated | 0.3385 | 0.4414 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2846G>T | G949V 2D AIThe SynGAP1 missense variant G949V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; 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 a benign outcome. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988861 | Disordered | 0.874971 | Binding | 0.365 | 0.923 | 0.750 | -7.364 | In-Between | 0.102 | Likely Benign | Likely Benign | 0.328 | Likely Benign | -0.55 | Neutral | 0.992 | Probably Damaging | 0.834 | Possibly Damaging | 2.21 | Pathogenic | 0.01 | Affected | 0.1493 | 0.3165 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2329C>A | L777I 2D  AIThe SynGAP1 missense variant L777I is listed in gnomAD (ID 6‑33442487‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which reports “Likely Benign.” Pathogenic predictions are made by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect for the variant, and this conclusion does not contradict any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.408655 | Structured | 0.876129 | Binding | 0.336 | 0.882 | 0.250 | 6-33442487-C-A | -5.346 | Likely Benign | 0.128 | Likely Benign | Likely Benign | 0.096 | Likely Benign | -0.85 | Neutral | 0.843 | Possibly Damaging | 0.920 | Probably Damaging | 4.05 | Benign | 0.02 | Affected | 3.64 | 6 | 0.1041 | 0.4327 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||||||||
| c.2329C>G | L777V 2D AIThe SynGAP1 missense variant L777V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for the variant, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.408655 | Structured | 0.876129 | Binding | 0.336 | 0.882 | 0.250 | -5.693 | Likely Benign | 0.134 | Likely Benign | Likely Benign | 0.084 | Likely Benign | -1.05 | Neutral | 0.843 | Possibly Damaging | 0.920 | Probably Damaging | 4.07 | Benign | 0.05 | Affected | 0.1651 | 0.3977 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2329C>T | L777F 2D  AIThe SynGAP1 missense variant L777F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.408655 | Structured | 0.876129 | Binding | 0.336 | 0.882 | 0.250 | -4.499 | Likely Benign | 0.175 | Likely Benign | Likely Benign | 0.115 | Likely Benign | -1.91 | Neutral | 0.968 | Probably Damaging | 0.966 | Probably Damaging | 3.98 | Benign | 0.01 | Affected | 0.0697 | 0.3576 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2330T>A | L777H 2D  AIThe SynGAP1 missense variant L777H has no ClinVar record and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors a benign outcome. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the balance of evidence—including the consensus of high‑accuracy tools—suggests that the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.408655 | Structured | 0.876129 | Binding | 0.336 | 0.882 | 0.250 | -6.719 | Likely Benign | 0.492 | Ambiguous | Likely Benign | 0.230 | Likely Benign | -2.51 | Deleterious | 0.997 | Probably Damaging | 0.993 | Probably Damaging | 3.95 | Benign | 0.00 | Affected | 0.1052 | 0.0972 | -2 | -3 | -7.0 | 23.98 | ||||||||||||||||||||||||||||||||||||||||
| c.2330T>C | L777P 2D AIThe SynGAP1 missense variant L777P is catalogued in gnomAD (6‑33442488‑T‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions are reported by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus also indicates a likely benign outcome. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign effect for the variant, 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 | 0.408655 | Structured | 0.876129 | Binding | 0.336 | 0.882 | 0.250 | 6-33442488-T-C | -5.807 | Likely Benign | 0.361 | Ambiguous | Likely Benign | 0.255 | Likely Benign | -2.13 | Neutral | 0.991 | Probably Damaging | 0.985 | Probably Damaging | 3.94 | Benign | 0.00 | Affected | 3.64 | 6 | 0.3732 | 0.1664 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||
| c.2330T>G | L777R 2D AIThe SynGAP1 missense variant L777R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. 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 | 0.408655 | Structured | 0.876129 | Binding | 0.336 | 0.882 | 0.250 | -6.084 | Likely Benign | 0.650 | Likely Pathogenic | Likely Benign | 0.227 | Likely Benign | -2.20 | Neutral | 0.991 | Probably Damaging | 0.985 | Probably Damaging | 3.97 | Benign | 0.00 | Affected | 0.1249 | 0.0846 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| 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.3469T>A | W1157R 2D  AIThe SynGAP1 missense variant W1157R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only ESM1b, whereas all other evaluated algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic. No Foldetta stability analysis is available, so it does not influence the conclusion. Overall, the preponderance of evidence indicates that W1157R is most likely pathogenic, and this assessment is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.694846 | Disordered | 0.877471 | Binding | 0.364 | 0.861 | 0.375 | -2.440 | Likely Benign | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.549 | Likely Pathogenic | -10.19 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.06 | Pathogenic | 0.00 | Affected | 0.4129 | 0.0612 | 2 | -3 | -3.6 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3469T>C | W1157R 2D AIThe SynGAP1 missense variant W1157R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only ESM1b, whereas all other evaluated algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic. No Foldetta stability analysis is available, so it does not influence the conclusion. Overall, the preponderance of evidence indicates that W1157R is most likely pathogenic, and this assessment is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.694846 | Disordered | 0.877471 | Binding | 0.364 | 0.861 | 0.375 | -2.440 | Likely Benign | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.549 | Likely Pathogenic | -10.19 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.06 | Pathogenic | 0.00 | Affected | 0.4129 | 0.0612 | 2 | -3 | -3.6 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3469T>G | W1157G 2D  AIThe SynGAP1 missense variant W1157G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate pathogenicity. Only ESM1b predicts a benign outcome, representing the sole disagreement. High‑accuracy assessments further support a harmful impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus labels it as Likely Pathogenic. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a pathogenic effect, and this conclusion is consistent with the absence of ClinVar annotation, so there is no contradiction with ClinVar status. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.694846 | Disordered | 0.877471 | Binding | 0.364 | 0.861 | 0.375 | -2.328 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.558 | Likely Pathogenic | -9.50 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 1.06 | Pathogenic | 0.00 | Affected | 0.4631 | 0.2065 | -7 | -2 | 0.5 | -129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3470G>C | W1157S 2D  AIThe SynGAP1 missense variant W1157S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence indicates that W1157S is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.694846 | Disordered | 0.877471 | Binding | 0.364 | 0.861 | 0.375 | -1.158 | Likely Benign | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.394 | Likely Benign | -9.96 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.06 | Pathogenic | 0.00 | Affected | 0.4772 | 0.1227 | -2 | -3 | 0.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3470G>T | W1157L 2D  AIThe SynGAP1 missense variant W1157L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—classify the change as pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic. Foldetta results are not available. Overall, the majority of evidence points to a pathogenic impact for W1157L, and this conclusion is consistent with the absence of a ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.694846 | Disordered | 0.877471 | Binding | 0.364 | 0.861 | 0.375 | -1.336 | Likely Benign | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.306 | Likely Benign | -9.46 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 1.08 | Pathogenic | 0.00 | Affected | 0.2400 | 0.2719 | -2 | -2 | 4.7 | -73.05 | |||||||||||||||||||||||||||||||||||||||
| c.3471G>C | W1157C 2D  AIThe SynGAP1 missense variant W1157C 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—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence indicates that W1157C 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 | 0.694846 | Disordered | 0.877471 | Binding | 0.364 | 0.861 | 0.375 | -4.730 | Likely Benign | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.478 | Likely Benign | -9.46 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.04 | Pathogenic | 0.00 | Affected | 0.3927 | 0.1406 | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||||||||||||||||
| c.3471G>T | W1157C 2D AIThe SynGAP1 missense variant W1157C 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—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence indicates that W1157C 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 | 0.694846 | Disordered | 0.877471 | Binding | 0.364 | 0.861 | 0.375 | -4.730 | Likely Benign | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.478 | Likely Benign | -9.46 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.04 | Pathogenic | 0.00 | Affected | 0.3927 | 0.1406 | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||||||||||||||||
