Table of SynGAP1 Isoform α2 (UniProt Q96PV0-1) Missense Variants.
| c.dna | Variant | SGM Consensus | Domain | ClinVar | gnomAD | ESM1b | AlphaMissense | REVEL | FoldX | Rosetta | Foldetta | PremPS | PROVEAN | PolyPhen-2 HumDiv | PolyPhen-2 HumVar | FATHMM | SIFT | PAM | Physical | SASA | Normalized B-factor backbone | Normalized B-factor sidechain | SynGAP Structural Annotation | DOI | |||||||||||||||||||||||||||||||||
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| Clinical Status | Review | Subm. | ID | Allele count | Allele freq. | LLR score | Prediction | Pathogenicity | Class | Optimized | Score | Prediction | Average ΔΔG | Prediction | StdDev | ΔΔG | Prediction | ΔΔG | Prediction | ΔΔG | Prediction | Score | Prediction | pph2_prob | Prediction | pph2_prob | Prediction | Nervous System Score | Prediction | Prediction | Status | Conservation | Sequences | PAM250 | PAM120 | Hydropathy Δ | MW Δ | Average | Δ | Δ | StdDev | Δ | StdDev | Secondary | Tertiary bonds | Inside out | GAP-Ras interface | At membrane | No effect | MD Alert | Verdict | Description | |||||
| c.1485A>C | E495D 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant E495D is listed in ClinVar with an uncertain significance (ClinVar ID 2000233.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions from SIFT and ESM1b, and pathogenic predictions from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN classifies the variant as likely pathogenic. AlphaMissense‑Optimized also predicts pathogenicity, whereas Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the majority of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status but suggests a higher likelihood of deleterious impact. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Conflicting | 2 | -3.574 | Likely Benign | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.566 | Likely Pathogenic | 1.39 | Ambiguous | 0.1 | 1.03 | Ambiguous | 1.21 | Ambiguous | 0.98 | Ambiguous | -2.52 | Deleterious | 0.998 | Probably Damaging | 0.989 | Probably Damaging | -1.41 | Pathogenic | 0.17 | Tolerated | 3.37 | 35 | 3 | 2 | 0.0 | -14.03 | 220.6 | 38.8 | 0.0 | 0.0 | 0.1 | 0.1 | X | X | Uncertain | Glu495 is located in the α-helix (res. Leu489-Glu519), and its carboxylate group forms salt bridges with the neighboring Lys492 and with Arg596 on an opposing α-helix (res. Glu582-Met603) in the WT simulations. In the variant simulations, the acidic carboxylate side chain of Asp495 can also form salt bridges with both Lys492 and Arg596. However, the shorter side chain of aspartate tends to favor forming a salt bridge with the nearby Arg499 on the same α-helix instead. Asp495 might not maintain the salt bridge with Arg596 on the opposing α-helix as efficiently as Glu495 in the WT, potentially weakening the tertiary structure. Regardless, the potential negative effect is likely to be minor, with no deleterious effects observed on the protein structure during the simulations. However, due to its location at the GAP-Ras interface, the effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||||||
| c.1717C>T | R573W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R573W is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on a pathogenic effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools with uncertain or inconclusive results are Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta yields an uncertain stability change. Overall, the majority of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Conflicting | 8 | -14.078 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.758 | Likely Pathogenic | 2.37 | Destabilizing | 0.7 | 0.57 | Ambiguous | 1.47 | Ambiguous | 0.88 | Ambiguous | -6.94 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.48 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 2 | -3 | 3.6 | 30.03 | 257.6 | 39.0 | 0.1 | 0.0 | 0.2 | 0.0 | X | X | Potentially Pathogenic | The guanidinium group of Arg573, located in an α-helix (res. Arg563-Glu578), forms a salt bridge with the carboxylate groups of Glu582 and/or Asp586 from a nearby α-helix (res. Glu582-Met603) in the WT simulations. Additionally, the Arg573 side chain stacks planarly with the aromatic phenol ring of Tyr665 and hydrogen bonds with the hydroxyl group of Ser668 from another α-helix (res. Ser641-Ser668). In the variant simulations, the indole ring of the Trp573 side chain is unable to maintain the same level of coordination as the positively charged Arg573 side chain. Indeed, Trp573 is seen hydrogen bonding only briefly with the carboxylate group of Glu582. Consequently, the integrity of the opposing α-helix end (res. Glu582-Met603) is weakened. Overall, the residue swap has the potential to substantially affect the tertiary structure assembly during the protein folding process. | ||||||||||
| c.1723C>T | R575C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R575C is listed in ClinVar with an “Uncertain” status (ClinVar ID 537013.0) and is present in gnomAD (ID 6‑33440775‑C‑T). Prediction tools that indicate a benign effect include only AlphaMissense‑Optimized. All other evaluated algorithms predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of predictions support a pathogenic effect. Thus, the variant is most likely pathogenic, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Conflicting | 3 | 6-33440775-C-T | 23 | 1.43e-5 | -11.179 | Likely Pathogenic | 0.630 | Likely Pathogenic | Likely Benign | 0.715 | Likely Pathogenic | 1.39 | Ambiguous | 0.2 | 0.50 | Ambiguous | 0.95 | Ambiguous | 0.73 | Ambiguous | -5.43 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.30 | Pathogenic | 0.02 | Affected | 3.37 | 35 | -4 | -3 | 7.0 | -53.05 | 227.7 | 99.2 | 0.0 | 0.0 | 0.0 | 0.1 | X | Potentially Pathogenic | The guanidinium group of Arg575, located in an α-helix (res. Arg563-Glu578), forms salt bridges with the carboxylate groups of Asp463 and Asp467, and it also hydrogen bonds with the hydroxyl group of Ser466 on an opposing α-helix (res. Ala461-Phe476) in the WT simulations. In the variant simulations, the thiol group of the Cys575 side chain, which is neither positively charged nor particularly hydrophilic, packs against the hydrophobic Met470 on an opposing α-helix (res. Ala461-Arg475). Additionally, although the thiol group is not an effective hydrogen bonder, the Cys575 side chain rotates to hydrogen bond with the backbone carbonyl group of Ser571 in the same α-helix, which could theoretically lower the helix integrity. Overall, the residue swap has the potential to substantially affect the tertiary structure assembly during the protein folding process. | ||||||||
| c.1724G>A | R575H 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R575H (ClinVar ID 1029088.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33440776‑G‑A). Prediction tools that indicate a benign effect include Rosetta, Foldetta, PROVEAN, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. 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, Foldetta as Benign, and the SGM Consensus as Pathogenic. Overall, the majority of evidence points to a pathogenic impact, which contrasts with the ClinVar designation of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Conflicting | 4 | 6-33440776-G-A | 204 | 1.27e-4 | -11.142 | Likely Pathogenic | 0.496 | Ambiguous | Likely Benign | 0.707 | Likely Pathogenic | 0.81 | Ambiguous | 0.2 | -0.22 | Likely Benign | 0.30 | Likely Benign | 1.31 | Destabilizing | -2.34 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.33 | Pathogenic | 0.05 | Affected | 3.37 | 35 | 2 | 0 | 1.3 | -19.05 | 244.7 | 80.6 | 0.0 | 0.0 | 0.3 | 0.0 | X | Potentially Pathogenic | The guanidinium group of Arg575, located in an α-helix (res. Arg563-Glu578), forms salt bridges with the carboxylate groups of Asp463 and Asp467, and it also hydrogen bonds with the hydroxyl group of Ser466 on an opposing α-helix (res. Ala461-Phe476) in the WT simulations. In the variant simulations, the imidazole ring of His575 (in its neutral epsilon protonated form) cannot form the same salt bridges as the guanidinium group of the non-mutated Arg575. Instead, His575 only forms weak hydrogen bonds with the hydroxyl groups of Ser466 and Ser571. Overall, the residue swap has the potential to substantially affect the tertiary structure assembly during the protein folding process. | |||||||||
| c.1726T>C | C576R 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant C576R is listed in ClinVar with an uncertain significance (ClinVar ID 2780076.0) and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores it pathogenic, the SGM‑Consensus (derived from the majority of high‑confidence predictors) is pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Taken together, the overwhelming majority of computational evidence indicates that C576R is likely pathogenic, a conclusion that is consistent with, but not in conflict with, the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Conflicting | 2 | -14.886 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.579 | Likely Pathogenic | 7.20 | Destabilizing | 1.0 | 4.09 | Destabilizing | 5.65 | Destabilizing | 1.64 | Destabilizing | -10.88 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.38 | Benign | 0.00 | Affected | 3.37 | 35 | -3 | -4 | -7.0 | 53.05 | ||||||||||||||||||||
| c.1768A>G | S590G 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant S590G is listed in ClinVar (ID 1721675.0) with an uncertain significance status and is present in gnomAD (6‑33440820‑A‑G). Functional prediction tools that report a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic majority. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive, as are FoldX, Rosetta, and premPS. Overall, the majority of evidence points toward a pathogenic impact, which does not contradict the ClinVar uncertain status but suggests a higher likelihood of pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Conflicting | 2 | 6-33440820-A-G | 14 | 8.67e-6 | -14.277 | Likely Pathogenic | 0.574 | Likely Pathogenic | Likely Benign | 0.379 | Likely Benign | 0.67 | Ambiguous | 0.1 | 1.28 | Ambiguous | 0.98 | Ambiguous | 0.71 | Ambiguous | -3.92 | Deleterious | 1.000 | Probably Damaging | 0.922 | Probably Damaging | 3.42 | Benign | 0.06 | Tolerated | 3.37 | 35 | 1 | 0 | 0.4 | -30.03 | 186.7 | 49.4 | 0.0 | 0.0 | 0.1 | 0.0 | X | Potentially Pathogenic | In the WT simulations, the hydroxyl group of Ser590, located on an α helix (res. Glu582-Met603), forms hydrogen bonds with the backbone carbonyl of Ala634 and/or the carboxamide group of the Asn635 side chain at the end of the opposing α helix (res. Thr619-Ala634).The residue swap could weaken the integrity of the α helix, as glycine is known as an “α helix breaker.” However, no discernible difference was observed between the WT and variant simulations in this regard. Importantly, Gly590 cannot form hydrogen bonds with the opposing helix in the same way that serine can, which could weaken the tertiary structure assembly between the two helices. | ||||||||
| c.1771G>A | A591T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A591T is listed in ClinVar with an uncertain significance designation and is observed in gnomAD (variant ID 6‑33440823‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic outcome. High‑accuracy assessments further show AlphaMissense‑Optimized as benign, SGM Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other folding‑stability metrics are available. Overall, the balance of evidence favors a pathogenic interpretation, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Conflicting | 3 | 6-33440823-G-A | 18 | 1.12e-5 | -9.572 | Likely Pathogenic | 0.704 | Likely Pathogenic | Likely Benign | 0.270 | Likely Benign | 1.61 | Ambiguous | 0.2 | 1.00 | Ambiguous | 1.31 | Ambiguous | 1.19 | Destabilizing | -3.40 | Deleterious | 0.955 | Possibly Damaging | 0.209 | Benign | 3.48 | Benign | 0.01 | Affected | 3.37 | 35 | 1 | 0 | -2.5 | 30.03 | 202.9 | -43.4 | 0.2 | 0.0 | 0.7 | 0.1 | X | Potentially Benign | The methyl group of the Ala591 side chain, located in the middle of an α helix (res. Glu582-Met603), packs against hydrophobic residues (e.g., Ile483, Phe484) of an opposing partially helical loop (res. Phe476-Asn487).In the variant simulations, the hydroxyl group of Thr591 can form hydrogen bonds with the backbone carbonyl of Ile843 in the opposing loop or the backbone carbonyl group of Arg587. These interactions could either reinforce the tertiary assembly or weaken the α helix unity. Additionally, the Thr591 side chain can hydrogen bond with the guanidinium group of the Arg587 side chain, potentially strengthening the α helix unity.Overall, the residue swap does not seem to cause any major negative effects on the protein structure. | ||||||||
| c.1786C>T | R596C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R596C is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33440838‑C‑T). Prediction tools that indicate a benign effect include only premPS. All other evaluated algorithms—REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—classify the variant as pathogenic or likely pathogenic, while Rosetta remains inconclusive. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. **Thus, the variant is most likely pathogenic based on the collective predictions, which does not contradict the ClinVar uncertain status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Conflicting | 2 | 6-33440838-C-T | 6 | 3.72e-6 | -10.805 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.633 | Likely Pathogenic | 2.94 | Destabilizing | 0.0 | 1.49 | Ambiguous | 2.22 | Destabilizing | -0.03 | Likely Benign | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.41 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -4 | -3 | 7.0 | -53.05 | 230.7 | 97.9 | -0.1 | 0.0 | -0.3 | 0.4 | X | X | Potentially Pathogenic | The guanidinium group of Arg596, located in an α helix (res. Glu582-Met603), forms a salt bridge with the carboxylate group of Glu495 from another α helix (res. Leu489-Glu519). In the WT simulations, the side chain of Arg596 hydrogen bonds with the backbone carbonyl groups of Asn487, Glu486, Arg485, and Phe484. Additionally, Arg596 can hydrogen bond with the carboxamide group of the Asn487 side chain on an opposing loop that links two α helices (res. Ala461-Arg475, res. Leu489-Glu519).In the variant simulations, the thiol group of the Cys596 side chain is unable to form salt bridges or any of the hydrogen bonds that the Arg596 side chain can. Thus, the residue swap could affect the tertiary structure assembly more profoundly than observed in the simulations. Notably, Arg596 plays a key role in positioning the aforementioned loop, which is crucial for the placement of the “arginine finger” or the Arg485 side chain during RasGTPase activation. | |||||||
| c.1802C>A | A601E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A601E is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity largely agree: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect, while only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No predictions or stability results are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Conflicting | 2 | -16.752 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.588 | Likely Pathogenic | 6.68 | Destabilizing | 0.8 | 5.76 | Destabilizing | 6.22 | Destabilizing | 1.24 | Destabilizing | -4.98 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.54 | Benign | 0.00 | Affected | 3.37 | 35 | 0 | -1 | -5.3 | 58.04 | 240.0 | -82.3 | 0.0 | 0.0 | 0.7 | 0.1 | X | X | X | Potentially Pathogenic | The methyl side chain of Ala601, located on an α helix (res. Glu582-Met603), packs hydrophobically against other hydrophobic residues in the inter-helix space (e.g., Phe597, Leu598, Leu506, Phe608).In the variant simulations, the carboxylate group of Glu601 faces the inter-helix space and is forced to shift slightly away from the hydrophobic niche. Additionally, in two of the simulations, Glu601 forms a salt bridge with Arg499, causing the otherwise stable salt bridge between Arg499 and Glu496 at the outer surface of an α helix (res. Leu489-Glu519) to break due to the residue swap.These effects suggest that the protein folding process could be seriously affected. Moreover, due to its location at the GAP-Ras interface, it could also impact the complex formation with the GTPase. | |||||||||
| c.1904A>G | N635S 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant N635S is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6-33440956-A-G). Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and ESM1b. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also inconclusive. Overall, the majority of available predictions lean 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. | GAP | Conflicting | 4 | 6-33440956-A-G | 10 | 6.20e-6 | -9.002 | Likely Pathogenic | 0.101 | Likely Benign | Likely Benign | 0.104 | Likely Benign | 0.80 | Ambiguous | 0.1 | 0.67 | Ambiguous | 0.74 | Ambiguous | 0.95 | Ambiguous | -4.45 | Deleterious | 0.261 | Benign | 0.044 | Benign | 3.06 | Benign | 0.05 | Affected | 3.37 | 34 | 1 | 1 | 2.7 | -27.03 | 196.0 | 30.9 | 0.1 | 0.0 | -0.3 | 0.2 | X | Uncertain | In the WT simulations, the carboxamide side chain of Asn635, located on the outer surface of an α helix (res. Glu617-Asn635), forms hydrogen bonds with Gln631 on the same α helix and with the hydroxyl side chain of Ser590 on an opposing α helix (res. Glu582-Met603).In the variant simulations, the side chain of Ser635 is shorter than asparagine and thus prefers to hydrogen bond with the carbonyl group of Gln631 on the same helix and, to a lesser extent, with Ser590 compared to Asn635 in the WT. Ser635 forms hydrogen bonds with the backbone atoms of the same helix, which may destabilize the helix, although this is not clearly evident in the simulations. The weakening of the hydrogen bond between Ser635 and Ser590 in the variant may also weaken the tertiary structure assembly between the helices.Additionally, Asn635 is at the GTPase interface. However, the implication of the residue swap on the complex formation with the GTPase cannot be investigated using solvent-only simulations. | |||||||||
| c.2015C>T | T672M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T672M is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33441274‑C‑T). Functional prediction tools that report a benign effect include REVEL, FoldX, premPS, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. Rosetta and Foldetta provide uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑2 split, and Foldetta is also inconclusive. Overall, the majority of predictions lean toward a benign impact, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Conflicting | 2 | 6-33441274-C-T | 19 | 1.18e-5 | -9.472 | Likely Pathogenic | 0.174 | Likely Benign | Likely Benign | 0.127 | Likely Benign | 0.31 | Likely Benign | 0.4 | 1.52 | Ambiguous | 0.92 | Ambiguous | 0.41 | Likely Benign | -4.34 | Deleterious | 0.993 | Probably Damaging | 0.520 | Possibly Damaging | 3.39 | Benign | 0.00 | Affected | 3.40 | 25 | -1 | -1 | 2.6 | 30.09 | 231.9 | -52.9 | 1.1 | 0.1 | 0.5 | 0.0 | X | X | Potentially Pathogenic | The hydroxyl group of Thr672, located in an entangled α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), is involved in a highly coordinated hydrogen-bonding network between residues from two α-helices (res. Ser641-Glu666 and res. Arg563-Glu578) and from the α-α loop itself, such as Lys566, Glu666, and Asn669. Met672 can only form a hydrogen bond with the amino group of the Lys566 side chain via its backbone carbonyl group. Nevertheless, the Lys566-Glu666 salt bridge forms intermittently. This is possible because Asn669 keeps the carboxylate group of Glu666 in the vicinity through hydrogen bonding, and the hydrophobic side chain of Met stays mostly rotated away from the salt bridge. Consequently, no drastic disruption of the hydrogen-bond network that keeps the loop close to the helices occurs in the variant simulations. | ||||||||