| c.3472G>A | V1158I 2D AIThe SynGAP1 missense variant V1158I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the balance of evidence leans toward 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. | 0.599170 | Disordered | 0.877504 | Binding | 0.369 | 0.847 | 0.250 | -3.504 | Likely Benign | 0.597 | Likely Pathogenic | Likely Benign | 0.129 | Likely Benign | -0.20 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.49 | Pathogenic | 0.07 | Tolerated | 0.0863 | 0.4180 | 4 | 3 | 0.3 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3472G>C | V1158L 2D AIThe SynGAP1 missense variant V1158L has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates 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 majority of evidence (five benign versus four pathogenic predictions, plus a benign consensus) points to a benign classification, and this does not contradict any ClinVar status because no ClinVar claim exists. Thus, the variant is most likely benign, though the AlphaMissense‑Optimized prediction introduces some uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.877504 | Binding | 0.369 | 0.847 | 0.250 | -2.345 | Likely Benign | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.187 | Likely Benign | -0.73 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.78 | Benign | 0.56 | Tolerated | 0.1066 | 0.4642 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3472G>T | V1158F 2D AIThe SynGAP1 missense variant V1158F is not 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, while the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is classified as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic. Foldetta results are unavailable. Overall, the majority of evidence indicates that V1158F is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar annotation exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.599170 | Disordered | 0.877504 | Binding | 0.369 | 0.847 | 0.250 | -3.888 | Likely Benign | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.264 | Likely Benign | -2.66 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.33 | Pathogenic | 0.02 | Affected | 0.0792 | 0.3577 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||||||||||||
| c.3473T>A | V1158D 2D AIThe SynGAP1 missense variant V1158D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence indicates that V1158D is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.599170 | Disordered | 0.877504 | Binding | 0.369 | 0.847 | 0.250 | -4.076 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.486 | Likely Benign | -4.56 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.29 | Pathogenic | 0.00 | Affected | 0.1502 | 0.1820 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||||||||||||
| c.3473T>C | V1158A 2D AIThe SynGAP1 missense variant V1158A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b. Tools that agree on a pathogenic effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence (six pathogenic vs. three benign predictions) indicates the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.599170 | Disordered | 0.877504 | Binding | 0.369 | 0.847 | 0.250 | -2.726 | Likely Benign | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.232 | Likely Benign | -2.46 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.34 | Pathogenic | 0.02 | Affected | 0.2789 | 0.2906 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||||||||||||||||
| c.3473T>G | V1158G 2D AIThe SynGAP1 missense variant V1158G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect are REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic outcome. High‑accuracy assessments reinforce this pattern: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a pathogenic verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that V1158G is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.599170 | Disordered | 0.877504 | Binding | 0.369 | 0.847 | 0.250 | -3.058 | Likely Benign | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.433 | Likely Benign | -4.62 | Deleterious | 0.997 | Probably Damaging | 0.999 | Probably Damaging | 2.30 | Pathogenic | 0.00 | Affected | 0.1870 | 0.3289 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3160G>A | G1054S 2D AIThe SynGAP1 missense variant G1054S is listed in ClinVar (ID 699126.0) as Benign and is present in gnomAD (variant ID 6‑33443712‑G‑A). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic or likely pathogenic outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts Benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the computational evidence strongly supports a benign effect, consistent with the ClinVar designation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.878015 | Binding | 0.389 | 0.936 | 0.875 | Benign | 1 | 6-33443712-G-A | 32 | 1.99e-5 | -5.294 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.160 | Likely Benign | 0.21 | Neutral | 0.121 | Benign | 0.013 | Benign | 4.04 | Benign | 0.63 | Tolerated | 3.77 | 5 | 0.2506 | 0.5311 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||
| c.3160G>C | G1054R 2D AIThe SynGAP1 missense variant G1054R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for G1054R, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.878015 | Binding | 0.389 | 0.936 | 0.875 | -8.863 | Likely Pathogenic | 0.326 | Likely Benign | Likely Benign | 0.234 | Likely Benign | 0.29 | Neutral | 0.988 | Probably Damaging | 0.589 | Possibly Damaging | 4.05 | Benign | 0.42 | Tolerated | 0.1164 | 0.4342 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3160G>T | G1054C 2D AIThe SynGAP1 missense variant G1054C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.878015 | Binding | 0.389 | 0.936 | 0.875 | -9.548 | Likely Pathogenic | 0.118 | Likely Benign | Likely Benign | 0.297 | Likely Benign | -0.59 | Neutral | 0.999 | Probably Damaging | 0.907 | Possibly Damaging | 4.00 | Benign | 0.10 | Tolerated | 0.1413 | 0.4427 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.3161G>A | G1054D 2D AISynGAP1 missense variant G1054D is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates the variant is most likely benign, which does not contradict the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.983019 | Disordered | 0.878015 | Binding | 0.389 | 0.936 | 0.875 | Uncertain | 1 | -10.385 | Likely Pathogenic | 0.351 | Ambiguous | Likely Benign | 0.279 | Likely Benign | -0.26 | Neutral | 0.818 | Possibly Damaging | 0.266 | Benign | 4.07 | Benign | 0.37 | Tolerated | 3.77 | 5 | 0.1824 | 0.2035 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||
| c.3161G>C | G1054A 2D AIThe SynGAP1 missense variant G1054A is catalogued in gnomAD (ID 6‑33443713‑G‑C) but has no ClinVar entry. Across a broad panel of in‑silico predictors, every tool reports a benign outcome: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity, so the pathogenic‑prediction group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant, so its status is unavailable. Based on the unanimous benign predictions and the lack of any ClinVar pathogenic classification, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.878015 | Binding | 0.389 | 0.936 | 0.875 | 6-33443713-G-C | -6.786 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.243 | Likely Benign | -0.05 | Neutral | 0.288 | Benign | 0.071 | Benign | 4.03 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.3305 | 0.5144 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.3161G>T | G1054V 2D AIThe SynGAP1 missense variant G1054V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus also reports likely benign; Foldetta results are unavailable. Overall, the consensus of the available predictions points to a benign impact, and this is consistent with the lack of ClinVar evidence; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.878015 | Binding | 0.389 | 0.936 | 0.875 | -6.994 | Likely Benign | 0.110 | Likely Benign | Likely Benign | 0.171 | Likely Benign | -0.22 | Neutral | 0.818 | Possibly Damaging | 0.221 | Benign | 4.01 | Benign | 0.18 | Tolerated | 0.1578 | 0.3694 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.2824C>A | P942T 2D AIThe SynGAP1 missense variant P942T is not reported in ClinVar (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 P942T, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.878102 | Binding | 0.365 | 0.915 | 0.625 | -5.745 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.027 | Likely Benign | -1.23 | Neutral | 0.224 | Benign | 0.096 | Benign | 2.49 | Pathogenic | 0.00 | Affected | 0.1683 | 0.5599 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2824C>G | P942A 2D AIThe SynGAP1 missense variant P942A is not reported in ClinVar (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 | 0.919029 | Disordered | 0.878102 | Binding | 0.365 | 0.915 | 0.625 | -4.404 | Likely Benign | 0.047 | Likely Benign | Likely Benign | 0.023 | Likely Benign | -0.90 | Neutral | 0.059 | Benign | 0.061 | Benign | 2.52 | Benign | 0.00 | Affected | 0.3362 | 0.4621 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2824C>T | P942S 2D AIThe SynGAP1 missense variant P942S is catalogued in gnomAD (ID 6‑33443376‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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, 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 | 0.919029 | Disordered | 0.878102 | Binding | 0.365 | 0.915 | 0.625 | 6-33443376-C-T | 1 | 6.20e-7 | -3.919 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.036 | Likely Benign | -0.80 | Neutral | 0.011 | Benign | 0.015 | Benign | 2.43 | Pathogenic | 0.00 | Affected | 4.32 | 4 | 0.3226 | 0.4806 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.2825C>A | P942Q 2D AIThe SynGAP1 missense variant P942Q is not reported in ClinVar (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 P942Q, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.878102 | Binding | 0.365 | 0.915 | 0.625 | -6.094 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.028 | Likely Benign | -1.12 | Neutral | 0.026 | Benign | 0.015 | Benign | 2.36 | Pathogenic | 0.00 | Affected | 0.1508 | 0.4703 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2825C>G | P942R 2D AIThe SynGAP1 missense variant P942R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.878102 | Binding | 0.365 | 0.915 | 0.625 | -5.405 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.78 | Neutral | 0.411 | Benign | 0.139 | Benign | 2.36 | Pathogenic | 0.00 | Affected | 0.1307 | 0.3693 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2825C>T | P942L 2D AIThe SynGAP1 missense variant P942L is listed in ClinVar (ID 2851884.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443377‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” 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 ClinVar “Uncertain” designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.878102 | Binding | 0.365 | 0.915 | 0.625 | Uncertain | 1 | 6-33443377-C-T | 4 | 2.48e-6 | -5.063 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -2.00 | Neutral | 0.411 | Benign | 0.239 | Benign | 2.37 | Pathogenic | 0.00 | Affected | 4.32 | 4 | 0.2094 | 0.5507 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||
| c.2275A>C | M759L 2D AIThe SynGAP1 missense variant M759L is listed in ClinVar with an uncertain significance (ClinVar ID 942432.0) and is present in gnomAD (gnomAD ID 6‑33441740‑A‑C). All evaluated in‑silico predictors agree on a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign classifications. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence strongly supports 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 | 0.525368 | Disordered | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | Uncertain | 1 | 6-33441740-A-C | 2 | 1.24e-6 | -2.431 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -0.53 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.84 | Benign | 1.00 | Tolerated | 3.99 | 5 | 0.1308 | 0.4005 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||
| c.2275A>G | M759V 2D AIThe SynGAP1 missense variant M759V is catalogued in gnomAD (ID 6‑33441740‑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 view: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available for this variant. 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 | 0.525368 | Disordered | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | 6-33441740-A-G | 20 | 1.24e-5 | -3.985 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -1.00 | Neutral | 0.267 | Benign | 0.127 | Benign | 2.67 | Benign | 0.23 | Tolerated | 3.99 | 5 | 0.2926 | 0.3041 | 1 | 2 | 2.3 | -32.06 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||||
| c.2275A>T | M759L 2D AIThe SynGAP1 missense variant M759L 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 classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | -2.431 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -0.53 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.84 | Benign | 1.00 | Tolerated | 3.99 | 5 | 0.1308 | 0.4005 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.2276T>A | M759K 2D AIThe SynGAP1 missense variant M759K (ClinVar ID 4178662) is listed as ClinVar status Uncertain and is not present in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar Uncertain designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | Uncertain | 1 | -5.670 | Likely Benign | 0.616 | Likely Pathogenic | Likely Benign | 0.288 | Likely Benign | -1.86 | Neutral | 0.891 | Possibly Damaging | 0.492 | Possibly Damaging | 2.55 | Benign | 0.06 | Tolerated | 0.1338 | 0.0688 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||||
| c.2276T>C | M759T 2D AIThe SynGAP1 missense variant M759T is not reported in ClinVar (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 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—including the SGM consensus and AlphaMissense‑Optimized—supports 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. | Likely Benign | 0.525368 | Disordered | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | -4.202 | Likely Benign | 0.380 | Ambiguous | Likely Benign | 0.197 | Likely Benign | -1.90 | Neutral | 0.891 | Possibly Damaging | 0.315 | Benign | 2.58 | Benign | 0.08 | Tolerated | 0.2063 | 0.1534 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||||||||||||
| c.2276T>G | M759R 2D AIThe SynGAP1 missense variant M759R is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of high‑accuracy predictors—AlphaMissense‑Optimized and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—also support a benign classification. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact, but these are the only tools in disagreement. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign effect for M759R, and 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 | 0.525368 | Disordered | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | -4.507 | Likely Benign | 0.531 | Ambiguous | Likely Benign | 0.244 | Likely Benign | -1.82 | Neutral | 0.891 | Possibly Damaging | 0.575 | Possibly Damaging | 2.55 | Benign | 0.06 | Tolerated | 0.1509 | 0.0637 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||||||
| c.2277G>A | M759I 2D AIThe SynGAP1 missense variant M759I is listed in ClinVar (ID 3686687.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33441742‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta 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 | 0.525368 | Disordered | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | Uncertain | 1 | 6-33441742-G-A | 1 | 6.20e-7 | -4.058 | Likely Benign | 0.393 | Ambiguous | Likely Benign | 0.075 | Likely Benign | -0.88 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 2.83 | Benign | 0.34 | Tolerated | 3.99 | 5 | 0.1235 | 0.3129 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||
| c.2277G>C | M759I 2D AIThe SynGAP1 missense variant M759I is catalogued in gnomAD (6‑33441742‑G‑C) and has no ClinVar entry. Consensus from multiple in‑silico predictors points to a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all score the variant as benign, while only polyPhen‑2 HumDiv flags it as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy tools reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are not available, so they do not influence the assessment. 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 | 0.525368 | Disordered | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | 6-33441742-G-C | -4.058 | Likely Benign | 0.393 | Ambiguous | Likely Benign | 0.075 | Likely Benign | -0.88 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 2.83 | Benign | 0.34 | Tolerated | 3.99 | 5 | 0.1235 | 0.3129 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||
| c.2277G>T | M759I 2D AIThe SynGAP1 missense variant M759I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the preponderance of evidence from multiple prediction algorithms and high‑accuracy tools points to a benign impact for M759I, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | -4.058 | Likely Benign | 0.393 | Ambiguous | Likely Benign | 0.075 | Likely Benign | -0.88 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 2.83 | Benign | 0.34 | Tolerated | 3.99 | 5 | 0.1235 | 0.3129 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.3874C>A | L1292I 2D AIThe SynGAP1 missense variant L1292I 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 does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.779859 | Disordered | 0.882643 | Binding | 0.586 | 0.800 | 0.625 | -5.480 | Likely Benign | 0.135 | Likely Benign | Likely Benign | 0.050 | Likely Benign | 0.71 | Neutral | 0.002 | Benign | 0.006 | Benign | 3.23 | Benign | 1.00 | Tolerated | 0.1101 | 0.3323 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3874C>G | L1292V 2D AIThe SynGAP1 missense variant L1292V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is benign, and this conclusion does not contradict any ClinVar annotation (none present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.779859 | Disordered | 0.882643 | Binding | 0.586 | 0.800 | 0.625 | -4.943 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -0.14 | Neutral | 0.058 | Benign | 0.038 | Benign | 2.67 | Benign | 0.07 | Tolerated | 0.1769 | 0.2605 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3874C>T | L1292F 2D AIThe SynGAP1 missense variant L1292F is reported in gnomAD (ID 6‑33447922‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates 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 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 | 0.779859 | Disordered | 0.882643 | Binding | 0.586 | 0.800 | 0.625 | 6-33447922-C-T | -5.759 | Likely Benign | 0.200 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -1.88 | Neutral | 0.611 | Possibly Damaging | 0.329 | Benign | 2.49 | Pathogenic | 0.03 | Affected | 3.77 | 5 | 0.0707 | 0.2799 | 0 | 2 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||||||
| c.3875T>A | L1292H 2D AIThe SynGAP1 missense variant L1292H is not reported in ClinVar (ClinVar status: None) but is present in gnomAD (ID 6‑33447923‑T‑A). 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 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 predictions are split, with a slight tilt toward pathogenicity (five pathogenic vs. four benign). Thus, the variant is most likely pathogenic based on the 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. | 0.779859 | Disordered | 0.882643 | Binding | 0.586 | 0.800 | 0.625 | 6-33447923-T-A | -5.692 | Likely Benign | 0.335 | Likely Benign | Likely Benign | 0.202 | Likely Benign | -4.42 | Deleterious | 0.992 | Probably Damaging | 0.820 | Possibly Damaging | 2.46 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1271 | 0.0649 | -3 | -2 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||||
| c.3875T>C | L1292P 2D AISynGAP1 missense variant L1292P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a 2‑to‑2 split and is therefore inconclusive. Foldetta, a protein‑folding stability method that combines FoldX‑MD and Rosetta outputs, has no available result for this variant. With half the tools indicating benign and half indicating pathogenic, the overall computational evidence is ambiguous. Consequently, the variant is neither clearly benign nor pathogenic based on current predictions, and there is no ClinVar entry to contradict this uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.779859 | Disordered | 0.882643 | Binding | 0.586 | 0.800 | 0.625 | -3.761 | Likely Benign | 0.264 | Likely Benign | Likely Benign | 0.311 | Likely Benign | -4.58 | Deleterious | 0.971 | Probably Damaging | 0.773 | Possibly Damaging | 2.46 | Pathogenic | 0.01 | Affected | 0.3855 | 0.1220 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3875T>G | L1292R 2D AIThe SynGAP1 missense variant L1292R is not 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. Overall, five tools predict pathogenicity while four predict benignity, giving a slight tilt toward a pathogenic interpretation. This prediction does not contradict ClinVar status, as the variant has not yet been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.779859 | Disordered | 0.882643 | Binding | 0.586 | 0.800 | 0.625 | -4.249 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.223 | Likely Benign | -4.34 | Deleterious | 0.971 | Probably Damaging | 0.773 | Possibly Damaging | 2.46 | Pathogenic | 0.00 | Affected | 0.1286 | 0.0849 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3901C>A | P1301T 2D AIThe SynGAP1 missense variant P1301T is reported in gnomAD (ID 6‑33451775‑C‑A) 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, so the pathogenic group is empty. 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 “Likely Benign.” Foldetta results are unavailable. Based on the consensus of all available predictions, 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 | 0.728858 | Disordered | 0.885064 | Binding | 0.447 | 0.841 | 0.875 | 6-33451775-C-A | 1 | 6.20e-7 | -4.945 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.090 | Likely Benign | 0.34 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.87 | Benign | 0.47 | Tolerated | 3.77 | 5 | 0.1255 | 0.3312 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||