| c.2147G>A | R716Q 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R716Q is listed in ClinVar with an uncertain significance (ClinVar ID 411585.0) and is present in gnomAD (ID 6‑33441612‑G‑A). Functional prediction tools that report a benign effect include REVEL, FoldX, Rosetta, Foldetta, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b, while premPS is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the balance of evidence leans toward a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Conflicting | 2 | 6-33441612-G-A | 4 | 2.48e-6 | -8.338 | Likely Pathogenic | 0.308 | Likely Benign | Likely Benign | 0.210 | Likely Benign | -0.01 | Likely Benign | 0.0 | 0.47 | Likely Benign | 0.23 | Likely Benign | 0.58 | Ambiguous | -3.14 | Deleterious | 1.000 | Probably Damaging | 0.990 | Probably Damaging | 3.35 | Benign | 0.02 | Affected | 3.50 | 9 | 1 | 1 | 1.0 | -28.06 | 250.0 | 48.9 | 0.0 | 0.0 | -0.5 | 0.0 | X | Uncertain | The guanidinium group of Arg716, located on the outer surface of an α-helix (res. Leu714-Arg726), forms a salt bridge with the carboxylate group of Asp720. In the variant simulations, the carboxamide group of Gln716 also forms a hydrogen bond with the carboxylate group of Asp720, although this bond is weaker than the Arg716 salt bridge in the WT. Overall, no adverse effects on the protein structure are observed in the simulations. However, because the model ends abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations. | |||||||||
| c.2195G>A | R732K 2D  AIThe SynGAP1 missense variant R732K is listed in ClinVar (ID 537019.0) with an “Uncertain” clinical significance and is present in gnomAD (6‑33441660‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; no Foldetta stability result is available. Overall, the majority of evidence points to a benign impact, and this consensus does not conflict with the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | 6-33441660-G-A | 4 | 2.48e-6 | -5.278 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.82 | Neutral | 0.973 | Probably Damaging | 0.943 | Probably Damaging | 2.69 | Benign | 0.21 | Tolerated | 3.59 | 7 | 3 | 2 | 0.6 | -28.01 | |||||||||||||||||||||||||||
| c.2206C>T | R736C 2D AISynGAP1 missense variant R736C is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33441671‑C‑T). Functional prediction tools cluster into two groups: benign predictions from REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM, while ESM1b remains uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized scores benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also returns 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, which does not conflict with the ClinVar uncertain designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Conflicting | 3 | 6-33441671-C-T | 8 | 4.96e-6 | -7.113 | In-Between | 0.120 | Likely Benign | Likely Benign | 0.190 | Likely Benign | -2.06 | Neutral | 0.999 | Probably Damaging | 0.825 | Possibly Damaging | 2.48 | Pathogenic | 0.00 | Affected | 4.07 | 3 | -4 | -3 | 7.0 | -53.05 | ||||||||||||||||||||||||||||
| c.2243T>G | L748R 2D  AIThe SynGAP1 missense variant L748R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33441708‑T‑G). 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 the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: 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. Overall, the majority of evidence points to 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 | Conflicting | 2 | 6-33441708-T-G | 3 | 1.86e-6 | -3.331 | Likely Benign | 0.245 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.67 | Neutral | 0.912 | Possibly Damaging | 0.448 | Possibly Damaging | 2.73 | Benign | 0.02 | Affected | 4.32 | 2 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||
| c.2324G>A | R775Q 2D AIThe SynGAP1 missense variant R775Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33442482‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (derived from the same set of high‑confidence predictors) is “Likely Benign.” No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, 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 | Conflicting | 3 | 6-33442482-G-A | 11 | 1.41e-5 | -4.476 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -0.63 | Neutral | 0.969 | Probably Damaging | 0.863 | Possibly Damaging | 4.17 | Benign | 0.16 | Tolerated | 3.64 | 6 | 1 | 1 | 1.0 | -28.06 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||
| c.2369C>A | T790N 2D  AIThe SynGAP1 missense variant T790N is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33442921‑C‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and 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 and therefore unavailable, and Foldetta results are not reported. Overall, the majority of conventional tools (5 pathogenic vs. 4 benign) lean toward a pathogenic interpretation, while the single high‑accuracy tool suggests benign. The variant’s ClinVar status remains uncertain, so there is no contradiction with the current clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | Conflicting | 3 | 6-33442921-C-A | 69 | 4.28e-5 | -5.243 | Likely Benign | 0.276 | Likely Benign | Likely Benign | 0.103 | Likely Benign | -2.54 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.27 | Pathogenic | 0.02 | Affected | 3.64 | 6 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||
| c.2596G>A | V866I 2D  AIThe SynGAP1 missense variant V866I is listed in ClinVar with an “Uncertain” status (ClinVar ID 536995.0) and is present in gnomAD (6‑33443148‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 3 | 6-33443148-G-A | 5 | 3.10e-6 | -4.652 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 0.059 | Likely Benign | -0.39 | Neutral | 0.957 | Probably Damaging | 0.541 | Possibly Damaging | 2.69 | Benign | 0.27 | Tolerated | 3.82 | 4 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||
| c.2699C>T | T900M 2D AIThe SynGAP1 missense variant T900M is listed in ClinVar (ID 1063691.0) with an “Uncertain” clinical significance and is present in the gnomAD database (gnomAD ID 6‑33443251‑C‑T). Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign effects. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, which does not contradict the ClinVar “Uncertain” status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | 6-33443251-C-T | 14 | 8.68e-6 | -3.852 | Likely Benign | 0.176 | Likely Benign | Likely Benign | 0.015 | Likely Benign | -0.81 | Neutral | 0.060 | Benign | 0.016 | Benign | 2.79 | Benign | 0.08 | Tolerated | 4.32 | 4 | -1 | -1 | 2.6 | 30.09 | |||||||||||||||||||||||||||
| c.2713C>T | R905C 2D AIThe SynGAP1 missense variant R905C (ClinVar ID 469152.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33443265‑C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of standard predictors indicate a pathogenic impact, whereas the high‑accuracy AlphaMissense‑Optimized tool suggests a benign effect. Consequently, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict the ClinVar status of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Conflicting | 2 | 6-33443265-C-T | 15 | 9.31e-6 | -5.578 | Likely Benign | 0.723 | Likely Pathogenic | Likely Benign | 0.194 | Likely Benign | -3.14 | Deleterious | 1.000 | Probably Damaging | 0.980 | Probably Damaging | 2.57 | Benign | 0.01 | Affected | 3.77 | 5 | -4 | -3 | 7.0 | -53.05 | ||||||||||||||||||||||||||||
| c.2724G>C | Q908H 2D  AIThe SynGAP1 missense variant Q908H is listed in ClinVar (ID 436926.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443276‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This consensus does not contradict the ClinVar “Uncertain” classification, which remains inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 4 | 6-33443276-G-C | 1 | 6.20e-7 | -4.658 | Likely Benign | 0.311 | Likely Benign | Likely Benign | 0.112 | Likely Benign | -0.74 | Neutral | 0.996 | Probably Damaging | 0.995 | Probably Damaging | 2.58 | Benign | 0.05 | Affected | 3.77 | 5 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||
| 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 | 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 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||
| c.2854G>A | G952S 2D  AIThe SynGAP1 missense variant G952S is listed in ClinVar (ID 1325573.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33443406‑G‑A). 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 scores. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, 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 classification, which is consistent with the ClinVar “Uncertain” status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | 6-33443406-G-A | 2 | 1.24e-6 | -6.190 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.167 | Likely Benign | 0.19 | Neutral | 0.000 | Benign | 0.002 | Benign | 3.31 | Benign | 0.07 | Tolerated | 3.77 | 5 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||
| c.2864C>T | S955F 2D  AISynGAP1 missense variant S955F is listed in ClinVar as uncertain and is present in gnomAD (ID 6‑33443416‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM; ESM1b is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also returns benign, and Foldetta results are unavailable. Overall, the majority of high‑confidence predictions favor a benign impact, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Conflicting | 4 | 6-33443416-C-T | 95 | 5.89e-5 | -7.374 | In-Between | 0.176 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -1.73 | Neutral | 0.977 | Probably Damaging | 0.721 | Possibly Damaging | 2.32 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||
| c.2881C>T | H961Y 2D  AIThe SynGAP1 missense variant H961Y is listed in ClinVar with an uncertain significance (ClinVar ID 862637.0) and is present in gnomAD (ID 6‑33443433‑C‑T). 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 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 not in conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | 6-33443433-C-T | 3 | 1.86e-6 | -8.051 | Likely Pathogenic | 0.157 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -1.07 | Neutral | 0.716 | Possibly Damaging | 0.147 | Benign | 4.10 | Benign | 0.55 | Tolerated | 3.77 | 5 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||
| c.2971G>A | G991R 2D  AIThe SynGAP1 missense variant G991R is listed in ClinVar (ID 1029090.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443523‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 3 | 6-33443523-G-A | 8 | 4.96e-6 | -3.934 | Likely Benign | 0.411 | Ambiguous | Likely Benign | 0.102 | Likely Benign | -1.20 | Neutral | 0.984 | Probably Damaging | 0.772 | Possibly Damaging | 4.11 | Benign | 0.01 | Affected | 4.32 | 2 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||
| c.3055C>T | R1019C 2D AIThe SynGAP1 missense variant R1019C is listed in ClinVar with an “Uncertain” status (ClinVar ID 1676922.0) and is present in gnomAD (ID 6‑33443607‑C‑T). Prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact; ESM1b remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote) remains pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Conflicting | 2 | 6-33443607-C-T | 10 | 6.19e-6 | -7.386 | In-Between | 0.646 | Likely Pathogenic | Likely Benign | 0.168 | Likely Benign | -4.00 | Deleterious | 0.999 | Probably Damaging | 0.880 | Possibly Damaging | 2.36 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -4 | -3 | 7.0 | -53.05 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||
| c.3056G>A | R1019H 2D AIThe SynGAP1 missense variant R1019H is listed in ClinVar (ID 1195115.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443608‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote) also benign; Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact for R1019H, and this conclusion does not contradict the current ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | 6-33443608-G-A | 67 | 4.15e-5 | -4.610 | Likely Benign | 0.258 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -1.95 | Neutral | 0.995 | Probably Damaging | 0.845 | Possibly Damaging | 2.39 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 2 | 0 | 1.3 | -19.05 | |||||||||||||||||||||||||||
| c.3121C>T | P1041S 2D  AIThe SynGAP1 missense variant P1041S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443673‑C‑T). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv. 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 (majority vote) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | 6-33443673-C-T | 1 | 6.20e-7 | -4.246 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.344 | Likely Benign | -2.72 | Deleterious | 0.664 | Possibly Damaging | 0.283 | Benign | 5.48 | Benign | 0.11 | Tolerated | 3.77 | 5 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||
| 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 | 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 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||
| c.3181G>T | G1061C 2D  AIThe SynGAP1 missense variant G1061C is listed in ClinVar (ID 536997.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33443733‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, 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 (six benign vs. four pathogenic predictions) and the two high‑accuracy tools support a benign classification. This conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | 6-33443733-G-T | 6 | 3.73e-6 | -9.511 | Likely Pathogenic | 0.119 | Likely Benign | Likely Benign | 0.409 | Likely Benign | -1.46 | Neutral | 0.938 | Possibly Damaging | 0.665 | Possibly Damaging | 3.97 | Benign | 0.00 | Affected | 4.32 | 2 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||
| c.3184G>A | G1062R 2D AIThe SynGAP1 missense variant G1062R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443736‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, polyPhen‑2 HumVar, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | 6-33443736-G-A | 7 | 4.35e-6 | -6.933 | Likely Benign | 0.353 | Ambiguous | Likely Benign | 0.403 | Likely Benign | -0.34 | Neutral | 0.797 | Possibly Damaging | 0.139 | Benign | 4.10 | Benign | 0.01 | Affected | 4.32 | 2 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||
| c.3209G>A | R1070K 2D AIThe SynGAP1 missense variant R1070K is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All evaluated in‑silico predictors agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” High‑accuracy tools reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta results are unavailable. Based on the unanimous benign predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | -5.093 | Likely Benign | 0.326 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -1.42 | Neutral | 0.049 | Benign | 0.048 | Benign | 3.86 | Benign | 0.09 | Tolerated | 3.77 | 5 | 3 | 2 | 0.6 | -28.01 | ||||||||||||||||||||||||||||||
| c.3238G>A | A1080T 2D AIThe SynGAP1 missense variant A1080T (ClinVar ID 1473274.0) is listed as “Uncertain” in ClinVar and is present in gnomAD (ID 6‑33443790‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence strongly suggests the variant is most likely benign, which does not contradict the current ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | 6-33443790-G-A | 17 | 1.06e-5 | -3.928 | Likely Benign | 0.133 | Likely Benign | Likely Benign | 0.144 | Likely Benign | -0.19 | Neutral | 0.253 | Benign | 0.042 | Benign | 4.10 | Benign | 0.60 | Tolerated | 3.77 | 5 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||
| c.3293G>A | S1098N 2D  AIThe SynGAP1 missense variant S1098N is listed in ClinVar (ID 864704.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33443845‑G‑A). 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 scores. No tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, 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 classification, which is consistent with the ClinVar “Uncertain” status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | 6-33443845-G-A | 6 | 3.89e-6 | -5.120 | Likely Benign | 0.156 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -0.58 | Neutral | 0.369 | Benign | 0.120 | Benign | 2.76 | Benign | 0.36 | Tolerated | 3.77 | 5 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||
| c.3326T>C | L1109P 2D  AIThe SynGAP1 missense variant L1109P is listed in ClinVar with an uncertain significance (ClinVar ID 1730257.0) and is not reported in gnomAD. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized indicates a benign effect, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign classification, which does not contradict the ClinVar uncertain status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | -5.313 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.151 | Likely Benign | -0.52 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.65 | Benign | 0.07 | Tolerated | 4.32 | 2 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||
| 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. | 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 | -3 | -2 | -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 | 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 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||||
| 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 | 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 | 1 | 0 | 2.2 | 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 | 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 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||
| 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 | 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 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||
| 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 | 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 | -3 | -2 | 4.6 | 26.08 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||
| c.3635C>T | S1212F 2D AIThe SynGAP1 missense variant S1212F is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) score—predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely pathogenic. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence from multiple independent predictors indicates that the variant is most likely pathogenic, which is consistent with its ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | Conflicting | 2 | -14.445 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.271 | Likely Benign | -4.52 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.03 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.3638A>C | N1213T 2D  AIThe SynGAP1 missense variant N1213T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33446630‑A‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic 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 benignity: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | Conflicting | 2 | 6-33446630-A-C | 46 | 2.85e-5 | -5.428 | Likely Benign | 0.266 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -1.08 | Neutral | 0.959 | Probably Damaging | 0.721 | Possibly Damaging | 2.74 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0 | 0 | 2.8 | -13.00 | ||||||||||||||||||||||||||
| c.3661C>T | R1221W 2D AIThe SynGAP1 missense variant R1221W is listed in ClinVar with an uncertain significance (ClinVar ID 1050818.0) and is present in the gnomAD database (gnomAD ID 6‑33446653‑C‑T). Functional prediction tools show a split assessment: benign predictions come from REVEL and FATHMM, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy analyses further refine the picture: AlphaMissense‑Optimized classifies the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—deems it likely pathogenic. No Foldetta stability assessment is available for this residue. Overall, the majority of computational evidence points toward a pathogenic effect, which is consistent with the ClinVar designation of uncertain significance rather than a definitive benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | Conflicting | 3 | 6-33446653-C-T | 1 | 6.20e-7 | -10.938 | Likely Pathogenic | 0.651 | Likely Pathogenic | Likely Benign | 0.174 | Likely Benign | -4.57 | Deleterious | 1.000 | Probably Damaging | 0.987 | Probably Damaging | 2.50 | Benign | 0.01 | Affected | 3.77 | 5 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||
| c.3662G>A | R1221Q 2D AIThe SynGAP1 missense variant R1221Q is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33446654‑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 indicates a pathogenic effect. 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 this: AlphaMissense‑Optimized predicts benign, SGM Consensus is likely benign, while Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, which is consistent with the ClinVar “Uncertain” classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | Conflicting | 2 | 6-33446654-G-A | 4 | 2.48e-6 | -5.491 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.46 | Neutral | 0.836 | Possibly Damaging | 0.153 | Benign | 2.56 | Benign | 0.12 | Tolerated | 3.77 | 5 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||
| c.371C>T | A124V 2D  AIThe SynGAP1 A124V missense variant is listed in ClinVar (ID 1040523.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33432236‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of computational evidence indicates a benign effect, and this consensus does not contradict the ClinVar “Uncertain” designation. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 2 | 6-33432236-C-T | 9 | 5.58e-6 | -4.259 | Likely Benign | 0.138 | Likely Benign | Likely Benign | 0.073 | Likely Benign | -1.52 | Neutral | 0.173 | Benign | 0.009 | Benign | 4.07 | Benign | 0.03 | Affected | 3.61 | 5 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||
| 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 | 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 | 3 | 2 | 0.0 | -14.03 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||
| 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 | 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 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
| 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 | 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 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||
| c.3913A>G | T1305A 2D  AIThe SynGAP1 missense variant T1305A is listed in ClinVar (ID 411587.0) with an “Uncertain” clinical significance and is present in the gnomAD database (variant ID 6‑33451787‑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 reports a pathogenic or likely pathogenic outcome. 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. Overall, the computational evidence overwhelmingly supports a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 4 | 6-33451787-A-G | 30 | 1.86e-5 | -2.692 | Likely Benign | 0.055 | Likely Benign | Likely Benign | 0.069 | Likely Benign | 1.74 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.24 | Benign | 1.00 | Tolerated | 3.77 | 5 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||
| c.3922C>T | R1308C 2D AIThe SynGAP1 missense variant R1308C is listed in ClinVar with an “Uncertain” significance and is present in the gnomAD database (ID 6‑33451796‑C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact, and this assessment does not contradict the current ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Conflicting | 2 | 6-33451796-C-T | 4 | 2.48e-6 | -4.994 | Likely Benign | 0.421 | Ambiguous | Likely Benign | 0.352 | Likely Benign | -4.89 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 2.31 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -4 | -3 | 7.0 | -53.05 | ||||||||||||||||||||||||||||
| c.3949G>A | G1317S 2D AIThe SynGAP1 missense variant G1317S is listed in ClinVar with an uncertain significance and is present in the gnomAD database. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized returns a benign prediction, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the computational evidence overwhelmingly points to a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 3 | 6-33451823-G-A | 1 | 6.26e-7 | -3.522 | Likely Benign | 0.145 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -2.45 | Neutral | 0.127 | Benign | 0.045 | Benign | 4.08 | Benign | 0.00 | Affected | 3.77 | 5 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||
| c.3G>A | M1I 2D  AIThe SynGAP1 missense variant M1I is listed in ClinVar (ID 833646.0) with an uncertain significance annotation and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM all classify the substitution as benign, while SIFT uniquely predicts it to be pathogenic. The consensus score from the SGM framework, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy predictors are incomplete: AlphaMissense‑Optimized and the Foldetta stability assessment are unavailable for this variant. Taking the collective evidence into account, the variant is most likely benign, 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 | Conflicting | 3 | -5.397 | Likely Benign | 0.227 | Likely Benign | -0.17 | Neutral | 0.001 | Benign | 0.000 | Benign | 4.25 | Benign | 0.00 | Affected | 4.32 | 1 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||
| c.4003G>A | G1335S 2D AIThe SynGAP1 missense variant G1335S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33451877‑G‑A). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence indicates that G1335S is most likely pathogenic, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Conflicting | 2 | 6-33451877-G-A | 3 | 2.37e-6 | -4.495 | Likely Benign | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.362 | Likely Benign | -3.79 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.04 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||
| c.4013G>A | R1338Q 2D AIThe SynGAP1 missense variant R1338Q is listed in ClinVar (ID 450879.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451887‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which reports it as “Likely Benign.” In contrast, polyPhen‑2 HumDiv and SIFT predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; a Foldetta stability analysis is not available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 3 | 6-33451887-G-A | 12 | 8.40e-6 | -3.494 | Likely Benign | 0.317 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -1.87 | Neutral | 0.896 | Possibly Damaging | 0.194 | Benign | 3.81 | Benign | 0.02 | Affected | 3.77 | 5 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||
| c.4021G>A | A1341T 2D AIThe SynGAP1 missense variant A1341T is listed in ClinVar (ID 837815.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451895‑G‑A). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or likely 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 assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for A1341T, 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 | Conflicting | 3 | 6-33451895-G-A | 45 | 3.44e-5 | -3.224 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.099 | Likely Benign | -0.58 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.09 | Benign | 0.03 | Affected | 3.77 | 5 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||
| c.458C>A | T153N 2D AIThe SynGAP1 missense variant T153N is listed in ClinVar (ID 984906.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) predict pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence supports a benign classification, and this is consistent with the ClinVar “Uncertain” designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Conflicting | 3 | -0.739 | Likely Benign | 0.226 | Likely Benign | Likely Benign | 0.161 | Likely Benign | 0.88 | Neutral | 0.888 | Possibly Damaging | 0.537 | Possibly Damaging | 4.23 | Benign | 0.81 | Tolerated | 3.61 | 5 | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||||||||||
| c.603T>G | D201E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D201E missense variant (gnomAD ID 6‑33435245‑T‑G) is listed in ClinVar with an uncertain significance. Across a broad panel of in silico predictors, the majority indicate a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all score benign. Only polyPhen‑2 HumDiv predicts pathogenicity, while Rosetta, Foldetta, and AlphaMissense‑Default remain inconclusive. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to “likely benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta is inconclusive. Taken together, the preponderance of evidence points to a benign impact, which does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | Conflicting | 2 | 6-33435245-T-G | 20 | 1.24e-5 | -2.640 | Likely Benign | 0.406 | Ambiguous | Likely Benign | 0.165 | Likely Benign | 0.42 | Likely Benign | 0.2 | 1.99 | Ambiguous | 1.21 | Ambiguous | 0.23 | Likely Benign | -0.69 | Neutral | 0.633 | Possibly Damaging | 0.108 | Benign | 4.30 | Benign | 1.00 | Tolerated | 3.46 | 9 | 3 | 2 | 0.0 | 14.03 | 258.7 | -24.8 | 0.9 | 0.1 | -0.3 | 0.2 | X | Uncertain | Asp201, an acidic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another acidic residue, glutamate. The carboxylate groups of both Asp201 and Glu201 side chains form hydrogen bonds with the hydroxyl group of Ser221 in the simulations. Due to its shorter side chain, Asp201 can also hydrogen bond with the backbone amide groups of neighboring loop residues Ser204 and Asp203. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||
| c.667A>T | T223S 2D  3DClick to see structure in 3D Viewer AISynGAP1 T223S is listed in ClinVar as a variant of uncertain significance and is present in the gnomAD database (ID 6‑33435518‑A‑T). Functional prediction tools that reach consensus classify the variant as benign: FoldX, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict pathogenicity include REVEL, PROVEAN, and SIFT. Predictions that are inconclusive or uncertain are Rosetta, premPS, AlphaMissense‑Default, and ESM1b. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, Foldetta is benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 1‑to‑1 split between benign and pathogenic calls. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | Conflicting | 2 | 6-33435518-A-T | 3 | 1.86e-6 | -7.714 | In-Between | 0.410 | Ambiguous | Likely Benign | 0.535 | Likely Pathogenic | 0.26 | Likely Benign | 0.1 | 0.50 | Ambiguous | 0.38 | Likely Benign | 0.62 | Ambiguous | -2.86 | Deleterious | 0.421 | Benign | 0.058 | Benign | 5.80 | Benign | 0.02 | Affected | 3.41 | 13 | 1 | 1 | -0.1 | -14.03 | 200.7 | 17.3 | -0.2 | 0.2 | 0.0 | 0.0 | X | Uncertain | The introduced residue Ser223 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Its hydroxyl group forms hydrogen bonds with nearby residues Thr228 and Lys207 in the variant simulations, similar to the hydroxyl group of Thr223 in the WT simulations. These hydrogen-bonding interactions at the β sheet surface contribute to the stability of the secondary structure element and may prevent it from unfolding. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||
| c.680G>A | G227E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G227E is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6-33435531-G-A). Functional prediction tools largely agree on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all report pathogenicity, while only polyPhen‑2 (HumVar) and FATHMM predict a benign outcome; premPS remains inconclusive. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Taken together, the overwhelming majority of evidence points to a pathogenic effect. This conclusion is consistent with the ClinVar “Uncertain” classification, which does not contradict the predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | Conflicting | 2 | 6-33435531-G-A | 3 | 1.86e-6 | -9.186 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.792 | Likely Pathogenic | 2.56 | Destabilizing | 0.4 | 5.36 | Destabilizing | 3.96 | Destabilizing | 0.94 | Ambiguous | -6.49 | Deleterious | 0.906 | Possibly Damaging | 0.360 | Benign | 5.72 | Benign | 0.01 | Affected | 3.43 | 12 | 0 | -2 | -3.1 | 72.06 | 237.7 | -112.1 | 0.1 | 0.3 | 0.0 | 0.3 | X | X | Uncertain | The introduced residue Glu227 is located in a β hairpin loop connecting two anti-parallel β sheet strands (res. Cys219-Thr224 and Thr228-Ala232). In the variant simulations, the carboxylate group of Glu227 frequently forms a salt bridge with the amino group of the neighboring residue Lys229. Despite this interaction, the integrity of the secondary structure element is not compromised. However, the β hairpins are potential nucleation sites during the initial stages of protein folding. Additionally, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||
| c.895C>T | R299C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R299C is listed in ClinVar with an uncertain significance (ClinVar ID 1335623.0) and is present in gnomAD (ID 6‑33437800‑C‑T). Prediction tools that classify the variant as benign include REVEL, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict pathogenicity 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, reports the variant as likely pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Other stability predictors (FoldX, Rosetta, premPS) are also uncertain. Overall, the balance of evidence favors a pathogenic interpretation, which does not contradict the ClinVar uncertain status but suggests a higher likelihood of disease relevance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Conflicting | 2 | 6-33437800-C-T | 3 | 1.86e-6 | -6.326 | Likely Benign | 0.572 | Likely Pathogenic | Likely Benign | 0.344 | Likely Benign | 1.85 | Ambiguous | 0.4 | 0.61 | Ambiguous | 1.23 | Ambiguous | 0.76 | Ambiguous | -3.54 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.65 | Pathogenic | 0.06 | Tolerated | 3.39 | 19 | -4 | -3 | 7.0 | -53.05 | 210.7 | 91.3 | 0.1 | 0.0 | 0.0 | 0.2 | X | X | Potentially Pathogenic | The guanidinium group of Arg299, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), forms hydrogen bonds that stabilize the tight turn. In the WT simulations, the Arg299 side chain hydrogen bonds with the loop backbone carbonyl groups (e.g., Ser302, Thr305, Leu274, Gly303), the hydroxyl group of Ser300, and even forms a salt bridge with the carboxylate group of Asp304.In the variant simulations, the thiol group of the Cys299 side chain is unable to form any of these well-coordinated or strong interactions, which could affect the initial formation of the secondary hairpin loop during folding. β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Moreover, the positively charged Arg299 side chain faces the polar head group region of the inner leaflet membrane and could directly anchor the C2 domain to the membrane. In short, the residue swap could negatively affect both protein folding and the stability of the SynGAP-membrane association. | |||||||
| c.896G>A | R299H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R299H is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33437801‑G‑A). Functional prediction tools cluster into two groups: benign predictions from REVEL and AlphaMissense‑Optimized, and pathogenic predictions from FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; Rosetta, ESM1b, and AlphaMissense‑Default are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a tie between pathogenic and uncertain calls. Overall, the majority of evidence points to a pathogenic effect, which is consistent with the ClinVar uncertain designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | Conflicting | 2 | 6-33437801-G-A | 10 | 6.20e-6 | -7.731 | In-Between | 0.388 | Ambiguous | Likely Benign | 0.238 | Likely Benign | 3.97 | Destabilizing | 1.0 | 0.94 | Ambiguous | 2.46 | Destabilizing | 1.41 | Destabilizing | -3.35 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.69 | Pathogenic | 0.02 | Affected | 3.39 | 19 | 2 | 0 | 1.3 | -19.05 | 211.2 | 72.5 | -0.1 | 0.2 | -0.2 | 0.3 | X | Potentially Pathogenic | The guanidinium group of Arg299, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), forms hydrogen bonds that stabilize the tight turn. In the WT simulations, the Arg299 side chain hydrogen bonds with the loop backbone carbonyl groups (e.g., Ser302, Thr305, Leu274, Gly303), the hydroxyl group of Ser300, and even forms a salt bridge with the carboxylate group of Asp304.In the variant simulations, the imidazole ring of His299 (epsilon protonated state) hydrogen bonds with the carbonyl group of Asp304 and the hydroxyl group of Ser300. However, it does not form as many or as strong interactions as arginine, which could affect the initial formation of the secondary hairpin loop during folding. β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant.Additionally, His299 prefers to hydrophobically interact with other hydrophobic residues inside the C2 domain core (e.g., Val306, Leu274), which destabilizes the C2 domain. Indeed, the β strand partially unfolds during the second simulation. Moreover, the positively charged Arg299 side chain faces the polar head group region of the inner leaflet membrane and could directly anchor the C2 domain to the membrane. In short, the residue swap could negatively affect both protein folding and the stability of the SynGAP-membrane association. | |||||||||
| c.913A>G | T305A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T305A variant is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33437818‑A‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those 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, reports a “Likely Benign” outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | Conflicting | 2 | 6-33437818-A-G | 13 | 8.05e-6 | -4.307 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.144 | Likely Benign | 1.30 | Ambiguous | 0.6 | 1.55 | Ambiguous | 1.43 | Ambiguous | 0.77 | Ambiguous | -2.10 | Neutral | 0.939 | Possibly Damaging | 0.645 | Possibly Damaging | 1.76 | Pathogenic | 0.12 | Tolerated | 3.40 | 20 | 1 | 0 | 2.5 | -30.03 | 177.9 | 43.5 | -0.2 | 0.1 | 0.4 | 0.0 | Uncertain | The hydroxyl group of Thr305, located at the beginning of an anti-parallel β strand (res. Thr305-Asn315), hydrogen bonds with the carboxylate groups of Glu270 and Asp304 in the anti-parallel β strand and the adjacent β hairpin loop, respectively. In the variant simulations, the methyl group of the Ala305 side chain cannot hydrogen bond with either of the acidic residues, which could weaken the integrity of the tertiary structure and the β hairpin loop. Indeed, the guanidinium group of Arg299 does not acquire its central hairpin loop position due to the residue swap.β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Due to its location near the membrane surface, the residue swap could also affect the C2 loop dynamics and SynGAP-membrane association. However, this is beyond the scope of the solvent-only simulations to unravel. | |||||||||
| c.928G>A | E310K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E310K is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all return a deleterious signal: REVEL, FoldX (uncertain), Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenic or likely pathogenic. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Consequently, the variant is most likely pathogenic based on the available predictions, 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 Pathogenic | C2 | Conflicting | 4 | -14.601 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.764 | Likely Pathogenic | 1.97 | Ambiguous | 1.2 | 3.66 | Destabilizing | 2.82 | Destabilizing | 1.02 | Destabilizing | -3.68 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 1.19 | Pathogenic | 0.01 | Affected | 3.38 | 19 | 0 | 1 | -0.4 | -0.94 | 213.4 | 58.0 | 0.1 | 0.0 | 0.2 | 0.1 | X | Potentially Pathogenic | The carboxylate group of Glu310, located in an anti-parallel β sheet strand (res. Thr305-Asn315), is ideally positioned to interact with the side chain hydroxyl and backbone amide groups of Thr295 on a twisted anti-parallel β strand (res. Met289-Arg299). Because the carboxylate group can also interact with the GAP domain residues (e.g., Gln612, Tyr614), Glu310 plays a key role in maintaining the tertiary assembly between the C2 and GAP domains. In the variant simulations, the amino group of the Lys310 side chain hydrogen bonds with the GAP domain residues and forms a salt bridge with Glu613. Although no apparent negative effects are seen due to the residue swap, it is possible that the loss of hydrogen bonding with the hydroxyl group of the Thr295 side chain causes problems during folding, potentially compromising the twisting of the β sheet. | |||||||||||