| c.3901C>G | P1301A 2D AIThe SynGAP1 missense variant P1301A is catalogued in gnomAD (ID 6‑33451775‑C‑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 substitution as tolerated or benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as likely benign. Foldetta, a protein‑folding stability predictor, was not available for this residue. Overall, the consensus of all available predictions is 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 | 0.728858 | Disordered | 0.885064 | Binding | 0.447 | 0.841 | 0.875 | 6-33451775-C-G | 1 | 6.20e-7 | -4.290 | Likely Benign | 0.055 | Likely Benign | Likely Benign | 0.088 | Likely Benign | 0.66 | Neutral | 0.003 | Benign | 0.012 | Benign | 3.05 | Benign | 0.88 | Tolerated | 3.77 | 5 | 0.2850 | 0.3087 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.3901C>T | P1301S 2D AIThe SynGAP1 missense variant P1301S is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence strongly supports 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 | 0.728858 | Disordered | 0.885064 | Binding | 0.447 | 0.841 | 0.875 | -4.537 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.087 | Likely Benign | 1.84 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.29 | Benign | 0.95 | Tolerated | 0.2799 | 0.3436 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3902C>A | P1301H 2D AIThe SynGAP1 missense variant P1301H is listed in ClinVar (ID 212356.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451776‑C‑A). 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 methods report a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” No Foldetta stability result is available. Overall, the majority of predictions, including the high‑accuracy consensus, support a benign classification, 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 | 0.728858 | Disordered | 0.885064 | Binding | 0.447 | 0.841 | 0.875 | Conflicting | 2 | 6-33451776-C-A | 5 | 3.10e-6 | -5.756 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.232 | Likely Benign | -1.13 | Neutral | 0.642 | Possibly Damaging | 0.378 | Benign | 2.79 | Benign | 0.04 | Affected | 3.77 | 5 | 0.1305 | 0.2965 | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||
| c.3902C>G | P1301R 2D AIThe SynGAP1 missense variant P1301R is listed in ClinVar with an uncertain significance (ClinVar ID 2092739.0) and is present in gnomAD (ID 6‑33451776‑C‑G). Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign effects. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. In summary, all available predictions agree on a benign impact, and this consensus does not contradict the ClinVar uncertain status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.885064 | Binding | 0.447 | 0.841 | 0.875 | Uncertain | 1 | 6-33451776-C-G | 15 | 9.30e-6 | -4.753 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -1.13 | Neutral | 0.077 | Benign | 0.059 | Benign | 2.81 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.1352 | 0.1929 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||
| c.3902C>T | P1301L 2D AIThe SynGAP1 missense variant P1301L is reported in gnomAD (ID 6‑33451776‑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 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 | 0.728858 | Disordered | 0.885064 | Binding | 0.447 | 0.841 | 0.875 | 6-33451776-C-T | 3 | 1.86e-6 | -4.152 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -1.63 | Neutral | 0.017 | Benign | 0.028 | Benign | 2.83 | Benign | 0.11 | Tolerated | 3.77 | 5 | 0.1886 | 0.4655 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| c.3157A>C | S1053R 2D AIThe SynGAP1 missense variant S1053R is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority‑vote SGM‑Consensus also reports a likely benign outcome. In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy analyses reinforce the benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely benign, with no contradictory Foldetta data. Overall, the preponderance of evidence points to a benign effect for S1053R, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | -6.421 | Likely Benign | 0.359 | Ambiguous | Likely Benign | 0.225 | Likely Benign | 0.43 | Neutral | 0.969 | Probably Damaging | 0.581 | Possibly Damaging | 5.33 | Benign | 0.59 | Tolerated | 3.77 | 5 | 0.1321 | 0.3820 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.3157A>G | S1053G 2D AIThe SynGAP1 missense variant S1053G is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions strongly suggests that S1053G is most likely benign, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | -1.016 | Likely Benign | 0.050 | Likely Benign | Likely Benign | 0.220 | Likely Benign | -0.57 | Neutral | 0.001 | Benign | 0.002 | Benign | 5.32 | Benign | 0.59 | Tolerated | 0.2724 | 0.5046 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3157A>T | S1053C 2D AIThe SynGAP1 missense variant S1053C is catalogued in gnomAD (ID 6‑33443709‑A‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The ESM1b score is uncertain, providing no clear direction. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant. Overall, the majority of reliable predictors classify S1053C as benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | 6-33443709-A-T | -7.574 | In-Between | 0.095 | Likely Benign | Likely Benign | 0.220 | Likely Benign | -0.61 | Neutral | 0.977 | Probably Damaging | 0.777 | Possibly Damaging | 5.30 | Benign | 0.11 | Tolerated | 3.77 | 5 | 0.1675 | 0.5895 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||
| c.3158G>A | S1053N 2D AIThe SynGAP1 missense variant S1053N is reported in gnomAD (variant ID 6‑33443710‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, while the consensus score from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus also indicates a likely benign outcome. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | 6-33443710-G-A | 1 | 6.21e-7 | -6.282 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.208 | Likely Benign | -0.54 | Neutral | 0.625 | Possibly Damaging | 0.193 | Benign | 5.30 | Benign | 0.34 | Tolerated | 3.77 | 5 | 0.1953 | 0.4605 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||
| c.3158G>C | S1053T 2D AIThe SynGAP1 missense variant S1053T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the preponderance of evidence points to a benign impact for S1053T, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | -6.209 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.223 | Likely Benign | -0.25 | Neutral | 0.625 | Possibly Damaging | 0.249 | Benign | 5.32 | Benign | 0.70 | Tolerated | 0.2055 | 0.5976 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3158G>T | S1053I 2D AIThe SynGAP1 missense variant S1053I is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that S1053I is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | -6.572 | Likely Benign | 0.177 | Likely Benign | Likely Benign | 0.250 | Likely Benign | -0.46 | Neutral | 0.925 | Possibly Damaging | 0.413 | Benign | 5.32 | Benign | 0.10 | Tolerated | 0.1536 | 0.4780 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.3159C>A | S1053R 2D AIThe SynGAP1 missense variant S1053R is reported in gnomAD (variant ID 6‑33443711‑C‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. Overall, the majority of high‑accuracy predictors and consensus analyses indicate a benign impact. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | 6-33443711-C-A | 1 | 1.10e-6 | -6.421 | Likely Benign | 0.359 | Ambiguous | Likely Benign | 0.303 | Likely Benign | 0.43 | Neutral | 0.969 | Probably Damaging | 0.581 | Possibly Damaging | 5.33 | Benign | 0.59 | Tolerated | 3.77 | 5 | 0.1321 | 0.3820 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||
| c.3159C>G | S1053R 2D AIThe SynGAP1 missense variant S1053R is reported in gnomAD (ID 6‑33443711‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the high‑accuracy consensus methods give a benign verdict: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign.” Foldetta, a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact. The predictions do not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | 6-33443711-C-G | -6.421 | Likely Benign | 0.359 | Ambiguous | Likely Benign | 0.304 | Likely Benign | 0.43 | Neutral | 0.969 | Probably Damaging | 0.581 | Possibly Damaging | 5.33 | Benign | 0.59 | Tolerated | 3.77 | 5 | 0.1321 | 0.3820 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||
| c.3172G>A | G1058S 2D AIThe SynGAP1 missense variant G1058S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6-33443724-G-A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also benign. Foldetta results are unavailable. Overall, the majority of computational evidence indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.980739 | Disordered | 0.885724 | Binding | 0.407 | 0.929 | 0.875 | Conflicting | 3 | 6-33443724-G-A | 114 | 7.08e-5 | -5.178 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.108 | Likely Benign | 0.26 | Neutral | 0.001 | Benign | 0.001 | Benign | 5.38 | Benign | 0.04 | Affected | 3.77 | 5 | 0.2488 | 0.5511 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||
| c.3172G>C | G1058R 2D AIThe SynGAP1 missense variant G1058R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only two predictors—SIFT and ESM1b—suggest a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign consensus. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.980739 | Disordered | 0.885724 | Binding | 0.407 | 0.929 | 0.875 | -8.967 | Likely Pathogenic | 0.339 | Likely Benign | Likely Benign | 0.138 | Likely Benign | 0.34 | Neutral | 0.174 | Benign | 0.140 | Benign | 5.29 | Benign | 0.00 | Affected | 0.1145 | 0.4342 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3172G>T | G1058C 2D AIThe SynGAP1 missense variant G1058C is reported in gnomAD (ID 6‑33443724‑G‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, SIFT, and ESM1b. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of computational evidence points to a benign effect, and this is not contradicted by any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.980739 | Disordered | 0.885724 | Binding | 0.407 | 0.929 | 0.875 | 6-33443724-G-T | 1 | 6.21e-7 | -9.384 | Likely Pathogenic | 0.132 | Likely Benign | Likely Benign | 0.264 | Likely Benign | -0.19 | Neutral | 0.600 | Possibly Damaging | 0.433 | Benign | 5.19 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1456 | 0.4627 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||