| c.961C>T | R321C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321C is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33437866‑C‑T). Prediction tools that agree on a benign effect include REVEL, premPS, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Five tools (SGM‑Consensus, FoldX, Rosetta, AlphaMissense‑Default, and Foldetta) report uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions (six out of eleven) support a pathogenic impact, while three support benign and five are inconclusive. Thus, the variant is most likely pathogenic based on current computational evidence, and this does not contradict its ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Conflicting | 2 | 6-33437866-C-T | 9 | 5.58e-6 | -10.025 | Likely Pathogenic | 0.387 | Ambiguous | Likely Benign | 0.495 | Likely Benign | 0.57 | Ambiguous | 0.1 | 0.56 | Ambiguous | 0.57 | Ambiguous | 0.18 | Likely Benign | -4.59 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.89 | Pathogenic | 0.01 | Affected | 3.38 | 23 | -3 | -4 | 7.0 | -53.05 | |||||||||||||||||
| c.1003C>T | R335C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R335C is listed in ClinVar with an uncertain significance (ClinVar ID 2835865.0) and is present in gnomAD (ID 6‑33437908‑C‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL and premPS, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive are AlphaMissense‑Optimized, FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. This conclusion aligns with the ClinVar designation of uncertain significance, which does not contradict the prediction that the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Uncertain | 1 | 6-33437908-C-T | 1 | 6.20e-7 | -14.354 | Likely Pathogenic | 0.938 | Likely Pathogenic | Ambiguous | 0.277 | Likely Benign | 0.53 | Ambiguous | 0.1 | 0.85 | Ambiguous | 0.69 | Ambiguous | 0.46 | Likely Benign | -5.69 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.67 | Pathogenic | 0.01 | Affected | 3.38 | 22 | -3 | -4 | 7.0 | -53.05 | |||||||||||||||||
| c.1004G>A | R335H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R335H is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6-33437909‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and Foldetta, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by FoldX, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as pathogenic, whereas Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the preponderance 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. | Likely Pathogenic | C2 | Uncertain | 1 | 6-33437909-G-A | 2 | 1.24e-6 | -12.521 | Likely Pathogenic | 0.831 | Likely Pathogenic | Ambiguous | 0.132 | Likely Benign | 0.58 | Ambiguous | 0.1 | 0.22 | Likely Benign | 0.40 | Likely Benign | 0.72 | Ambiguous | -3.02 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.70 | Pathogenic | 0.03 | Affected | 3.38 | 22 | 2 | 0 | 1.3 | -19.05 | 242.4 | 82.1 | -2.4 | 0.6 | -0.1 | 0.1 | Uncertain | The guanidinium group of Arg335, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Ala322-Asp330, res. Gly341-Pro349), faces the post-synaptic inner membrane surface. In the WT simulations, the Arg335 side chain dynamically forms salt bridges with the carboxylate groups of Asp322, Asp338, and Asp616. In contrast, the imidazole ring of His335, which is not double protonated and thus not positively charged in the variant simulations, continues to move dynamically without forming any lasting or strong interactions. Importantly, the positively charged arginine residues of the C2 domain are ideal membrane anchors for ensuring SynGAP-membrane association. However, this phenomenon cannot be addressed using solvent-only simulations. | |||||||||
| c.1025A>C | Y342S 2D  3DClick to see structure in 3D Viewer AISynGAP1 variant Y342S is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the majority of algorithms predict a pathogenic impact: FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and the Foldetta stability assessment (combining FoldX‑MD and Rosetta). Uncertain results come from premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy methods specifically give AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta as pathogenic. Overall, the preponderance of evidence points to a pathogenic effect, which contradicts the ClinVar uncertain classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Uncertain | 2 | -7.996 | In-Between | 0.925 | Likely Pathogenic | Ambiguous | 0.407 | Likely Benign | 3.03 | Destabilizing | 0.1 | 2.87 | Destabilizing | 2.95 | Destabilizing | 0.93 | Ambiguous | -6.60 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.75 | Pathogenic | 0.04 | Affected | 3.37 | 25 | -3 | -2 | 0.5 | -76.10 | 200.1 | 77.8 | 0.0 | 0.0 | -0.2 | 0.1 | Potentially Pathogenic | The phenol ring of Tyr342, located at the end of an anti-parallel β sheet strand (res. Gly341-Pro349), faces outward in the C2 domain. In the WT simulations, the phenol ring of Tyr342 contributes to a triple tyrosine stack (Tyr342, Tyr328, and Tyr281) that links together three anti-parallel β sheet strands. Additionally, it shields Gly344 from the solvent, reducing its exposure and providing stability for the β-sandwich. This motif also contributes to a twist formation in the β sheet.In the variant simulations, the Ser342 side chain cannot participate in the stack formation. Instead, the hydroxyl group of the Ser342 side chain forms a hydrogen bond with the imidazole ring of His326 in a neighboring β strand (res. Ala322-Asp330). This disrupts the formation of a hydrogen bond between His326 and the carboxylate group of the Glu283 side chain from another β strand (res. Arg279-Cys285). Although these changes in surface interactions could weaken the characteristic twist that strengthens the β sheet fold, no major structural effects are observed in the variant simulations. The residue swap could also affect the SynGAP-membrane association, as the hydroxyl group of Ser342 could form hydrogen bonds with membrane-facing loop residues. However, this phenomenon cannot be addressed using solvent-only simulations. | ||||||||||||
| c.1027G>A | V343I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V343I is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33437932‑G‑A). Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to “Likely Benign” (3 benign vs. 1 pathogenic). High‑accuracy assessments are consistent: AlphaMissense‑Optimized is benign; the SGM‑Consensus is likely benign; and Foldetta, combining FoldX‑MD and Rosetta outputs, is benign. Overall, the collective evidence strongly supports a benign classification, and this does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | Uncertain | 2 | 6-33437932-G-A | 1 | 6.20e-7 | -6.020 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.020 | Likely Benign | -0.27 | Likely Benign | 0.0 | -0.04 | Likely Benign | -0.16 | Likely Benign | -0.39 | Likely Benign | -0.14 | Neutral | 0.159 | Benign | 0.084 | Benign | 1.98 | Pathogenic | 0.27 | Tolerated | 3.37 | 25 | 4 | 3 | 0.3 | 14.03 | 240.2 | -26.9 | -0.2 | 0.2 | -0.2 | 0.2 | X | Potentially Benign | The iso-propyl side chain of Val343, located in an anti-parallel β sheet strand (res. Gly341-Pro349), is packing against multiple hydrophobic residues of the C2 domain (e.g., Leu327, Leu274, Val365). In the variant simulations, the sec-butyl side chain of Ile343 is basically able to form the same interactions as valine due to its similar hydrophobic profile. The residue swap also does not seem to cause negative effects on the protein structure based on the simulations. | ||||||||
| c.103G>A | V35I 2D AIThe SynGAP1 missense variant V35I is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33423512‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a benign outcome. No Foldetta stability data are available. 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 | Uncertain | 1 | 6-33423512-G-A | 5 | 3.10e-6 | -3.764 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.017 | Likely Benign | -0.32 | Neutral | 0.672 | Possibly Damaging | 0.369 | Benign | 4.16 | Benign | 0.00 | Affected | 4.32 | 1 | 3 | 4 | 0.3 | 14.03 | |||||||||||||||||||||||||||
| c.1040C>A | T347N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T347N is listed in ClinVar with an uncertain significance (ClinVar ID 3672484.0) and is present in the gnomAD database (gnomAD ID 6‑33437945‑C‑A). Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to “Likely Benign” (3 benign vs. 1 pathogenic). High‑accuracy assessments are consistent: AlphaMissense‑Optimized is benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Overall, the collective evidence points to a benign effect, aligning with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | Uncertain | 1 | 6-33437945-C-A | 9 | 5.58e-6 | -5.545 | Likely Benign | 0.165 | Likely Benign | Likely Benign | 0.059 | Likely Benign | 0.41 | Likely Benign | 0.1 | 0.46 | Likely Benign | 0.44 | Likely Benign | -0.06 | Likely Benign | 1.96 | Neutral | 0.001 | Benign | 0.001 | Benign | 1.67 | Pathogenic | 0.60 | Tolerated | 3.37 | 25 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||
| c.1042G>A | V348M 2D  3DClick to see structure in 3D Viewer AISynGAP1 variant V348M is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that report a clear outcome fall into two groups: benign calls come from REVEL, Foldetta, PROVEAN, and AlphaMissense‑Optimized; pathogenic calls come from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools (FoldX, Rosetta, premPS, AlphaMissense‑Default, ESM1b) give uncertain results, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is unavailable due to no majority. High‑accuracy methods specifically show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus is not available. With four benign and four pathogenic predictions, the evidence is evenly split, providing no definitive direction. Therefore, the variant is not clearly benign or pathogenic based on current predictions, and this lack of consensus does not contradict its ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | Uncertain | 1 | -7.076 | In-Between | 0.546 | Ambiguous | Likely Benign | 0.191 | Likely Benign | -1.19 | Ambiguous | 0.1 | 0.72 | Ambiguous | -0.24 | Likely Benign | 0.76 | Ambiguous | -1.62 | Neutral | 0.966 | Probably Damaging | 0.564 | Possibly Damaging | 1.58 | Pathogenic | 0.03 | Affected | 3.37 | 25 | 2 | 1 | -2.3 | 32.06 | 253.8 | -47.4 | -0.3 | 0.1 | 0.2 | 0.1 | X | Potentially Benign | The iso-propyl side chain of Val348, located in an anti-parallel β sheet strand (res. Gly341-Pro349), packs against multiple hydrophobic C2 domain residues (e.g., Leu353, Leu323, Leu402). In the variant simulations, the thioether side chain of Met348 can form similar interactions as valine due to its comparable hydrophobic profile. In fact, the thioether group of methionine can even stack favorably with the phenol ring of Tyr363 in the anti-parallel β sheet strand (res. Ala399-Ile411). Overall, the residue swap does not appear to cause negative effects on the protein structure based on the simulations. | ||||||||||||
| c.1045C>T | P349S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P349S missense variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive or uncertain are FoldX, ESM1b, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of tools, including the high‑accuracy methods, predict a pathogenic effect. Thus, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | Uncertain | 1 | -7.654 | In-Between | 0.217 | Likely Benign | Likely Benign | 0.277 | Likely Benign | 1.92 | Ambiguous | 0.1 | 2.28 | Destabilizing | 2.10 | Destabilizing | 0.87 | Ambiguous | -6.13 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.66 | Pathogenic | 0.06 | Tolerated | 3.37 | 25 | 1 | -1 | 0.8 | -10.04 | 194.9 | -18.1 | -0.1 | 0.0 | 0.2 | 0.1 | X | X | Potentially Pathogenic | The cyclic pyrrolidine side chain of Pro349, located at the end of an anti-parallel β sheet strand (res. Gly341-Pro349), allows the strand to end and make a tight turn before a short α helical section within a loop connecting to another β strand (res. Thr359-Pro364). In the variant simulations, the hydroxyl group of Ser349 forms a hydrogen bond with the backbone amide group of Ala351 in the short helical section. Conversely, the backbone amide group of Ser349 (absent in proline) does not form any intra-protein hydrogen bonds. However, the β strand end connects to the α helical section in a more stable and consistent manner compared to the WT. Although the residue swap does not cause major adverse effects on the protein structure in the simulations, it is possible that the tight turn at the β strand end could not be created during folding without the presence of proline. | |||||||||||
| c.1058T>C | L353P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L353P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a strong bias toward pathogenicity: REVEL predicts benign, whereas FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all predict pathogenic. Two tools report uncertainty: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Overall, the majority of evidence points to a pathogenic impact, which is consistent with the ClinVar designation of uncertain significance but leans toward pathogenicity rather than benign. Thus, the variant is most likely pathogenic, and this prediction does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Uncertain | 1 | -7.913 | In-Between | 0.936 | Likely Pathogenic | Ambiguous | 0.464 | Likely Benign | 4.63 | Destabilizing | 0.1 | 10.19 | Destabilizing | 7.41 | Destabilizing | 2.17 | Destabilizing | -3.70 | Deleterious | 0.947 | Possibly Damaging | 0.454 | Possibly Damaging | 1.29 | Pathogenic | 0.02 | Affected | 3.37 | 25 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||
| c.106C>T | H36Y 2D AIThe SynGAP1 missense variant H36Y is listed in ClinVar with an uncertain significance (ClinVar ID 2089635.0) and is present in the gnomAD database (gnomAD ID 6‑33423515‑C‑T). Functional prediction tools largely agree that the substitution is benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a benign effect. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Benign. No Foldetta stability prediction is available. Overall, the computational evidence overwhelmingly supports a benign classification, which is consistent with the ClinVar designation of uncertain significance rather than a pathogenic claim. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | 6-33423515-C-T | 2 | 1.24e-6 | -3.461 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.023 | Likely Benign | -1.03 | Neutral | 0.219 | Benign | 0.066 | Benign | 4.16 | Benign | 0.00 | Affected | 4.32 | 1 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||
| c.1108G>A | G370S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G370S is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6‑33438013‑G‑A). Consensus predictions from standard in silico tools cluster into two groups: benign (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic (FoldX, FATHMM). Two tools report uncertainty: Rosetta and Foldetta. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Benign; Foldetta remains uncertain. Overall, the preponderance of evidence points to a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | Uncertain | 1 | 6-33438013-G-A | 15 | 9.31e-6 | -3.533 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.282 | Likely Benign | 2.83 | Destabilizing | 2.0 | 1.05 | Ambiguous | 1.94 | Ambiguous | -0.02 | Likely Benign | 0.47 | Neutral | 0.000 | Benign | 0.000 | Benign | 1.33 | Pathogenic | 0.77 | Tolerated | 3.42 | 19 | 1 | 0 | -0.4 | 30.03 | 196.6 | -49.6 | 0.9 | 2.2 | -0.1 | 0.4 | Uncertain | Gly370 is located in the Gly-rich Ω loop (res. Pro364- Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because, the Ω loop is assumed to be directly interacting with the membrane, it is only seen to move arbitrarily throughout the WT solvent simulations. The Ω loop is potentially playing a crucial loop in the SynGAP-membrane complex association, stability and dynamics, regardless, this aspect cannot be addressed through the solvent simulations only. The Ω-loops are known to have a major role in protein functions that requires flexibility and thus, they are rich in glycines, prolines and to a lesser extent, hydrophilic residues to ensure maximum flexibility. Thus, Ser370 in the variant is potentially tolerated in the Ω loop. However, since the effect on the Gly-rich Ω loop dynamics can only be well-studied through the SynGAP-membrane complex, no definite conclusions can be withdrawn. | |||||||||
| c.1118G>A | G373E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G373E is listed in ClinVar with an Uncertain significance and is not present in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, Foldetta, SIFT, and AlphaMissense‑Default. Predictions from Rosetta and ESM1b are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as pathogenic. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar status of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | Uncertain | 1 | -7.281 | In-Between | 0.569 | Likely Pathogenic | Likely Benign | 0.420 | Likely Benign | 4.13 | Destabilizing | 3.2 | 0.52 | Ambiguous | 2.33 | Destabilizing | -0.02 | Likely Benign | -0.69 | Neutral | 0.001 | Benign | 0.000 | Benign | 3.90 | Benign | 0.01 | Affected | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||
| c.1118G>T | G373V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G373V is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6‑33438023‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic outcome are FoldX, Foldetta, and SIFT, while Rosetta is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta as pathogenic. Overall, the majority of predictions support a benign impact, and this consensus does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | Uncertain | 1 | 6-33438023-G-T | 6 | 5.03e-6 | -6.062 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.428 | Likely Benign | 5.32 | Destabilizing | 3.2 | 0.82 | Ambiguous | 3.07 | Destabilizing | 0.09 | Likely Benign | -0.98 | Neutral | 0.007 | Benign | 0.001 | Benign | 3.90 | Benign | 0.00 | Affected | 3.53 | 16 | -1 | -3 | 4.6 | 42.08 | 207.6 | -68.1 | 1.9 | 1.1 | -0.6 | 0.1 | Uncertain | Gly373 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus hydrophobic residues like valine are rarely tolerated. Although no negative structural effects are observed in the variant simulations, Val373 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effect on the Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||
| c.1121C>A | S374Y 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant S374Y is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, whereas polyPhen‑2 HumDiv and SIFT predict a pathogenic impact. Uncertain calls come from FoldX, Rosetta, Foldetta, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive, and Foldetta likewise yields an uncertain stability change. Overall, the majority of available predictions favor a benign effect, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | Uncertain | 1 | -7.774 | In-Between | 0.344 | Ambiguous | Likely Benign | 0.310 | Likely Benign | 0.71 | Ambiguous | 1.2 | 0.66 | Ambiguous | 0.69 | Ambiguous | -0.02 | Likely Benign | -1.18 | Neutral | 0.875 | Possibly Damaging | 0.271 | Benign | 5.41 | Benign | 0.01 | Affected | 4.32 | 13 | -3 | -2 | -0.5 | 76.10 | 237.3 | -76.9 | 0.5 | 0.4 | 0.5 | 0.3 | Uncertain | Ser374 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus, large and relatively hydrophobic residues like tyrosine are rarely tolerated. Additionally, the hydroxyl group of Tyr374 frequently forms various hydrogen bonds with other loop residues in the variant simulations. Although no negative structural effects are observed in the variant simulations, Tyr374 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effect on Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||||||
| c.1126G>T | G376C 2D AISynGAP1 missense variant G376C is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from Rosetta, premPS, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic calls come from REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Two tools report uncertainty: Foldetta and ESM1b. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also yields a benign verdict; Foldetta remains uncertain. Overall, the majority of conventional predictors lean toward pathogenicity, whereas the most accurate methods favor a benign effect. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | Uncertain | 1 | -7.686 | In-Between | 0.125 | Likely Benign | Likely Benign | 0.560 | Likely Pathogenic | 2.56 | Destabilizing | 0.5 | 0.22 | Likely Benign | 1.39 | Ambiguous | 0.16 | Likely Benign | -1.15 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.32 | Pathogenic | 0.01 | Affected | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||
| c.1131G>A | M377I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377I (ClinVar ID 3803473.0, status = Uncertain) is present in gnomAD (ID = 6‑33438036‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Overall, the computational evidence strongly favors a benign classification, which does not contradict the ClinVar status of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | Uncertain | 1 | 6-33438036-G-A | 1 | 6.23e-7 | -2.895 | Likely Benign | 0.212 | Likely Benign | Likely Benign | 0.227 | Likely Benign | 0.76 | Ambiguous | 0.3 | 0.54 | Ambiguous | 0.65 | Ambiguous | 0.24 | Likely Benign | -0.41 | Neutral | 0.000 | Benign | 0.001 | Benign | 5.46 | Benign | 0.26 | Tolerated | 4.32 | 12 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||
| c.1136C>G | S379W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S379W is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438041‑C‑G). Prediction tools that indicate a benign effect include premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact comprise REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus as benign. Because the majority of conventional tools favor pathogenicity while the high‑accuracy subset is split, the overall evidence leans toward a pathogenic effect. This conclusion does not contradict the ClinVar uncertain status, which remains unresolved. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | Uncertain | 1 | 6-33438041-C-G | -8.898 | Likely Pathogenic | 0.388 | Ambiguous | Likely Benign | 0.520 | Likely Pathogenic | 4.32 | Destabilizing | 3.4 | 3.56 | Destabilizing | 3.94 | Destabilizing | 0.16 | Likely Benign | -1.02 | Neutral | 0.998 | Probably Damaging | 0.844 | Possibly Damaging | 3.82 | Benign | 0.01 | Affected | 4.32 | 11 | -2 | -3 | -0.1 | 99.14 | 271.3 | -75.7 | 1.4 | 1.0 | 0.6 | 0.5 | Uncertain | Ser379 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus hydrophobic residues like tryptophan are rarely tolerated. Although no major negative structural effects are observed in the variant simulations, Trp379 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effect on Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn | ||||||||||||
| c.1142G>T | G381V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G381V is listed in ClinVar with an uncertain significance (ClinVar ID 1940172.0) and is present in the gnomAD database (6‑33438047‑G‑T). Functional prediction tools that report a benign effect include premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, FoldX, Rosetta, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a majority‑benign vote and is reported as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of predictions lean toward 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 | C2 | Uncertain | 1 | 6-33438047-G-T | 2 | 1.25e-6 | -5.967 | Likely Benign | 0.146 | Likely Benign | Likely Benign | 0.618 | Likely Pathogenic | 7.16 | Destabilizing | 1.0 | 4.10 | Destabilizing | 5.63 | Destabilizing | -0.32 | Likely Benign | -0.95 | Neutral | 0.386 | Benign | 0.157 | Benign | 1.32 | Pathogenic | 0.10 | Tolerated | 4.32 | 9 | -1 | -3 | 4.6 | 42.08 | 214.6 | -68.8 | 0.3 | 0.7 | -0.5 | 0.3 | Uncertain | Gly381 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus hydrophobic residues like valine are rarely tolerated. Although no negative structural effects are observed in the variant simulations, Val381 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effects on Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||
| c.1147G>T | G383W 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant G383W is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438052‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as benign, and Foldetta as pathogenic. Because the majority of conventional predictors favor pathogenicity while the high‑accuracy subset is split, the overall evidence leans toward a pathogenic interpretation. This conclusion does not conflict with the ClinVar uncertain status, which reflects the current lack of definitive clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | Uncertain | 1 | 6-33438052-G-T | 1 | 6.22e-7 | -10.161 | Likely Pathogenic | 0.439 | Ambiguous | Likely Benign | 0.469 | Likely Benign | 5.81 | Destabilizing | 3.6 | 4.44 | Destabilizing | 5.13 | Destabilizing | 0.08 | Likely Benign | -1.01 | Neutral | 0.959 | Probably Damaging | 0.704 | Possibly Damaging | 4.09 | Benign | 0.00 | Affected | 4.32 | 7 | -2 | -7 | -0.5 | 129.16 | ||||||||||||||||||
| c.1150G>A | G384S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G384S (gnomAD ID 6-33438055‑G‑A) is listed in ClinVar with an uncertain significance. Functional prediction tools cluster into two groups: benign predictions from REVEL, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote) is likely benign, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. No evidence from FoldX or Rosetta alone is available. Overall, the preponderance of evidence points to a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | Uncertain | 1 | 6-33438055-G-A | 1 | 6.22e-7 | -5.243 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.315 | Likely Benign | 1.92 | Ambiguous | 0.2 | 1.66 | Ambiguous | 1.79 | Ambiguous | 0.19 | Likely Benign | -0.67 | Neutral | 0.980 | Probably Damaging | 0.968 | Probably Damaging | 1.33 | Pathogenic | 0.04 | Affected | 4.32 | 2 | 1 | 0 | -0.4 | 30.03 | 202.4 | -49.8 | 0.5 | 1.0 | -0.2 | 0.0 | Uncertain | Gly384 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and so they are rich in glycines, prolines, and, to a lesser extent, small hydrophilic residues to ensure maximum flexibility. Thus, the variant’s Ser384 is potentially tolerated in the Ω loop, although the hydroxyl group of Ser384 forms various hydrogen bonds with several other loop residues in the variant simulations. However, since the effects on Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||
| c.1153T>C | S385P 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant S385P is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6-33438058‑T‑C). Prediction tools that classify the variant as benign include REVEL, Foldetta, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Predictions from FoldX and Rosetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of computational evidence supports a benign effect, which is consistent with the ClinVar uncertain status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | Uncertain | 1 | 6-33438058-T-C | -5.431 | Likely Benign | 0.123 | Likely Benign | Likely Benign | 0.385 | Likely Benign | 0.91 | Ambiguous | 0.6 | -0.90 | Ambiguous | 0.01 | Likely Benign | 0.19 | Likely Benign | -0.26 | Neutral | 0.676 | Possibly Damaging | 0.693 | Possibly Damaging | 4.63 | Benign | 0.04 | Affected | 4.32 | 3 | 1 | -1 | -0.8 | 10.04 | 210.3 | 18.5 | 1.8 | 0.9 | 0.3 | 0.0 | Uncertain | Ser385 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and so they are rich in glycine residues, prolines, and, to a lesser extent, small hydrophilic residues to ensure maximum flexibility. Thus, the variant’s Pro385 is potentially tolerated in the Ω loop. However, since the effects on Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||||
| c.1154C>T | S385L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S385L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438059‑C‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus itself is benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of computational evidence indicates the variant is most likely benign, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | Uncertain | 2 | 6-33438059-C-T | 9 | 4.60e-5 | -6.018 | Likely Benign | 0.167 | Likely Benign | Likely Benign | 0.304 | Likely Benign | 0.16 | Likely Benign | 0.1 | 0.08 | Likely Benign | 0.12 | Likely Benign | -0.26 | Likely Benign | -0.68 | Neutral | 0.829 | Possibly Damaging | 0.706 | Possibly Damaging | 4.63 | Benign | 0.01 | Affected | 4.32 | 3 | -3 | -2 | 4.6 | 26.08 | 244.6 | -50.1 | 0.0 | 0.6 | -0.1 | 0.1 | Uncertain | Ser385 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus hydrophobic residues like leucine are rarely tolerated. Although no negative structural effects are observed in the variant simulations, Leu385 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effects on Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||
| c.1157G>A | G386E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G386E is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438062‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are FoldX, Foldetta, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. Uncertain predictions come from Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive. Overall, the majority of tools predict a pathogenic impact, suggesting the variant is most likely pathogenic, which does not contradict the ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | Uncertain | 1 | 6-33438062-G-A | -9.286 | Likely Pathogenic | 0.686 | Likely Pathogenic | Likely Benign | 0.447 | Likely Benign | 3.69 | Destabilizing | 2.9 | 0.79 | Ambiguous | 2.24 | Destabilizing | 0.54 | Ambiguous | -0.83 | Neutral | 0.860 | Possibly Damaging | 0.354 | Benign | 3.93 | Benign | 0.01 | Affected | 4.32 | 3 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||
| c.1160G>T | G387V 2D 3DClick to see structure in 3D Viewer AISynGAP1 G387V is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6-33438065-G-T). Functional prediction tools that report a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, SIFT, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as likely benign, while the Foldetta stability assessment (combining FoldX‑MD and Rosetta) indicates a pathogenic change. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as pathogenic. Overall, the majority of predictions favor 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 | C2 | Uncertain | 1 | 6-33438065-G-T | 22 | 1.37e-5 | -6.199 | Likely Benign | 0.153 | Likely Benign | Likely Benign | 0.390 | Likely Benign | 5.13 | Destabilizing | 1.8 | 6.44 | Destabilizing | 5.79 | Destabilizing | -0.33 | Likely Benign | -0.54 | Neutral | 0.069 | Benign | 0.077 | Benign | 1.32 | Pathogenic | 0.01 | Affected | 4.32 | 3 | -1 | -3 | 4.6 | 42.08 | 207.7 | -68.4 | -0.7 | 0.8 | -0.5 | 0.1 | Uncertain | Gly387 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364 and res. Ala399-Ile411). The Ω loop is assumed to directly interact with the membrane, and it is observed to move arbitrarily throughout the WT solvent simulations. This loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play significant roles in protein functions that require flexibility, and thus hydrophobic residues like valine are rarely tolerated. Although no negative structural effects are visualized in the variant’s simulations, Val387 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. Since the effects on the Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||
| c.1169G>A | G390E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G390E is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, FoldX, Rosetta, Foldetta, SIFT, FATHMM, and AlphaMissense‑Default. A high‑accuracy assessment shows AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of predictions support a pathogenic effect, and this aligns with the ClinVar designation of uncertain significance rather than contradicting it. Thus, the variant is most likely pathogenic based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | Uncertain | 1 | -7.913 | In-Between | 0.646 | Likely Pathogenic | Likely Benign | 0.575 | Likely Pathogenic | 2.61 | Destabilizing | 0.9 | 4.28 | Destabilizing | 3.45 | Destabilizing | 0.47 | Likely Benign | -0.87 | Neutral | 0.276 | Benign | 0.045 | Benign | 1.32 | Pathogenic | 0.05 | Affected | 4.32 | 8 | 0 | -2 | -3.1 | 72.06 | 241.5 | -108.4 | 0.6 | 0.5 | -0.1 | 0.1 | Uncertain | Gly390 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364 and res. Ala399-Ile411). The Ω loop is assumed to directly interact with the membrane, and it is observed to move arbitrarily throughout the WT solvent simulations. This loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play significant roles in protein functions that require flexibility, and so they are rich in glycine residues, prolines, and to a lesser extent, small hydrophilic residues to ensure maximum flexibility. Thus, the variant’s Glu390 may not be as well tolerated in the Ω loop. Additionally, the carboxylate group of Glu390 occasionally forms H-bonds with other loop residues in the variant simulations. The interaction between the acidic carboxylate side chain and the acidic membrane lipids may further influence the SynGAP-membrane complex. However, since the effects on the Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||||||
| c.1193C>T | P398L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P398L (ClinVar ID 2415189.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33438098‑C‑T). Functional prediction tools that agree on a benign effect include Foldetta, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, and SIFT. Predictions that are uncertain or inconclusive are FoldX, Rosetta, premPS, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive. Based on the available predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | Uncertain | 1 | 6-33438098-C-T | 8 | 4.96e-6 | -7.518 | In-Between | 0.547 | Ambiguous | Likely Benign | 0.599 | Likely Pathogenic | 1.48 | Ambiguous | 0.2 | -0.54 | Ambiguous | 0.47 | Likely Benign | 0.62 | Ambiguous | -7.10 | Deleterious | 0.961 | Probably Damaging | 0.256 | Benign | 5.72 | Benign | 0.01 | Affected | 3.40 | 16 | -3 | -3 | 5.4 | 16.04 | 245.8 | -68.6 | -0.1 | 0.0 | -0.3 | 0.2 | X | Potentially Pathogenic | Pro398 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364 and res. Ala399-Ile411). The Ω loop is assumed to directly interact with the membrane, and it is observed to move arbitrarily throughout the WT solvent simulations. Although the residue swap does not influence the nearby secondary structure elements, proline is often found at the ends of β sheets due to its disfavored status during folding.Additionally, the Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone. Ω loops are known to play significant roles in protein functions that require flexibility, and thus hydrophobic residues like leucine are rarely tolerated. Although no negative structural effects are visualized in the variant’s simulations, Leu398 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. Since the effects on the Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||
| c.1199T>A | V400E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V400E is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect are polyPhen‑2 HumVar and FATHMM; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Uncertain | 1 | -13.686 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.810 | Likely Pathogenic | 3.70 | Destabilizing | 0.2 | 2.46 | Destabilizing | 3.08 | Destabilizing | 2.29 | Destabilizing | -4.88 | Deleterious | 0.920 | Possibly Damaging | 0.335 | Benign | 5.31 | Benign | 0.00 | Affected | 3.38 | 27 | -2 | -2 | -7.7 | 29.98 | 249.1 | -38.8 | -0.1 | 0.1 | 1.0 | 0.0 | X | X | X | Potentially Pathogenic | The iso-propyl side chain of Val400, located in an anti-parallel β sheet strand (res. Ala399-Ile411), hydrophobically packs against hydrophobic residues within the anti-parallel β sheet of the C2 domain (e.g., Ile268, Ala404, Leu325, Leu402). In the variant simulations, the negatively charged carboxylate group of the Glu400 side chain is not suitable for occupying the hydrophobic niche. Consequently, the side chain escapes the center of the C2 domain and interacts with the backbone amide groups of Leu402 in the same β strand and/or Ile269 and Glu270 in a neighboring β strand (res. Arg259-Arg272). This residue swap disrupts the hydrophobic packing and generally has extensive negative effects on the C2 domain structure. At a minimum, the residue swap could affect the C2 domain stability and membrane association. | |||||||||
| c.1202G>A | R401Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R401Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438107‑G‑A). Prediction tools that agree on a benign effect are limited to FATHMM, whereas the majority of algorithms (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy methods reinforce the pathogenic prediction: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic,” and Foldetta’s stability assessment is inconclusive. Overall, the preponderance of evidence points to a pathogenic effect, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Uncertain | 1 | 6-33438107-G-A | -11.213 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 0.780 | Likely Pathogenic | 0.96 | Ambiguous | 0.1 | 1.50 | Ambiguous | 1.23 | Ambiguous | 1.20 | Destabilizing | -3.69 | Deleterious | 0.999 | Probably Damaging | 0.978 | Probably Damaging | 5.47 | Benign | 0.04 | Affected | 3.38 | 27 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||
| c.1214G>C | R405P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R405P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict it to be pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores it as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates it is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies it as pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Uncertain | 1 | -14.206 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.572 | Likely Pathogenic | 3.11 | Destabilizing | 0.3 | 5.19 | Destabilizing | 4.15 | Destabilizing | 1.26 | Destabilizing | -6.32 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.62 | Benign | 0.01 | Affected | 3.38 | 28 | -2 | 0 | 2.9 | -59.07 | ||||||||||||||||||||
| c.1221G>T | Q407H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q407H is listed in ClinVar with an uncertain significance (ClinVar ID 2772184.0) 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 premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions marked as uncertain include FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for Q407H. This conclusion does not conflict with the ClinVar designation of uncertain significance, which remains unresolved pending further evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Uncertain | 1 | -10.526 | Likely Pathogenic | 0.830 | Likely Pathogenic | Ambiguous | 0.206 | Likely Benign | 0.59 | Ambiguous | 0.0 | 0.61 | Ambiguous | 0.60 | Ambiguous | 1.10 | Destabilizing | -4.51 | Deleterious | 0.982 | Probably Damaging | 0.947 | Probably Damaging | 3.88 | Benign | 0.01 | Affected | 3.38 | 28 | 0 | 3 | 0.3 | 9.01 | ||||||||||||||||||||
| c.1222A>G | T408A 2D AISynGAP1 missense variant T408A is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv), and ESM1b. The high‑accuracy AlphaMissense‑Optimized score is benign, while the SGM consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Foldetta, a protein‑folding stability method, also predicts benign. Overall, the balance of evidence favors 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. | C2 | Uncertain | 1 | -8.304 | Likely Pathogenic | 0.114 | Likely Benign | Likely Benign | 0.118 | Likely Benign | 0.37 | Likely Benign | 0.6 | -0.06 | Likely Benign | 0.16 | Likely Benign | 0.72 | Ambiguous | -3.07 | Deleterious | 0.540 | Possibly Damaging | 0.131 | Benign | 4.16 | Benign | 0.14 | Tolerated | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||