| c.3173G>A | G1058D 2D AIThe SynGAP1 missense variant G1058D is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443725‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and ESM1b, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.980739 | Disordered | 0.885724 | Binding | 0.407 | 0.929 | 0.875 | 6-33443725-G-A | 1 | 6.21e-7 | -10.344 | Likely Pathogenic | 0.391 | Ambiguous | Likely Benign | 0.177 | Likely Benign | -0.33 | Neutral | 0.077 | Benign | 0.042 | Benign | 5.20 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1889 | 0.2435 | -1 | 1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||
| c.3173G>C | G1058A 2D AIThe SynGAP1 missense variant G1058A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.980739 | Disordered | 0.885724 | Binding | 0.407 | 0.929 | 0.875 | -6.823 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.159 | Likely Benign | 0.21 | Neutral | 0.000 | Benign | 0.002 | Benign | 5.29 | Benign | 0.55 | Tolerated | 0.3288 | 0.5144 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3173G>T | G1058V 2D AIThe SynGAP1 missense variant G1058V is reported in gnomAD (variant ID 6‑33443725‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.980739 | Disordered | 0.885724 | Binding | 0.407 | 0.929 | 0.875 | 6-33443725-G-T | 1 | 6.21e-7 | -6.877 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -0.12 | Neutral | 0.000 | Benign | 0.001 | Benign | 5.22 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1561 | 0.3694 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||
| c.3898C>A | P1300T 2D AIThe SynGAP1 missense variant P1300T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence supports a benign classification, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.885826 | Binding | 0.400 | 0.834 | 0.875 | -4.522 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.070 | Likely Benign | -0.64 | Neutral | 0.649 | Possibly Damaging | 0.266 | Benign | 2.87 | Benign | 0.21 | Tolerated | 0.1546 | 0.4729 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3898C>G | P1300A 2D AIThe SynGAP1 missense variant P1300A is reported in gnomAD (ID 6‑33451772‑C‑G) and has no ClinVar entry. Across the evaluated in‑silico tools, every predictor classifies 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, so the pathogenic‑prediction group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates a benign effect, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Based on the unanimous benign predictions and the absence of any pathogenic signal, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.885826 | Binding | 0.400 | 0.834 | 0.875 | 6-33451772-C-G | 2 | 1.24e-6 | -3.802 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.065 | Likely Benign | 0.55 | Neutral | 0.008 | Benign | 0.006 | Benign | 3.23 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.3342 | 0.3744 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.3898C>T | P1300S 2D AIThe SynGAP1 missense variant P1300S is reported in gnomAD (variant ID 6‑33451772‑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 prediction tools and the high‑accuracy methods indicates that P1300S 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 | 0.788093 | Disordered | 0.885826 | Binding | 0.400 | 0.834 | 0.875 | 6-33451772-C-T | 1 | 6.20e-7 | -3.476 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.036 | Likely Benign | -0.29 | Neutral | 0.481 | Possibly Damaging | 0.157 | Benign | 2.89 | Benign | 0.27 | Tolerated | 3.77 | 5 | 0.3242 | 0.4139 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3899C>A | P1300H 2D AIThe SynGAP1 missense variant P1300H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.885826 | Binding | 0.400 | 0.834 | 0.875 | -5.062 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -1.48 | Neutral | 0.990 | Probably Damaging | 0.840 | Possibly Damaging | 2.80 | Benign | 0.01 | Affected | 0.1757 | 0.3802 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3899C>G | P1300R 2D AIThe SynGAP1 missense variant P1300R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized returns “Benign” and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates “Likely Benign.” No Foldetta stability analysis is available, so it does not influence the conclusion. Overall, the majority of evidence points to a benign effect for P1300R, and this is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.885826 | Binding | 0.400 | 0.834 | 0.875 | -3.930 | Likely Benign | 0.195 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -1.27 | Neutral | 0.901 | Possibly Damaging | 0.516 | Possibly Damaging | 2.82 | Benign | 0.05 | Affected | 0.1516 | 0.2733 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3899C>T | P1300L 2D AIThe SynGAP1 missense variant P1300L is reported in gnomAD (variant ID 6‑33451773‑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 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, supports a benign interpretation. This prediction 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 | 0.788093 | Disordered | 0.885826 | Binding | 0.400 | 0.834 | 0.875 | 6-33451773-C-T | 1 | 6.20e-7 | -3.562 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -1.35 | Neutral | 0.649 | Possibly Damaging | 0.209 | Benign | 2.84 | Benign | 0.19 | Tolerated | 3.77 | 5 | 0.2348 | 0.5680 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| 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.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.2326G>A | G776S 2D AIThe SynGAP1 missense variant G776S is reported in ClinVar as “Not submitted” and is present in gnomAD (variant ID 6-33442484-G-A). 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, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus likewise indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of predictive evidence points to a benign effect, 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 | 0.377384 | Structured | 0.886983 | Binding | 0.296 | 0.888 | 0.250 | 6-33442484-G-A | 1 | 1.28e-6 | -3.334 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 0.163 | Likely Benign | -1.21 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 4.28 | Benign | 0.13 | Tolerated | 3.64 | 6 | 0.2539 | 0.5785 | 0 | 1 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.2326G>C | G776R 2D AIThe SynGAP1 missense variant G776R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which collectively suggest a likely benign outcome. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the Foldetta protein‑folding stability assessment is unavailable for this variant. Overall, the balance of evidence leans toward a benign interpretation, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.377384 | Structured | 0.886983 | Binding | 0.296 | 0.888 | 0.250 | -6.209 | Likely Benign | 0.886 | Likely Pathogenic | Ambiguous | 0.181 | Likely Benign | -2.28 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 4.22 | Benign | 0.01 | Affected | 0.0932 | 0.5115 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2326G>T | G776C 2D AIThe SynGAP1 missense variant G776C is not reported in ClinVar but is present in gnomAD (ID 6‑33442484‑G‑T). Prediction tools cluster into benign (REVEL, FATHMM, AlphaMissense‑Optimized) and pathogenic (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT). Two tools (ESM1b, AlphaMissense‑Default) return uncertain results. High‑accuracy assessments are limited: AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta data are unavailable. Overall, the majority of conventional predictors indicate pathogenicity, whereas the single high‑accuracy tool suggests benign. Given the preponderance of pathogenic predictions and the absence of a ClinVar entry, the variant is most likely pathogenic and does not contradict any existing ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.377384 | Structured | 0.886983 | Binding | 0.296 | 0.888 | 0.250 | 6-33442484-G-T | -7.974 | In-Between | 0.380 | Ambiguous | Likely Benign | 0.181 | Likely Benign | -2.59 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 4.15 | Benign | 0.01 | Affected | 3.64 | 6 | 0.1235 | 0.4403 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||
| c.2327G>A | G776D 2D AIThe SynGAP1 missense variant G776D is catalogued in gnomAD (ID 6‑33442485‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from AlphaMissense‑Default, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (majority of the four high‑accuracy tools) also indicates benign. Foldetta stability analysis is unavailable, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign effect for G776D, 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 | 0.377384 | Structured | 0.886983 | Binding | 0.296 | 0.888 | 0.250 | 6-33442485-G-A | 0.388 | Likely Benign | 0.566 | Likely Pathogenic | Likely Benign | 0.188 | Likely Benign | 0.16 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 4.30 | Benign | 0.10 | Tolerated | 3.64 | 6 | 0.1835 | 0.2971 | -1 | 1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||
| c.2327G>C | G776A 2D AIThe SynGAP1 missense variant G776A 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 G776A, and 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 | 0.377384 | Structured | 0.886983 | Binding | 0.296 | 0.888 | 0.250 | -5.275 | Likely Benign | 0.296 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -1.82 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 4.26 | Benign | 0.03 | Affected | 0.3648 | 0.4971 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2327G>T | G776V 2D AIThe SynGAP1 missense variant G776V is listed in gnomAD (ID 6‑33442485‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (FoldX‑MD/Rosetta stability assessment) has no result for this variant. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also indicates a likely benign outcome; Foldetta data are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status because none is reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.377384 | Structured | 0.886983 | Binding | 0.296 | 0.888 | 0.250 | 6-33442485-G-T | -6.541 | Likely Benign | 0.515 | Ambiguous | Likely Benign | 0.180 | Likely Benign | -2.25 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 4.19 | Benign | 0.01 | Affected | 3.64 | 6 | 0.0993 | 0.4223 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||
| c.3976C>A | P1326T 2D AIThe SynGAP1 missense variant P1326T is reported in gnomAD (ID 6‑33451850‑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 classify the change as benign, while the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority of the same four high‑accuracy tools) is benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that P1326T is most likely benign, and this assessment does not contradict any ClinVar classification because no ClinVar variant is listed. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.948786 | Disordered | 0.887377 | Binding | 0.393 | 0.782 | 0.875 | 6-33451850-C-A | -5.755 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.135 | Likely Benign | -0.26 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.71 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1955 | 0.5517 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3976C>G | P1326A 2D AIThe SynGAP1 missense variant P1326A 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 | 0.948786 | Disordered | 0.887377 | Binding | 0.393 | 0.782 | 0.875 | -4.450 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.76 | Neutral | 0.996 | Probably Damaging | 0.986 | Probably Damaging | 3.73 | Benign | 0.00 | Affected | 0.3728 | 0.4333 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3976C>T | P1326S 2D AIThe SynGAP1 missense variant P1326S is listed in ClinVar with no submitted interpretation and is present in gnomAD (ID 6‑33451850‑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; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence—including the high‑accuracy tools—supports a benign classification. This conclusion does not contradict the ClinVar status, which currently has no pathogenic assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.948786 | Disordered | 0.887377 | Binding | 0.393 | 0.782 | 0.875 | 6-33451850-C-T | -5.221 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.107 | Likely Benign | -0.35 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.74 | Benign | 0.00 | Affected | 3.77 | 5 | 0.3722 | 0.4563 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||
| c.3977C>A | P1326Q 2D AIThe SynGAP1 missense variant P1326Q is listed in ClinVar (ID 2806103.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33451851‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict the ClinVar “Uncertain” classification, which remains inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.948786 | Disordered | 0.887377 | Binding | 0.393 | 0.782 | 0.875 | Uncertain | 1 | 6-33451851-C-A | 1 | 6.40e-7 | -5.422 | Likely Benign | 0.128 | Likely Benign | Likely Benign | 0.138 | Likely Benign | -0.86 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 3.62 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1769 | 0.4457 | -1 | 0 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||
| c.3977C>G | P1326R 2D AIThe SynGAP1 missense variant P1326R is listed in ClinVar (ID 2429486.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) also benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.948786 | Disordered | 0.887377 | Binding | 0.393 | 0.782 | 0.875 | Uncertain | 1 | -5.097 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.133 | Likely Benign | -0.82 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 3.62 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1710 | 0.2808 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.3977C>T | P1326L 2D AIThe SynGAP1 missense variant P1326L is listed in ClinVar (ID 1004879.0) 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, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. 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 (FoldX‑MD/ Rosetta) stability result is available for this variant. Overall, the majority of evidence—including the high‑confidence SGM consensus and AlphaMissense‑Optimized prediction—supports a benign classification, 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 | 0.948786 | Disordered | 0.887377 | Binding | 0.393 | 0.782 | 0.875 | Uncertain | 1 | -5.541 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.117 | Likely Benign | -1.06 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 3.62 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2723 | 0.6113 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||
| c.2848G>A | G950S 2D AIThe SynGAP1 missense variant G950S is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign impact. 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 | 0.987317 | Disordered | 0.888649 | Binding | 0.368 | 0.923 | 0.750 | -5.286 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.288 | Likely Benign | 0.46 | Neutral | 0.004 | Benign | 0.008 | Benign | 2.32 | Pathogenic | 0.52 | Tolerated | 0.2459 | 0.5502 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2848G>C | G950R 2D AIThe SynGAP1 missense variant G950R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for G950R, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.987317 | Disordered | 0.888649 | Binding | 0.368 | 0.923 | 0.750 | -6.929 | Likely Benign | 0.318 | Likely Benign | Likely Benign | 0.388 | Likely Benign | -1.10 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.26 | Pathogenic | 0.01 | Affected | 0.1009 | 0.4733 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2848G>T | G950C 2D AIThe SynGAP1 missense variant G950C is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. 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 high‑confidence predictors (five pathogenic vs. four benign) indicate 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. | 0.987317 | Disordered | 0.888649 | Binding | 0.368 | 0.923 | 0.750 | -9.589 | Likely Pathogenic | 0.092 | Likely Benign | Likely Benign | 0.395 | Likely Benign | -0.35 | Neutral | 0.983 | Probably Damaging | 0.750 | Possibly Damaging | 2.26 | Pathogenic | 0.01 | Affected | 0.1406 | 0.4439 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||||||
| c.2849G>A | G950D 2D AIThe SynGAP1 missense variant G950D is not reported 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), AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM, while ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign outcome. 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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.888649 | Binding | 0.368 | 0.923 | 0.750 | -7.515 | In-Between | 0.245 | Likely Benign | Likely Benign | 0.402 | Likely Benign | -0.61 | Neutral | 0.411 | Benign | 0.131 | Benign | 2.26 | Pathogenic | 0.02 | Affected | 0.1874 | 0.2826 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2849G>C | G950A 2D AIThe SynGAP1 missense variant G950A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only FATHMM predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict, reflecting the majority of benign calls. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.987317 | Disordered | 0.888649 | Binding | 0.368 | 0.923 | 0.750 | -6.557 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.339 | Likely Benign | -0.13 | Neutral | 0.059 | Benign | 0.061 | Benign | 2.28 | Pathogenic | 0.08 | Tolerated | 0.3343 | 0.4957 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2849G>T | G950V 2D AIThe SynGAP1 missense variant G950V is not reported 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM, while ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign prediction. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that G950V 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. | 0.987317 | Disordered | 0.888649 | Binding | 0.368 | 0.923 | 0.750 | -7.796 | In-Between | 0.093 | Likely Benign | Likely Benign | 0.428 | Likely Benign | -0.91 | Neutral | 0.411 | Benign | 0.239 | Benign | 2.26 | Pathogenic | 0.01 | Affected | 0.1392 | 0.3507 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3904T>A | L1302M 2D AIThe SynGAP1 missense variant L1302M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) support a benign classification. There is no ClinVar entry to contradict this assessment, so the variant is most likely benign based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.889642 | Binding | 0.429 | 0.842 | 0.875 | -5.246 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.171 | Likely Benign | -1.34 | Neutral | 0.960 | Probably Damaging | 0.799 | Possibly Damaging | 1.54 | Pathogenic | 0.00 | Affected | 0.0929 | 0.3439 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3904T>G | L1302V 2D AIThe SynGAP1 missense variant L1302V is not reported 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. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.889642 | Binding | 0.429 | 0.842 | 0.875 | -4.140 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.214 | Likely Benign | -1.71 | Neutral | 0.004 | Benign | 0.022 | Benign | 1.58 | Pathogenic | 0.00 | Affected | 0.1603 | 0.2686 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3905T>C | L1302S 2D  AIThe SynGAP1 missense variant L1302S is not 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 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 tools specifically show AlphaMissense‑Optimized as benign, while SGM Consensus and Foldetta remain unavailable. Overall, the majority of predictions (five pathogenic vs. four benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.784345 | Disordered | 0.889642 | Binding | 0.429 | 0.842 | 0.875 | -3.411 | Likely Benign | 0.196 | Likely Benign | Likely Benign | 0.307 | Likely Benign | -4.17 | Deleterious | 0.960 | Probably Damaging | 0.726 | Possibly Damaging | 1.50 | Pathogenic | 0.00 | Affected | 0.3237 | 0.0982 | -3 | -2 | -4.6 | -26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3905T>G | L1302W 2D  AIThe SynGAP1 missense variant L1302W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM; ESM1b is uncertain and not counted. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs. three benign) lean toward pathogenicity, and this is consistent with the SGM Consensus result. Therefore, the variant is most likely pathogenic based on current computational evidence, and this does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.784345 | Disordered | 0.889642 | Binding | 0.429 | 0.842 | 0.875 | -7.133 | In-Between | 0.297 | Likely Benign | Likely Benign | 0.290 | Likely Benign | -4.20 | Deleterious | 0.996 | Probably Damaging | 0.946 | Probably Damaging | 1.49 | Pathogenic | 0.00 | Affected | 0.0671 | 0.2530 | -2 | -2 | -4.7 | 73.05 | ||||||||||||||||||||||||||||||||||||||||