| c.1240A>G | M414V 2D  AISynGAP1 M414V 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, FATHMM, and AlphaMissense‑Optimized; pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and ESM1b; the remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) are inconclusive. The SGM consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a pathogenic majority. High‑accuracy assessments give AlphaMissense‑Optimized benign, SGM consensus pathogenic, and Foldetta uncertain. Because the high‑accuracy predictions are divided and the overall tool set is evenly split, there is no definitive evidence for pathogenicity or benignity. Thus, the variant is most likely inconclusive, and this lack of consensus does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Uncertain | 1 | -8.003 | Likely Pathogenic | 0.541 | Ambiguous | Likely Benign | 0.261 | Likely Benign | 1.81 | Ambiguous | 0.4 | 1.73 | Ambiguous | 1.77 | Ambiguous | 0.95 | Ambiguous | -2.95 | Deleterious | 0.999 | Probably Damaging | 0.987 | Probably Damaging | 3.43 | Benign | 0.24 | Tolerated | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||
| c.1256A>G | E419G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E419G is listed in ClinVar with an uncertain significance (ClinVar ID 2004834.0) 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, 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 pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus confirms likely pathogenic, and the Foldetta stability analysis is inconclusive. No evidence from FoldX, Rosetta, or premPS is available. Overall, the preponderance of predictions indicates that E419G is most likely pathogenic, which contrasts with the current ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -10.589 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.469 | Likely Benign | 1.41 | Ambiguous | 0.0 | 1.94 | Ambiguous | 1.68 | Ambiguous | 0.83 | Ambiguous | -6.42 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.31 | Benign | 0.02 | Affected | 3.37 | 29 | 0 | -2 | 3.1 | -72.06 | 165.3 | 110.8 | 0.0 | 0.0 | -0.1 | 0.0 | X | Potentially Pathogenic | The carboxylate group of Glu419, located on an α helix (res. Met414-Glu436), forms a salt bridge with the side chain of either Arg716 or Lys418 from an opposing helix (res. Pro713-Arg726). The backbone amide group of Glu419 does not form H-bonds, resulting in a slight bend in the α helix. Thus, although glycine is known as an “α helix breaker,” the residue swap does not disrupt the continuity or integrity of the α helix. However, because Gly419 cannot form a salt bridge with the guanidinium group of the Arg716 side chain, the C2-GAP domain tertiary structure could be compromised during folding. | |||||||||||
| c.1260T>G | F420L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420L is listed in ClinVar (ID 1397885.0) with an “Uncertain” clinical significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Those that predict a pathogenic effect comprise premPS, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Stability‑based methods (FoldX, Rosetta, Foldetta) yield inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus also as pathogenic, while Foldetta remains uncertain. Overall, the majority of evidence points toward a pathogenic impact, which does not contradict the ClinVar “Uncertain” status but suggests 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 | GAP | Uncertain | 1 | -8.432 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.146 | Likely Benign | 1.76 | Ambiguous | 0.0 | 1.41 | Ambiguous | 1.59 | Ambiguous | 1.04 | Destabilizing | -5.39 | Deleterious | 0.009 | Benign | 0.005 | Benign | 4.22 | Benign | 0.39 | Tolerated | 3.37 | 29 | 2 | 0 | 1.0 | -34.02 | 231.1 | 13.2 | 0.0 | 0.0 | -0.1 | 0.0 | X | Potentially Benign | In the WT, the phenyl ring of the Phe420 side chain, located on an α helix (res. Met414-Glu436), packs against hydrophobic residues in the interhelix area of the GAP domain (e.g., Leu689, Leu714, Leu717, Leu718). In the variant simulations, the iso-butyl side chain of Leu420 also packs into the hydrophobic inter-helix niche, but due to its smaller size, the resulting steric interactions are not as favorable as with phenylalanine. In short, the residue swap does not cause severe effects on the protein structure based on the variant simulations. | |||||||||||
| c.127G>A | G43S 2D AIThe SynGAP1 missense variant G43S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (6‑33423536‑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 (derived from the same four high‑accuracy tools) also as benign; Foldetta results are unavailable. Based on the collective evidence, 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 | Uncertain | 2 | 6-33423536-G-A | 1 | 6.20e-7 | -3.301 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.057 | Likely Benign | -0.30 | Neutral | 0.162 | Benign | 0.096 | Benign | 4.29 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||
| c.1286G>A | R429Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R429Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33438191‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b, while premPS is inconclusive. The high‑accuracy consensus (SGM Consensus) – a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN – yields a “Likely Benign” result. AlphaMissense‑Optimized itself predicts benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Taken together, the preponderance of evidence points to a benign impact for R429Q, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Uncertain | 2 | 6-33438191-G-A | 10 | 6.20e-6 | -8.227 | Likely Pathogenic | 0.143 | Likely Benign | Likely Benign | 0.156 | Likely Benign | 0.45 | Likely Benign | 0.1 | 0.36 | Likely Benign | 0.41 | Likely Benign | 0.98 | Ambiguous | -1.25 | Neutral | 1.000 | Probably Damaging | 0.979 | Probably Damaging | 3.47 | Benign | 0.58 | Tolerated | 3.38 | 25 | 1 | 1 | 1.0 | -28.06 | 235.8 | 59.5 | 0.0 | 0.0 | -0.3 | 0.4 | X | Potentially Pathogenic | The guanidinium group of the Arg429 side chain, located in an α helix (res. Met414-Glu436), either forms a salt bridge with the carboxylate group of an acidic residue (Asp474, Asp467) or an H-bond with the hydroxyl group of Ser471 in an opposing α helix (res. Ala461-Phe476). In the variant simulations, Gln429 cannot form ionic interactions with the acidic residues; however, the carboxamide group can form multiple H-bonds. The H-bonding coordination of the Asn429 side chain varied between the replica simulations. In one simulation, three H-bonds were formed simultaneously with the Asp467 side chain, the backbone carbonyl group of Asn426, and the amide group of Met430 at the end of the same α helix. The residue swap could affect the tertiary structure assembly during folding due to weaker bond formation, but no large-scale negative effects were seen during the simulations. | ||||||||
| c.1300G>A | V434I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V434I (ClinVar ID 212346.0, status Uncertain) is present in gnomAD (ID 6‑33438205‑G‑A). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No predictions or stability results are missing or inconclusive. Based on the collective evidence, the variant is most likely benign, which does not contradict the ClinVar status of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Uncertain | 1 | 6-33438205-G-A | 1 | 6.19e-7 | -6.999 | Likely Benign | 0.129 | Likely Benign | Likely Benign | 0.192 | Likely Benign | -0.04 | Likely Benign | 0.0 | 0.22 | Likely Benign | 0.09 | Likely Benign | 0.31 | Likely Benign | -0.82 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.53 | Benign | 0.18 | Tolerated | 3.37 | 29 | 4 | 3 | 0.3 | 14.03 | 246.7 | -27.7 | 0.0 | 0.0 | 0.1 | 0.0 | X | Potentially Benign | The iso-propyl side chain of Val434, located at the end of an α helix (res. Met414-Glu436), packs against hydrophobic residues in an interhelix space (e.g., Met430, Ala707, Leu711). In the variant simulations, the sec-butyl group of Ile434 is able to form the same hydrophobic interactions. Accordingly, the residue swap does not negatively affect the protein structure based on the simulations. | ||||||||
| c.1304T>G | L435W 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant L435W is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM. The majority of other in silico predictors (REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the change as pathogenic, and the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, while Foldetta’s stability analysis is inconclusive. Overall, the computational evidence strongly favors a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -14.889 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.572 | Likely Pathogenic | 2.11 | Destabilizing | 0.1 | 0.69 | Ambiguous | 1.40 | Ambiguous | 1.66 | Destabilizing | -5.63 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.15 | Benign | 0.00 | Affected | 3.37 | 29 | -2 | -2 | -4.7 | 73.05 | 242.2 | -25.2 | 0.0 | 0.0 | 0.3 | 0.1 | X | Potentially Pathogenic | The iso-butyl side chain of Leu435, located in an α helix (res. Met414-Glu436), packs against other hydrophobic residues in an interhelix space (e.g., Val699, Val447, Leu489, Leu439) in the WT simulations. In the variant simulations, the indole ring of Trp435 fits into the same niche despite its considerably bulkier size. Additionally, the side chain forms an H-bond with the backbone carbonyl of Leu696 in an α helix (res. Asp684-Gln702). Although no apparent negative changes are observed during the variant simulation, the size difference between the swapped residues could affect the protein folding process. | |||||||||||
| c.1306G>A | E436K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E436K is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining evaluated algorithms (REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) uniformly predict a pathogenic impact; FoldX, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E436K, which does not conflict with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -13.869 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.829 | Likely Pathogenic | 0.56 | Ambiguous | 0.1 | 2.86 | Destabilizing | 1.71 | Ambiguous | 0.82 | Ambiguous | -3.77 | Deleterious | 0.994 | Probably Damaging | 0.951 | Probably Damaging | 4.71 | Benign | 0.02 | Affected | 3.37 | 29 | 0 | 1 | -0.4 | -0.94 | 186.8 | 39.8 | 0.0 | 0.0 | -0.2 | 0.0 | X | X | X | Potentially Pathogenic | The carboxylate group of Glu436, located on the α helix (res. Met414-Glu436), forms a salt bridge with the amino group of the Lys444 side chain on an opposing α helix (res. Val441-Ser457). The backbone carbonyl of Glu436 also H-bonds with the Lys444 side chain, which helps keep the ends of the two α helices tightly connected. In contrast, in the variant simulations, the salt bridge formation with Lys444 is not possible. Instead, the repelled Lys436 side chain rotates outward, causing a change in the α helix backbone H-bonding: the amide group of Lys444 H-bonds with the carbonyl of Ala433 instead of the carbonyl of Cys432. | |||||||||
| c.1339G>C | V447L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V447L is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict pathogenicity are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Uncertain results are reported by FoldX, Rosetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Benign. Overall, the majority of evidence points to a benign effect, and this consensus does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Uncertain | 1 | -5.136 | Likely Benign | 0.491 | Ambiguous | Likely Benign | 0.180 | Likely Benign | -1.13 | Ambiguous | 0.1 | 0.54 | Ambiguous | -0.30 | Likely Benign | 0.03 | Likely Benign | -0.29 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.61 | Benign | 0.90 | Tolerated | 3.37 | 32 | 1 | 2 | -0.4 | 14.03 | ||||||||||||||||||||
| c.1345A>G | S449G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449G is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (variant ID 6‑33438250‑A‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while Rosetta, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as “Likely Benign,” and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect, 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 | GAP | Uncertain | 1 | 6-33438250-A-G | 3 | 1.86e-6 | -5.936 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.116 | Likely Benign | 0.47 | Likely Benign | 0.0 | 0.55 | Ambiguous | 0.51 | Ambiguous | 0.85 | Ambiguous | -2.32 | Neutral | 0.948 | Possibly Damaging | 0.124 | Benign | 3.35 | Benign | 0.13 | Tolerated | 3.37 | 32 | 0 | 1 | 0.4 | -30.03 | |||||||||||||||||
| c.1349C>A | A450E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A450E is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include SIFT and FATHMM, whereas the majority of tools predict it to be pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. No predictions are inconclusive. Overall, the evidence strongly favors a pathogenic impact for A450E, which does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -16.578 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.653 | Likely Pathogenic | 3.86 | Destabilizing | 0.2 | 5.23 | Destabilizing | 4.55 | Destabilizing | 1.59 | Destabilizing | -4.67 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.38 | Benign | 0.07 | Tolerated | 3.37 | 32 | 0 | -1 | -5.3 | 58.04 | 240.1 | -82.6 | 0.0 | 0.0 | 0.7 | 0.0 | X | X | Potentially Pathogenic | The methyl group of Ala450, located in an α helix (res. Asn440-Thr458), packs against hydrophobic residues in the inter-helix space (e.g., Leu692). In the variant simulations, the carboxylate group of the Glu450 side chain rotates outward, away from the hydrophobic niche, where it does not form any lasting salt bridges or H-bonds. Although the residue swap does not negatively affect the protein structure based on the simulations, it is possible that the introduction of the negatively charged residue adversely affects the folding process or tertiary assembly. | ||||||||||
| c.1354G>A | V452I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V452I is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and SIFT, while ESM1b also predicts pathogenicity. Uncertain predictions come from Rosetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Taken together, 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. | GAP | Uncertain | 1 | -8.985 | Likely Pathogenic | 0.361 | Ambiguous | Likely Benign | 0.218 | Likely Benign | -0.08 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.22 | Likely Benign | 0.25 | Likely Benign | -0.99 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.26 | Benign | 0.05 | Affected | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||
| c.1354G>T | V452F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 V452F variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect are Rosetta and FATHMM, whereas the remaining tools (REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict a pathogenic impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Based on the preponderance of evidence, the variant is most likely pathogenic, a conclusion that contradicts its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -14.769 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.511 | Likely Pathogenic | 9.21 | Destabilizing | 0.1 | 0.37 | Likely Benign | 4.79 | Destabilizing | 0.61 | Ambiguous | -4.94 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.29 | Benign | 0.00 | Affected | 3.37 | 34 | -1 | -1 | -1.4 | 48.04 | 249.4 | -35.7 | 0.0 | 0.0 | 0.4 | 0.1 | X | Potentially Pathogenic | The iso-propyl side chain of Val452, located in the middle of an α helix (res. Val441-Ser457), packs against hydrophobic residues in the inter-helix space at the intersection of three α helices (e.g., Leu500, His453, Leu465). In the variant simulations, the larger side chain of Phe452 cannot pack against the opposing α helix (res. Leu489-Glu519) as efficiently as valine. Due to space restrictions, the phenol ring adjusts to make room by rotating slightly sideways in the inter-helix space. Besides this small and local shift, no large-scale effects on the protein structure are seen based on the simulations. However, the size difference between the swapped residues could affect the protein folding process. | |||||||||||
| c.1367A>C | Q456P 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q456P is listed in ClinVar with an uncertain significance (ClinVar ID 2697090.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions are made by FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta. High‑accuracy methods specifically report pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are inconclusive. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, which contradicts the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -15.250 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.469 | Likely Benign | 3.68 | Destabilizing | 0.2 | 8.43 | Destabilizing | 6.06 | Destabilizing | 0.82 | Ambiguous | -5.66 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.34 | Benign | 0.07 | Tolerated | 3.37 | 34 | -1 | 0 | 1.9 | -31.01 | ||||||||||||||||||||
| c.136C>T | P46S 2D AIThe SynGAP1 missense variant P46S 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 ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -3.338 | Likely Benign | 0.302 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -0.60 | Neutral | 0.909 | Possibly Damaging | 0.901 | Possibly Damaging | 4.15 | Benign | 0.00 | Affected | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||
| c.1370G>A | S457N 2D AIThe SynGAP1 missense variant S457N is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, Rosetta, SIFT, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus methods give a mixed picture: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) favors pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Overall, the majority of individual predictors lean toward pathogenicity, but the high‑accuracy Foldetta result suggests a benign impact. Thus, the variant is most likely pathogenic based on the preponderance of predictions, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -10.221 | Likely Pathogenic | 0.949 | Likely Pathogenic | Ambiguous | 0.241 | Likely Benign | 0.19 | Likely Benign | 0.0 | -0.22 | Likely Benign | -0.02 | Likely Benign | 0.67 | Ambiguous | -2.76 | Deleterious | 0.940 | Possibly Damaging | 0.843 | Possibly Damaging | 3.28 | Benign | 0.06 | Tolerated | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||
| c.1390T>G | F464V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 F464V variant is listed in ClinVar with an “Uncertain” status (ClinVar ID 1716596.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective predictions, the variant is most likely pathogenic, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -12.254 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.592 | Likely Pathogenic | 3.61 | Destabilizing | 0.1 | 2.89 | Destabilizing | 3.25 | Destabilizing | 1.40 | Destabilizing | -6.96 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 3.36 | Benign | 0.04 | Affected | 3.37 | 34 | -1 | -1 | 1.4 | -48.04 | 210.1 | 40.5 | -0.1 | 0.0 | -0.9 | 0.3 | X | Potentially Pathogenic | The phenyl ring of Phe464, located in the middle of an α helix (res. Ala461–Phe476), packs against hydrophobic residues (e.g., Met468, Leu451, Leu455, and Tyr428) in the inter-helix space formed with two other α helices (res. Asn440-Lys460 and res. Pro413-Glu436). The iso-propyl side chain of Val464 is similarly hydrophobic but considerably smaller than the original phenyl ring of Phe464. To compensate for the size difference, neighboring residues need to fill in the gap in the variant simulations.The phenolic side chain of Tyr428, located at the middle bend of an α helix (res. Glu436-Pro413), assumes a new position in the inter-helix space or rotates inward next to the third α helix (res. Asn440-Lys460) when the stable H-bond between Tyr428 and Asp467 seen in the WT simulations breaks. The residue swap also leads to the loss of the methionine-aromatic interaction between the Met468 and Phe464 side chains, which could weaken the integrity of the parent α helix (res. Ala461-Phe476). Although the simulations likely underestimate the full adverse effect of the introduced mutation during folding, the two opposing α helices (res. Ala461–Phe476 and res. Glu436-Pro413) move substantially closer to each other in the variant simulations. | |||||||||||
| c.1393C>G | L465V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L465V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL and SIFT, while the remaining tools—FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default—indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports likely pathogenic; and Foldetta, which combines FoldX‑MD and Rosetta stability outputs, predicts pathogenic. Overall, the majority of evidence points to a pathogenic impact, which is consistent with the ClinVar uncertain status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -9.893 | Likely Pathogenic | 0.838 | Likely Pathogenic | Ambiguous | 0.276 | Likely Benign | 2.46 | Destabilizing | 0.1 | 2.66 | Destabilizing | 2.56 | Destabilizing | 1.21 | Destabilizing | -2.98 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.44 | Pathogenic | 0.10 | Tolerated | 3.37 | 34 | 2 | 1 | 0.4 | -14.03 | 204.3 | 30.9 | 0.0 | 0.0 | -0.4 | 0.6 | X | Potentially Benign | The iso-butyl side chain of Leu465, located in the middle of an α helix (res. Ala461–Phe476), packs with hydrophobic residues (e.g., Phe464, Met468, Tyr497, Ile494) in an inter-helix space formed with two other α helices (res. Ala461–Phe476 and res. Thr488-Gly502). In the variant simulations, the iso-propyl side chain of Val465 is equally sized and similarly hydrophobic as the original side chain of Leu465. Hence, the mutation does not exert any negative effects on the protein structure based on the variant simulations. | |||||||||||
| c.13C>G | R5G 2D  AIThe SynGAP1 missense variant R5G is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only SIFT predicts a pathogenic outcome. 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, 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 | Uncertain | 1 | -3.639 | Likely Benign | 0.150 | Likely Benign | Likely Benign | 0.169 | Likely Benign | -0.16 | Neutral | 0.013 | Benign | 0.003 | Benign | 4.12 | Benign | 0.00 | Affected | 4.32 | 1 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||
| c.1402A>G | M468V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from PROVEAN, SIFT, and AlphaMissense‑Optimized, while pathogenic predictions are made by REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools, premPS and AlphaMissense‑Default, return uncertain results. High‑accuracy assessments further clarify the variant’s impact: AlphaMissense‑Optimized predicts a benign effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also classifies the variant as pathogenic. Overall, the preponderance of evidence points to a pathogenic effect, which does not contradict the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Uncertain | 1 | -9.461 | Likely Pathogenic | 0.361 | Ambiguous | Likely Benign | 0.570 | Likely Pathogenic | 2.69 | Destabilizing | 0.1 | 2.20 | Destabilizing | 2.45 | Destabilizing | 0.89 | Ambiguous | -1.66 | Neutral | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.21 | Pathogenic | 0.08 | Tolerated | 3.37 | 31 | 1 | 2 | 2.3 | -32.06 | |||||||||||||||||||||
| c.1403T>C | M468T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468T is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database. Prediction tools that are available all converge on a pathogenic interpretation: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool reports a benign outcome. High‑accuracy assessments are consistent: AlphaMissense‑Optimized is “Uncertain,” SGM Consensus is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. **Based on the aggregate predictions, the variant is most likely pathogenic, which does not contradict the ClinVar “Uncertain” classification.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 2 | 6-33438435-T-C | 1 | 6.20e-7 | -12.399 | Likely Pathogenic | 0.862 | Likely Pathogenic | Ambiguous | 0.801 | Likely Pathogenic | 3.47 | Destabilizing | 0.1 | 3.10 | Destabilizing | 3.29 | Destabilizing | 1.84 | Destabilizing | -3.85 | Deleterious | 0.994 | Probably Damaging | 0.985 | Probably Damaging | -1.31 | Pathogenic | 0.01 | Affected | 3.37 | 31 | -1 | -1 | -2.6 | -30.09 | 214.6 | 47.1 | 0.0 | 0.0 | 0.1 | 0.0 | X | Potentially Pathogenic | The thioether group of Met468, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues (e.g., Phe464, Leu465, Leu489) in an inter-helix space formed by two other α helices (res. Ala461–Phe476, res. Thr488–Gly502). In the variant simulations, the hydrophilic side chain of Thr468 does not pack favorably in the hydrophobic niche, and the methionine-aromatic stacking is lost. Although the hydroxyl group of Thr468 forms an H-bond with the backbone carbonyl group of Phe464, the integrity of the α helix is not affected in the simulations. No large-scale structural changes are observed during the variant simulations; however, due to the importance of hydrophobic packing, the effects could be more pronounced during protein folding. | ||||||||
| c.1404G>A | M468I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M468I is listed in ClinVar with an uncertain significance (ClinVar ID 3657719.0) and is present in gnomAD (6‑33438436‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from premPS, PROVEAN, and SIFT, while pathogenic predictions arise from REVEL, FoldX, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools report uncertainty: AlphaMissense‑Optimized and Rosetta. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, SGM Consensus is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Overall, the preponderance of evidence indicates a pathogenic impact for M468I, which does not contradict the ClinVar uncertain status but suggests a likely pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | 6-33438436-G-A | 1 | 6.20e-7 | -8.583 | Likely Pathogenic | 0.907 | Likely Pathogenic | Ambiguous | 0.508 | Likely Pathogenic | 2.53 | Destabilizing | 0.2 | 1.89 | Ambiguous | 2.21 | Destabilizing | 0.37 | Likely Benign | -1.06 | Neutral | 0.748 | Possibly Damaging | 0.886 | Possibly Damaging | -1.10 | Pathogenic | 0.07 | Tolerated | 3.37 | 31 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||
| c.1405G>A | A469T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A469T is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and the Foldetta stability assessment (combining FoldX‑MD and Rosetta). The high‑accuracy subset shows AlphaMissense‑Optimized as benign, whereas SGM Consensus and Foldetta both predict pathogenic. Overall, the majority of evidence supports a pathogenic effect, 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. | Likely Pathogenic | GAP | Uncertain | 1 | -9.540 | Likely Pathogenic | 0.723 | Likely Pathogenic | Likely Benign | 0.527 | Likely Pathogenic | 2.26 | Destabilizing | 0.1 | 1.90 | Ambiguous | 2.08 | Destabilizing | 0.34 | Likely Benign | -1.46 | Neutral | 0.994 | Probably Damaging | 0.986 | Probably Damaging | -1.21 | Pathogenic | 0.42 | Tolerated | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||
| c.1406C>A | A469D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A469D is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that assess the variant’s effect fall into two groups: the single benign prediction from SIFT, and a consensus of pathogenic predictions from the remaining 15 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus). High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenic. Taken together, the overwhelming majority of evidence points to a pathogenic 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 Pathogenic | GAP | Uncertain | 1 | -14.643 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.738 | Likely Pathogenic | 5.09 | Destabilizing | 0.2 | 4.16 | Destabilizing | 4.63 | Destabilizing | 1.68 | Destabilizing | -3.48 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.34 | Pathogenic | 0.21 | Tolerated | 3.37 | 34 | 0 | -2 | -5.3 | 44.01 | 237.0 | -58.2 | -0.2 | 0.1 | 0.8 | 0.1 | X | X | Potentially Pathogenic | The methyl group of Ala469, located in an α helix (res. Ala461–Phe476), interacts with hydrophobic residues (e.g., Trp572, Leu588, Met470) in an inter-helix space formed by two other α helices (res. Glu582–Ser604, res. Arg563–Gly580). In the variant simulations, Asp469 introduces a negatively charged and bulky side chain into the hydrophobic niche. Consequently, the side chain of Asp469 rotates outward, allowing the carboxylate group to form a salt bridge with the guanidinium group of Arg575 on the protein surface. This interaction affects the continuity of the parent α helix (Ala461–Phe476). Due to the importance of hydrophobic packing, the structural effects could be more pronounced during actual protein folding. | ||||||||||
| c.1408A>G | M470V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M470V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Consensus from most in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM all score it as deleterious. Only two tools—SIFT and AlphaMissense‑Optimized—classify it as benign, while Rosetta and AlphaMissense‑Default remain inconclusive. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized reports a benign outcome, but the SGM‑Consensus (derived from a majority of pathogenic calls among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and Foldetta (combining pathogenic FoldX with uncertain Rosetta) both predict pathogenicity. Overall, the preponderance of evidence supports a likely pathogenic classification, which does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -8.856 | Likely Pathogenic | 0.478 | Ambiguous | Likely Benign | 0.770 | Likely Pathogenic | 2.73 | Destabilizing | 0.1 | 1.88 | Ambiguous | 2.31 | Destabilizing | 1.31 | Destabilizing | -3.58 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.20 | Pathogenic | 0.15 | Tolerated | 3.37 | 34 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||
| c.1409T>C | M470T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M470T is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic impact. High‑accuracy methods further support this: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or folding‑stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -8.104 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.763 | Likely Pathogenic | 3.19 | Destabilizing | 0.1 | 2.68 | Destabilizing | 2.94 | Destabilizing | 1.49 | Destabilizing | -5.30 | Deleterious | 0.996 | Probably Damaging | 0.985 | Probably Damaging | -1.08 | Pathogenic | 0.24 | Tolerated | 3.37 | 34 | -1 | -1 | -2.6 | -30.09 | 213.8 | 46.5 | 0.0 | 0.0 | -0.2 | 0.2 | X | X | Potentially Pathogenic | The thioether group of Met470, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues in the inter-helix space (e.g., Val473, Leu558, Cys576, Trp572) formed by two other α helices (res. Ser604–Arg581, res. Pro562–Arg579). In the WT simulations, the Met470 side chain also packs against the positively charged guanidinium groups of Arg575, Arg429, and Arg579, which form salt bridges with the negatively charged carboxylate groups of the Asp474 and Asp467 side chains at the protein surface. In the variant simulations, the hydroxyl group of the Thr470 side chain forms an H-bond with the backbone carbonyl group of Ser466 in the α helix, potentially lowering its structural integrity. Importantly, the hydroxyl group of Thr470 also forms an H-bond with the guanidinium group of Arg575, which helps it form a more permanent salt bridge with Asp467. | ||||||||||
| c.1417G>A | V473I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473I is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438449‑G‑A). Functional prediction tools that agree on benign impact include REVEL, FoldX, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Pathogenic predictions are provided by both polyPhen‑2 HumDiv and HumVar. Predictions that are inconclusive are AlphaMissense‑Default, ESM1b, Foldetta, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is unavailable due to no majority, and Foldetta is uncertain. Overall, the balance of evidence favors a benign effect for V473I, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Uncertain | 1 | 6-33438449-G-A | 1 | 6.20e-7 | -7.481 | In-Between | 0.418 | Ambiguous | Likely Benign | 0.203 | Likely Benign | -0.12 | Likely Benign | 0.0 | 1.20 | Ambiguous | 0.54 | Ambiguous | -0.06 | Likely Benign | -0.91 | Neutral | 0.929 | Possibly Damaging | 0.917 | Probably Damaging | 3.74 | Benign | 0.18 | Tolerated | 3.37 | 34 | 3 | 4 | 0.3 | 14.03 | ||||||||||||||||||
| c.1423C>T | R475W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R475W is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33438455‑C‑T). Prediction tools that agree on a benign effect include only Foldetta, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) uniformly predict a pathogenic impact; FoldX, Rosetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of evidence points to 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 | GAP | Uncertain | 1 | 6-33438455-C-T | 1 | 6.20e-7 | -13.235 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.725 | Likely Pathogenic | 1.44 | Ambiguous | 0.4 | -0.92 | Ambiguous | 0.26 | Likely Benign | 0.56 | Ambiguous | -7.56 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.45 | Pathogenic | 0.00 | Affected | 3.39 | 28 | 2 | -3 | 3.6 | 30.03 | 266.9 | 39.6 | 0.0 | 0.0 | 0.0 | 0.1 | X | X | X | Potentially Pathogenic | In the WT simulations, the guanidinium group of Arg475, located near the end of an α-helix (res. Ala461-Phe476), stacks with the phenyl ring of Phe476 and forms a salt bridge with Glu472. Additionally, Arg475 occasionally forms another salt bridge with the carboxylate group of Glu486 on the α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. Therefore, Arg475 potentially plays a key role in positioning the loop by interacting with Glu486, which is necessary for the positioning of the “arginine finger” (Arg485) and, ultimately, for RasGTPase activation.In the variant simulations, Trp475 moves and stacks with Arg479 on the proceeding α-α loop, disrupting the terminal end of the α-helix. Lastly, the potential effect of the residue swap on the SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||
| c.1424G>A | R475Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R475Q is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6-33438456‑G‑A). Prediction tools that indicate a benign effect include AlphaMissense‑Optimized, Foldetta, and Rosetta. Those that predict a pathogenic effect comprise SGM Consensus, SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Default; FoldX and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points toward a pathogenic impact, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 2 | 6-33438456-G-A | 5 | 3.10e-6 | -12.087 | Likely Pathogenic | 0.721 | Likely Pathogenic | Likely Benign | 0.632 | Likely Pathogenic | 0.71 | Ambiguous | 0.1 | 0.12 | Likely Benign | 0.42 | Likely Benign | 0.82 | Ambiguous | -3.65 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 3.39 | 28 | 1 | 1 | 1.0 | -28.06 | 253.6 | 52.7 | 0.0 | 0.0 | -0.8 | 0.0 | X | X | X | Potentially Pathogenic | In the WT simulations, the guanidinium group of Arg475, located near the end of an α-helix (res. Ala461-Phe476), stacks with the phenyl ring of Phe476 and forms a salt bridge with Glu472. Additionally, Arg475 occasionally forms another salt bridge with the carboxylate group of Glu486 on the α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. Therefore, Arg475 potentially plays a key role in positioning the loop by interacting with Glu486, which is necessary for the positioning of the “arginine finger” (Arg485) and, ultimately, for RasGTPase activation. In the variant simulations, Asn475 forms a hydrogen bond with Arg479 on the proceeding α-α loop. The absence of Phe476/Arg475 stacking and the Arg475-Glu472 salt bridge weakens the integrity of the terminal end of the α-helix during the variant simulations. Lastly, the potential effect of the residue swap on the SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||
| c.1428C>G | F476L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F476L is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438460‑C‑G). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that returned uncertain results—FoldX, Rosetta, Foldetta, and premPS—do not contribute to the assessment. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, with two pathogenic and two benign calls; Foldetta also reports an uncertain stability change. Overall, the balance of evidence favors a pathogenic effect for F476L, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Uncertain | 2 | 6-33438460-C-G | 4 | 2.48e-6 | -10.109 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.180 | Likely Benign | 1.00 | Ambiguous | 0.1 | 1.04 | Ambiguous | 1.02 | Ambiguous | 0.75 | Ambiguous | -1.10 | Neutral | 0.997 | Probably Damaging | 0.978 | Probably Damaging | 3.53 | Benign | 0.60 | Tolerated | 3.40 | 22 | 2 | 0 | 1.0 | -34.02 | 235.9 | 16.1 | 0.0 | 0.1 | -0.2 | 0.0 | X | Potentially Benign | In the WT simulations, the phenyl ring of Phe476, located at the end of an α-helix (res. Ala461-Phe476), packs with the hydrophobic side chains of Leu482 and Ile483. Additionally, Phe476 stacks with the Arg475 side chain on the preceding α-α loop connecting the two α-helices (res. Ala461-Phe476 and res. Leu489-Glu519) near the GAP-Ras interface.In the variant simulations, Leu476 can maintain hydrophobic packing with neighboring residues, although not as efficiently as the phenylalanine in the WT system. The absence of Phe476/Arg475 stacking weakens the integrity of the α-helix end in the variant simulations. Nonetheless, no large-scale adverse effects are observed in the simulations. Lastly, the potential effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||
| c.1436G>A | R479Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R479Q is listed in ClinVar with an “Uncertain” significance and is present in gnomAD (variant ID 6‑33438468‑G‑A). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 HumDiv and HumVar both predict a pathogenic impact. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also as likely benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign effect, and this consensus does not contradict the ClinVar “Uncertain” status; thus the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Uncertain | 1 | 6-33438468-G-A | 7 | 4.34e-6 | -7.109 | In-Between | 0.259 | Likely Benign | Likely Benign | 0.191 | Likely Benign | 0.54 | Ambiguous | 0.1 | 0.57 | Ambiguous | 0.56 | Ambiguous | 0.49 | Likely Benign | -1.16 | Neutral | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 3.42 | Benign | 0.31 | Tolerated | 3.39 | 32 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||
| c.1436G>C | R479P 2D 3DClick to see structure in 3D Viewer AIClinVar lists the SynGAP1 R479P variant as Uncertain, and it is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM. Those that predict a pathogenic effect are FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Predictions that are inconclusive are AlphaMissense‑Optimized and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as pathogenic. Overall, the majority of tools and the high‑accuracy methods support a pathogenic classification, which is in contrast to the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -11.795 | Likely Pathogenic | 0.938 | Likely Pathogenic | Ambiguous | 0.277 | Likely Benign | 2.86 | Destabilizing | 0.2 | 3.88 | Destabilizing | 3.37 | Destabilizing | 0.81 | Ambiguous | -3.52 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.41 | Benign | 0.18 | Tolerated | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||