| c.3906G>C | L1302F 2D AISynGAP1 missense variant L1302F 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, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments indicate AlphaMissense‑Optimized predicts benign, whereas the SGM consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split; Foldetta stability analysis is unavailable. Overall, the majority of predictions (five pathogenic versus four benign) lean toward a pathogenic effect. Thus, the variant is most likely pathogenic, a conclusion that contrasts with its current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.784345 | Disordered | 0.889642 | Binding | 0.429 | 0.842 | 0.875 | Uncertain | 1 | -5.674 | Likely Benign | 0.148 | Likely Benign | Likely Benign | 0.211 | Likely Benign | -2.70 | Deleterious | 0.960 | Probably Damaging | 0.657 | Possibly Damaging | 1.53 | Pathogenic | 0.00 | Affected | 0.0721 | 0.2648 | 2 | 0 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||||||||
| c.3906G>T | L1302F 2D AIThe SynGAP1 missense variant L1302F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. 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. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it yields a 2‑to‑2 split. Foldetta, a protein‑folding stability method that combines FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools that are available indicate a benign outcome (AlphaMissense‑Optimized) while the consensus and stability analyses are missing. Consequently, the overall prediction is ambiguous, but the most reliable evidence points toward a benign effect, and this does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.784345 | Disordered | 0.889642 | Binding | 0.429 | 0.842 | 0.875 | -5.674 | Likely Benign | 0.148 | Likely Benign | Likely Benign | 0.215 | Likely Benign | -2.70 | Deleterious | 0.960 | Probably Damaging | 0.657 | Possibly Damaging | 1.53 | Pathogenic | 0.00 | Affected | 0.0721 | 0.2648 | 2 | 0 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.2752G>A | A918T 2D AISynGAP1 missense variant A918T is listed in ClinVar with an uncertain significance (ClinVar ID 3964538.0) and is present in gnomAD (6‑33443304‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions are reported by 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. Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.632174 | Disordered | 0.891459 | Binding | 0.317 | 0.860 | 0.250 | Uncertain | 1 | 6-33443304-G-A | 1 | 6.20e-7 | -4.139 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -1.09 | Neutral | 0.980 | Probably Damaging | 0.721 | Possibly Damaging | 2.64 | Benign | 0.03 | Affected | 4.32 | 4 | 0.1742 | 0.6430 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||
| c.2752G>C | A918P 2D AIThe SynGAP1 missense variant A918P 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 | 0.632174 | Disordered | 0.891459 | Binding | 0.317 | 0.860 | 0.250 | -2.087 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -0.60 | Neutral | 0.998 | Probably Damaging | 0.924 | Probably Damaging | 2.59 | Benign | 0.04 | Affected | 0.2052 | 0.4985 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2752G>T | A918S 2D AIThe SynGAP1 missense variant A918S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that A918S 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 | 0.632174 | Disordered | 0.891459 | Binding | 0.317 | 0.860 | 0.250 | -3.279 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.04 | Neutral | 0.910 | Possibly Damaging | 0.554 | Possibly Damaging | 2.66 | Benign | 0.07 | Tolerated | 0.2824 | 0.5442 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2753C>A | A918D 2D AIThe SynGAP1 missense variant A918D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic outcome. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized independently predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence—including the high‑accuracy tools—points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation; there is no contradictory ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.632174 | Disordered | 0.891459 | Binding | 0.317 | 0.860 | 0.250 | -4.281 | Likely Benign | 0.445 | Ambiguous | Likely Benign | 0.102 | Likely Benign | -0.99 | Neutral | 0.961 | Probably Damaging | 0.721 | Possibly Damaging | 2.64 | Benign | 0.01 | Affected | 0.2037 | 0.2412 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2753C>G | A918G 2D AIThe SynGAP1 missense variant A918G is not reported 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 outcome. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are not available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.632174 | Disordered | 0.891459 | Binding | 0.317 | 0.860 | 0.250 | -2.906 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.099 | Likely Benign | 0.14 | Neutral | 0.954 | Possibly Damaging | 0.630 | Possibly Damaging | 2.72 | Benign | 0.70 | Tolerated | 0.2125 | 0.4376 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2753C>T | A918V 2D AIThe SynGAP1 missense variant A918V is listed in ClinVar with an “Uncertain” status and is present in gnomAD (gnomAD ID 6‑33443305‑C‑T). 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; a Foldetta stability prediction is not available. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.632174 | Disordered | 0.891459 | Binding | 0.317 | 0.860 | 0.250 | Uncertain | 3 | 6-33443305-C-T | 2 | 1.24e-6 | -3.684 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.119 | Likely Benign | -1.61 | Neutral | 0.980 | Probably Damaging | 0.782 | Possibly Damaging | 2.61 | Benign | 0.03 | Affected | 4.32 | 4 | 0.1226 | 0.5586 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||
| c.3154G>A | G1052R 2D AISynGAP1 missense variant G1052R is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores the variant as benign, and the SGM consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar uncertain status but provides additional support toward a likely benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | Uncertain | 1 | -9.050 | Likely Pathogenic | 0.383 | Ambiguous | Likely Benign | 0.497 | Likely Benign | -0.41 | Neutral | 0.990 | Probably Damaging | 0.798 | Possibly Damaging | 3.90 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.0976 | 0.4142 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||
| c.3154G>C | G1052R 2D AIThe SynGAP1 missense variant G1052R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and ESM1b predict a pathogenic outcome; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | -9.050 | Likely Pathogenic | 0.383 | Ambiguous | Likely Benign | 0.497 | Likely Benign | -0.41 | Neutral | 0.990 | Probably Damaging | 0.798 | Possibly Damaging | 3.90 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.0976 | 0.4142 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3154G>T | G1052W 2D AIThe SynGAP1 missense variant G1052W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | -11.322 | Likely Pathogenic | 0.309 | Likely Benign | Likely Benign | 0.457 | Likely Benign | -0.90 | Neutral | 0.997 | Probably Damaging | 0.946 | Probably Damaging | 3.90 | Benign | 0.02 | Affected | 0.0872 | 0.4046 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3155G>A | G1052E 2D AIThe SynGAP1 missense variant G1052E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral impact. In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign effect. Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign classification, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | -9.869 | Likely Pathogenic | 0.287 | Likely Benign | Likely Benign | 0.448 | Likely Benign | -0.64 | Neutral | 0.901 | Possibly Damaging | 0.537 | Possibly Damaging | 3.90 | Benign | 0.12 | Tolerated | 0.1405 | 0.3873 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3155G>C | G1052A 2D AIThe SynGAP1 missense variant G1052A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic outcome, creating a single discordant signal. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence supports a benign classification, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | -6.945 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.382 | Likely Benign | -0.14 | Neutral | 0.649 | Possibly Damaging | 0.287 | Benign | 3.93 | Benign | 1.00 | Tolerated | 0.3259 | 0.4949 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3155G>T | G1052V 2D AIThe SynGAP1 missense variant G1052V is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign, while the high‑accuracy AlphaMissense‑Optimized score is benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign. In contrast, polyPhen‑2 HumDiv and HumVar both predict pathogenic, and ESM1b remains uncertain. No Foldetta stability assessment is available, so it does not influence the overall interpretation. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | -7.717 | In-Between | 0.094 | Likely Benign | Likely Benign | 0.452 | Likely Benign | -0.12 | Neutral | 0.901 | Possibly Damaging | 0.619 | Possibly Damaging | 3.90 | Benign | 0.19 | Tolerated | 0.1329 | 0.3499 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| 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.3877G>A | D1293N 2D AIThe SynGAP1 missense variant D1293N is reported in gnomAD (6‑33447925‑G‑A) but has no ClinVar entry. Functional prediction tools split in a 5‑to‑4 ratio: benign calls come from REVEL, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive and Foldetta results are unavailable. Overall, the majority of evidence points toward a benign effect, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.779859 | Disordered | 0.892346 | Binding | 0.569 | 0.801 | 0.625 | 6-33447925-G-A | 5 | 3.22e-6 | -3.983 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.175 | Likely Benign | -3.30 | Deleterious | 0.950 | Possibly Damaging | 0.414 | Benign | 2.33 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1264 | 0.3421 | 1 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||
| c.3877G>C | D1293H 2D AIThe SynGAP1 missense variant D1293H is not 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, and PROVEAN) predicts pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (five pathogenic vs. three benign) and the SGM Consensus support a pathogenic classification, whereas AlphaMissense‑Optimized suggests benign. The variant is most likely pathogenic based on the collective evidence, and this conclusion 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. | 0.779859 | Disordered | 0.892346 | Binding | 0.569 | 0.801 | 0.625 | -4.422 | Likely Benign | 0.391 | Ambiguous | Likely Benign | 0.278 | Likely Benign | -4.59 | Deleterious | 0.984 | Probably Damaging | 0.888 | Possibly Damaging | 2.17 | Pathogenic | 0.00 | Affected | 0.1609 | 0.3731 | 1 | -1 | 0.3 | 22.05 | ||||||||||||||||||||||||||||||||||||||||
| c.3877G>T | D1293Y 2D AIThe SynGAP1 missense variant D1293Y is not 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, and PROVEAN) predicts pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (five pathogenic vs. three benign) and the SGM Consensus support a pathogenic classification, with no ClinVar entry to contradict this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.779859 | Disordered | 0.892346 | Binding | 0.569 | 0.801 | 0.625 | -5.452 | Likely Benign | 0.392 | Ambiguous | Likely Benign | 0.310 | Likely Benign | -6.15 | Deleterious | 0.995 | Probably Damaging | 0.897 | Possibly Damaging | 2.15 | Pathogenic | 0.00 | Affected | 0.0627 | 0.3577 | -4 | -3 | 2.2 | 48.09 | ||||||||||||||||||||||||||||||||||||||||
| c.3878A>C | D1293A 2D AIThe SynGAP1 missense variant D1293A is not 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 (5 benign vs 4 pathogenic predictions) leans toward 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. | 0.779859 | Disordered | 0.892346 | Binding | 0.569 | 0.801 | 0.625 | -2.251 | Likely Benign | 0.197 | Likely Benign | Likely Benign | 0.302 | Likely Benign | -5.19 | Deleterious | 0.770 | Possibly Damaging | 0.255 | Benign | 2.20 | Pathogenic | 0.00 | Affected | 0.3267 | 0.3447 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.3878A>G | D1293G 2D AIThe SynGAP1 missense variant D1293G is not 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 (5 benign vs 4 pathogenic predictions, with the most accurate tool indicating benign) suggests the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.779859 | Disordered | 0.892346 | Binding | 0.569 | 0.801 | 0.625 | -3.060 | Likely Benign | 0.261 | Likely Benign | Likely Benign | 0.332 | Likely Benign | -4.91 | Deleterious | 0.872 | Possibly Damaging | 0.399 | Benign | 2.19 | Pathogenic | 0.00 | Affected | 0.3022 | 0.3944 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3878A>T | D1293V 2D AIThe SynGAP1 missense variant D1293V is not 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, was not available for this variant. Overall, the majority of available predictions (five pathogenic vs. four benign) lean toward a pathogenic impact. This assessment does not contradict ClinVar status, as the variant has not yet been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.779859 | Disordered | 0.892346 | Binding | 0.569 | 0.801 | 0.625 | -3.817 | Likely Benign | 0.328 | Likely Benign | Likely Benign | 0.343 | Likely Benign | -6.03 | Deleterious | 0.960 | Probably Damaging | 0.679 | Possibly Damaging | 2.16 | Pathogenic | 0.00 | Affected | 0.0896 | 0.3603 | -2 | -3 | 7.7 | -15.96 | ||||||||||||||||||||||||||||||||||||||||
| c.3879C>A | D1293E 2D AIThe SynGAP1 missense variant D1293E is reported in gnomAD (variant ID 6‑33447927‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, SIFT and FATHMM predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments further support benignity: 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 majority of evidence points to a benign effect, 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 | 0.779859 | Disordered | 0.892346 | Binding | 0.569 | 0.801 | 0.625 | 6-33447927-C-A | -2.627 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.042 | Likely Benign | -1.86 | Neutral | 0.011 | Benign | 0.008 | Benign | 2.39 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1512 | 0.3425 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.3879C>G | D1293E 2D AIThe SynGAP1 missense variant D1293E is not reported in ClinVar (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 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 D1293E, 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 | 0.779859 | Disordered | 0.892346 | Binding | 0.569 | 0.801 | 0.625 | -2.627 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -1.86 | Neutral | 0.011 | Benign | 0.008 | Benign | 2.39 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1512 | 0.3425 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||
| 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.2278A>C | M760L 2D AIThe SynGAP1 missense variant M760L is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity 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 a pathogenic outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign effect, 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 is that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.541878 | Disordered | 0.893402 | Binding | 0.346 | 0.865 | 0.375 | -2.260 | Likely Benign | 0.134 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -0.68 | Neutral | 0.065 | Benign | 0.033 | Benign | 2.69 | Benign | 0.15 | Tolerated | 0.1802 | 0.4805 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2278A>G | M760V 2D AIThe SynGAP1 missense variant M760V is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a 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 | 0.541878 | Disordered | 0.893402 | Binding | 0.346 | 0.865 | 0.375 | -2.803 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -1.20 | Neutral | 0.001 | Benign | 0.008 | Benign | 2.69 | Benign | 0.22 | Tolerated | 0.3974 | 0.4381 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||||||||||||
| c.2278A>T | M760L 2D AIThe SynGAP1 missense variant M760L is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity 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 a pathogenic outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign effect, 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 is that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.541878 | Disordered | 0.893402 | Binding | 0.346 | 0.865 | 0.375 | -2.260 | Likely Benign | 0.134 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -0.68 | Neutral | 0.065 | Benign | 0.033 | Benign | 2.69 | Benign | 0.15 | Tolerated | 0.1802 | 0.4805 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2279T>A | M760K 2D AIThe SynGAP1 missense variant M760K is not reported 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, 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 | 0.541878 | Disordered | 0.893402 | Binding | 0.346 | 0.865 | 0.375 | -4.069 | Likely Benign | 0.654 | Likely Pathogenic | Likely Benign | 0.108 | Likely Benign | -1.18 | Neutral | 0.784 | Possibly Damaging | 0.492 | Possibly Damaging | 2.75 | Benign | 0.12 | Tolerated | 0.1751 | 0.1071 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||||||
| c.2279T>C | M760T 2D AIThe SynGAP1 missense variant M760T is reported in gnomAD (ID 6‑33441744‑T‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (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 the variant is most likely benign, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.541878 | Disordered | 0.893402 | Binding | 0.346 | 0.865 | 0.375 | 6-33441744-T-C | 1 | 6.20e-7 | -2.365 | Likely Benign | 0.519 | Ambiguous | Likely Benign | 0.096 | Likely Benign | -1.56 | Neutral | 0.425 | Benign | 0.252 | Benign | 2.71 | Benign | 0.41 | Tolerated | 3.99 | 5 | 0.2515 | 0.2875 | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||||||||||||||||
| c.2279T>G | M760R 2D AIThe SynGAP1 missense variant M760R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence points to a benign impact, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.541878 | Disordered | 0.893402 | Binding | 0.346 | 0.865 | 0.375 | -2.794 | Likely Benign | 0.594 | Likely Pathogenic | Likely Benign | 0.125 | Likely Benign | -1.61 | Neutral | 0.975 | Probably Damaging | 0.690 | Possibly Damaging | 2.71 | Benign | 0.09 | Tolerated | 0.1804 | 0.1318 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||||||
| c.2280G>A | M760I 2D AIThe SynGAP1 missense variant M760I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the collective evidence strongly suggests that M760I 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 | 0.541878 | Disordered | 0.893402 | Binding | 0.346 | 0.865 | 0.375 | -3.696 | Likely Benign | 0.486 | Ambiguous | Likely Benign | 0.065 | Likely Benign | -1.03 | Neutral | 0.029 | Benign | 0.033 | Benign | 2.67 | Benign | 0.09 | Tolerated | 0.1595 | 0.4054 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2280G>C | M760I 2D AIThe SynGAP1 missense variant M760I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the collective evidence strongly suggests that M760I 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 | 0.541878 | Disordered | 0.893402 | Binding | 0.346 | 0.865 | 0.375 | -3.696 | Likely Benign | 0.486 | Ambiguous | Likely Benign | 0.065 | Likely Benign | -1.03 | Neutral | 0.029 | Benign | 0.033 | Benign | 2.67 | Benign | 0.09 | Tolerated | 0.1595 | 0.4054 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2280G>T | M760I 2D AIThe SynGAP1 missense variant M760I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the collective evidence strongly suggests that M760I 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 | 0.541878 | Disordered | 0.893402 | Binding | 0.346 | 0.865 | 0.375 | -3.696 | Likely Benign | 0.486 | Ambiguous | Likely Benign | 0.065 | Likely Benign | -1.03 | Neutral | 0.029 | Benign | 0.033 | Benign | 2.67 | Benign | 0.09 | Tolerated | 0.1595 | 0.4054 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| 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.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 | |||||||||||||||||||||||||||||||||||||||
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