| c.1453C>A | R485S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R485S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FoldX, which scores the variant as benign. In contrast, the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that return uncertain results are Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for R485S, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -15.603 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.609 | Likely Pathogenic | 0.40 | Likely Benign | 0.1 | 1.07 | Ambiguous | 0.74 | Ambiguous | 0.82 | Ambiguous | -5.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.93 | Pathogenic | 0.00 | Affected | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||
| c.1453C>T | R485C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R485C (gnomAD ID 6‑33438485‑C‑T) is listed in ClinVar with an uncertain significance. Functional prediction tools largely disagree: benign calls come from Rosetta and premPS, whereas pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus is labeled likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. With the majority of evidence pointing to pathogenicity and no contradictory data from ClinVar, the variant is most likely pathogenic, although ClinVar has not yet reached a definitive classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 2 | 6-33438485-C-T | 9 | 5.58e-6 | -14.294 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.597 | Likely Pathogenic | 1.00 | Ambiguous | 0.1 | 0.26 | Likely Benign | 0.63 | Ambiguous | 0.44 | Likely Benign | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.90 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -4 | -3 | 7.0 | -53.05 | 225.5 | 99.6 | -0.1 | 0.0 | -0.3 | 0.2 | X | Uncertain | The guanidinium group of Arg485 is located in a short helical structure (res. Glu480-Leu482) within an α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. The side chain of Arg485 acts as the “arginine finger” of SynGAP, playing a crucial role in Ras-GTPase activation. Consequently, the residue swap inhibits the conversion of GTP to GDP at the enzyme’s active site. Although no negative effects on the protein structure are observed during the simulations, no definite conclusions can be drawn due to the critical role of Arg485 in GTPase activation. | ||||||||
| c.1456G>A | E486K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E486K is listed in ClinVar with an uncertain significance status and is not reported in gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and the Foldetta stability analysis (combining FoldX‑MD and Rosetta) predicts benign. Overall, the majority of high‑confidence tools and the consensus analysis favor a pathogenic interpretation, which contrasts with the ClinVar uncertain designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -14.545 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.435 | Likely Benign | 0.06 | Likely Benign | 0.1 | 0.37 | Likely Benign | 0.22 | Likely Benign | 0.41 | Likely Benign | -3.58 | Deleterious | 1.000 | Probably Damaging | 0.988 | Probably Damaging | 3.40 | Benign | 0.12 | Tolerated | 3.37 | 35 | 0 | 1 | -0.4 | -0.94 | 206.8 | 52.1 | -0.3 | 0.1 | 0.2 | 0.0 | X | X | Uncertain | Glu486 is located in an α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. It is adjacent to the arginine finger (Arg485) and is expected to closely interact with Ras. The residue swap could affect complex formation with the GTPase and its activation. In the WT simulations, the carboxylate group of Glu486 forms salt bridges with Arg485 and Arg475 on the preceding α-helix (res. Ala461-Phe476). In the variant simulations, Lys486 does not form any specific interactions. Although the amino group of the Lys486 side chain cannot form these salt bridges, no negative effects on the protein structure are observed. Nevertheless, the potential role of Glu486 in SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations, and no definite conclusions can be drawn. | ||||||||||
| c.1463C>T | T488M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T488M is listed in ClinVar with an uncertain significance (ClinVar ID 2824521.0) and is present in gnomAD (ID 6‑33438495‑C‑T). Prediction tools that indicate a benign effect include premPS and FATHMM, whereas the majority of algorithms predict a pathogenic outcome: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as inconclusive. No other tools provide definitive evidence. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | 6-33438495-C-T | 2 | 1.24e-6 | -12.459 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.746 | Likely Pathogenic | 0.66 | Ambiguous | 0.3 | 1.62 | Ambiguous | 1.14 | Ambiguous | 0.46 | Likely Benign | -5.70 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.21 | Benign | 0.00 | Affected | 3.37 | 35 | -1 | -1 | 2.6 | 30.09 | |||||||||||||||||
| c.1465C>T | L489F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L489F is listed in ClinVar with an uncertain significance (ClinVar ID 522018.0) and is present in the gnomAD database (gnomAD ID 6‑33438497‑C‑T). In silico 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 report a pathogenic outcome, while no tool predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. No prediction or folding‑stability result is missing or ambiguous. **Thus, the variant is most likely pathogenic based on the collective predictions, and this does not contradict the ClinVar uncertain status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 2 | 6-33438497-C-T | 1 | 6.20e-7 | -12.066 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.724 | Likely Pathogenic | 1.72 | Ambiguous | 0.5 | 1.14 | Ambiguous | 1.43 | Ambiguous | 0.56 | Ambiguous | -3.76 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.51 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 2 | 0 | -1.0 | 34.02 | 246.4 | -17.8 | 0.0 | 0.0 | 0.6 | 0.1 | X | Potentially Benign | The iso-butyl side chain of Leu489, located in the α-helix (res. Leu489-Glu519) within an inter-helix space of four helices (res. Ala461-Phe476, res. Val441-Ser457, and res. Met414-Glu436), packs with hydrophobic residues (e.g., Cys432, Ala448, Lys444, Ala493, Val447, Met468) in the inter-helix space. In the variant simulations, the phenyl ring of the Phe489 side chain can also pack favorably in the hydrophobic region. However, due to the size difference, the aromatic side chain of Phe489 tends to reposition to escape the tight region to accommodate the larger side chain, stacking with Lys444. Although no apparent negative changes are observed during the variant simulation, the size difference between the swapped residues could affect the protein folding process. | ||||||||
| c.1468G>C | A490P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A490P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Among the available in‑silico predictors, 10 tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) uniformly predict a pathogenic effect, whereas only Foldetta predicts a benign outcome; FoldX, Rosetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) is benign. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -12.905 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 0.878 | Likely Pathogenic | -1.27 | Ambiguous | 0.1 | 1.31 | Ambiguous | 0.02 | Likely Benign | 1.07 | Destabilizing | -4.81 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.42 | Pathogenic | 0.01 | Affected | 3.37 | 35 | -1 | 1 | -3.4 | 26.04 | ||||||||||||||||||||
| c.1483G>A | E495K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E495K is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include FoldX and Foldetta, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools with inconclusive results (Rosetta and premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus also as pathogenic, while Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) indicates a benign effect. Overall, the preponderance of evidence from standard and high‑accuracy predictors points to a pathogenic effect for E495K, which is not in conflict with the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -11.478 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.869 | Likely Pathogenic | 0.15 | Likely Benign | 0.2 | 0.66 | Ambiguous | 0.41 | Likely Benign | 0.70 | Ambiguous | -3.91 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.29 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||
| c.1484A>G | E495G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E495G missense variant is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438516‑A‑G). Among the available in‑silico predictors, the following tools uniformly indicate a pathogenic effect: REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (which itself is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). No tool in the dataset predicts a benign outcome; predictions that are uncertain (FoldX, Foldetta, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM‑Consensus as “Likely Pathogenic,” and Foldetta as “Uncertain.” Overall, the preponderance of pathogenic predictions strongly suggests that the variant is most likely pathogenic, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | 6-33438516-A-G | 1 | 6.20e-7 | -9.400 | Likely Pathogenic | 0.923 | Likely Pathogenic | Ambiguous | 0.867 | Likely Pathogenic | 1.21 | Ambiguous | 0.0 | 2.06 | Destabilizing | 1.64 | Ambiguous | 0.78 | Ambiguous | -6.70 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.46 | Pathogenic | 0.02 | Affected | 3.37 | 35 | -2 | 0 | 3.1 | -72.06 | |||||||||||||||||
| c.1487A>G | E496G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E496G missense variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess the variant’s effect fall into two groups: no tool predicts a benign outcome, while eight tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic effect. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus remains likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the preponderance of evidence points to a pathogenic effect, contradicting the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -13.529 | Likely Pathogenic | 0.850 | Likely Pathogenic | Ambiguous | 0.825 | Likely Pathogenic | 1.83 | Ambiguous | 0.1 | 1.76 | Ambiguous | 1.80 | Ambiguous | 0.92 | Ambiguous | -6.16 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.45 | Pathogenic | 0.02 | Affected | 3.37 | 35 | 0 | -2 | 3.1 | -72.06 | 173.9 | 103.1 | 0.0 | 0.0 | -0.7 | 0.0 | X | X | Potentially Pathogenic | Glu496 is located in the α-helix (res. Leu489-Glu519), and its carboxylate group forms salt bridges with the neighbouring residues Lys492 and Arg499 in the WT simulations. Glu496 also forms a hydrogen bond with Ser449 on an opposing helix (res. Val441-Ser457). In the variant simulations, Gly496 cannot form these salt bridges, which could weaken the secondary structure. Additionally, the loss of the hydrogen bond with Ser449 on the opposite helix can weaken the tertiary structure assembly. Moreover, glycine is an α-helix breaker, and it is seen to weaken the integrity of the helix as the hydrogen bonding between the backbone atoms of Gly496 and Ala493 breaks down. Also, due to its location at the GAP-Ras interface, the interaction of Glu496 with Arg499 and Lys492 might play a role in complex association and stability, which cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||||||
| c.1490A>G | Y497C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497C is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all return a deleterious signal: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict pathogenic. No tool reports a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM Consensus as “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) as “Pathogenic.” Overall, the variant is most likely pathogenic based on the consensus of predictive algorithms, which contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -11.872 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.806 | Likely Pathogenic | 3.88 | Destabilizing | 0.1 | 4.76 | Destabilizing | 4.32 | Destabilizing | 1.40 | Destabilizing | -8.82 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.65 | Pathogenic | 0.03 | Affected | 3.37 | 35 | 0 | -2 | 3.8 | -60.04 | 209.9 | 59.1 | -0.1 | 0.0 | -0.3 | 0.1 | X | X | Potentially Pathogenic | Tyr497 is located in the α-helix (res. Leu489-Glu519) within the inter-helix space of four α-helices (res. Leu489-Ile501, res. Val441-Ser457, res. Arg563-Glu578, res. Ala461-Val473). In the WT simulations, the phenol ring of Tyr497 hydrophobically packs with other residues in the inter-helix space (e.g., Leu465, Leu565, Val568). The hydroxyl group of Tyr497 also alternately forms hydrogen bonds with the carboxylate side chain of Gln456 and the backbone carbonyl of Glu564. Thus, Tyr497 plays a role in the folding and maintenance of the tertiary structure assembly between these four helices.In the variant simulations, the comparatively smaller residue, Cys497, cannot maintain any of the interactions seen with Tyr497 in the WT. Although no severe deleterious consequences are observed in the simulations, the structural effects could be more pronounced during actual protein folding. Indeed, the tertiary structure is seen to slightly break apart in the variant simulations. | ||||||||||
| c.1502T>C | I501T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501T 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, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and premPS, while Rosetta remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of predictions lean toward a benign effect, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Uncertain | 1 | -5.996 | Likely Benign | 0.252 | Likely Benign | Likely Benign | 0.362 | Likely Benign | 2.40 | Destabilizing | 0.1 | 1.81 | Ambiguous | 2.11 | Destabilizing | 1.57 | Destabilizing | -3.48 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.44 | Benign | 0.16 | Tolerated | 3.37 | 35 | 0 | -1 | -5.2 | -12.05 | 214.5 | 26.9 | 0.0 | 0.0 | 0.5 | 0.0 | X | Potentially Pathogenic | Ile501 is located near a hinge in the middle of an α-helix (res. Leu489-Glu519). The sec-butyl side chain of Ile501 is hydrophobically packed with other residues in the inter-helix space (e.g., Leu500, Tyr497, Phe679) in the WT simulations. In the variant simulations, the hydroxyl group of Thr501 forms a hydrogen bond with the backbone atoms of Tyr497 on the same α-helix, which may weaken the α-helix integrity. Additionally, the polar hydroxyl group of Thr501 is not suitable for the hydrophobic inter-helix space, and thus, the residue swap could affect protein folding. However, Ile501 is followed by Gly502, which facilitates a hinge in the middle of the α-helix, making further weakening caused by Thr501 unlikely to be harmful to the α-helix integrity. | |||||||||||
| c.1505G>A | G502D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G502D is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Based on the uniform predictions, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -14.796 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.915 | Likely Pathogenic | 3.79 | Destabilizing | 0.9 | 5.69 | Destabilizing | 4.74 | Destabilizing | 1.38 | Destabilizing | -6.80 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | -1.66 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 1 | -1 | -3.1 | 58.04 | 224.2 | -80.0 | -0.8 | 0.7 | 0.6 | 0.3 | X | X | X | Potentially Pathogenic | Gly502 is located in a hinge in the middle of an α-helix (res. Leu489-Glu519). In the WT, Gly502 acts as an α-helix breaker due to its lack of a side chain, facilitating a bend in the middle of the α-helix. In the variant simulations, the carboxylate group of Asp502 forms hydrogen bonds with neighboring residues (e.g., Ser677, Lys504), disrupting the hinge. Additionally, Asp502 struggles to fit into the α-helix hinge and cannot generate a similar bend as Gly502, which would drastically affect the secondary structure during folding. Thus, the deleterious effect seen in the simulations is likely an underestimate of the impact of the residue swap on the protein structure during protein folding. | |||||||||
| c.1511A>G | K504R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K504R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438543‑A‑G). Consensus from most in‑silico predictors is benign: REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a benign effect, while only FATHMM predicts pathogenicity. Uncertain calls come from Rosetta and premPS. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. Overall, the preponderance of evidence indicates 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 | GAP | Uncertain | 1 | 6-33438543-A-G | 2 | 1.24e-6 | -4.365 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.238 | Likely Benign | 0.13 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.32 | Likely Benign | 0.94 | Ambiguous | -2.16 | Neutral | 0.002 | Benign | 0.015 | Benign | -1.41 | Pathogenic | 0.11 | Tolerated | 3.37 | 35 | 2 | 3 | -0.6 | 28.01 | |||||||||||||||||
| c.1516C>T | L506F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L506F is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact; premPS and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain, the SGM Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, which is consistent with its ClinVar “Uncertain” classification and does not contradict the available data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -11.262 | Likely Pathogenic | 0.883 | Likely Pathogenic | Ambiguous | 0.464 | Likely Benign | 4.92 | Destabilizing | 0.8 | 5.76 | Destabilizing | 5.34 | Destabilizing | 0.91 | Ambiguous | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.62 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0 | 2 | -1.0 | 34.02 | ||||||||||||||||||||
| c.1540A>T | I514F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514F is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—report it as pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, classifies the variant as pathogenic. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, which is consistent with its ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -13.383 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.601 | Likely Pathogenic | 2.35 | Destabilizing | 0.3 | 3.74 | Destabilizing | 3.05 | Destabilizing | 0.93 | Ambiguous | -3.98 | Deleterious | 0.997 | Probably Damaging | 0.993 | Probably Damaging | 2.89 | Benign | 0.00 | Affected | 3.37 | 35 | 0 | 1 | -1.7 | 34.02 | ||||||||||||||||||||
| c.1544G>A | R515H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R515H is listed in ClinVar with an uncertain significance (ClinVar ID 638438.0) and is present in gnomAD (variant ID 6‑33438787‑G‑A). Prediction tools that agree on a benign effect include AlphaMissense‑Default and AlphaMissense‑Optimized. Those that predict a pathogenic impact comprise REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus remains pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Overall, the balance of evidence favors a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | 6-33438787-G-A | 3 | 1.86e-6 | -10.774 | Likely Pathogenic | 0.337 | Likely Benign | Likely Benign | 0.730 | Likely Pathogenic | 1.07 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.91 | Ambiguous | 1.09 | Destabilizing | -3.44 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 2 | 0 | 1.3 | -19.05 | 239.2 | 77.8 | 0.0 | 0.0 | 0.4 | 0.2 | X | Potentially Benign | The guanidinium group of Arg515, located in the middle of an α-helix at the GAP domain (res. Gly502-Tyr518), forms salt bridges with the carboxylate groups of Glu512 on the same helix and Glu217 on a loop in the PH domain. Additionally, the positively charged Arg515 side chain forms hydrogen bonds with Leu610 and Gln612 in an opposing loop (res. Gly609-Asp616). In contrast, in the variant simulations, the imidazole ring of His515 cannot form salt bridges with either of the acidic residues, and its side chain is too short to form hydrogen bonds with the loop residues. Accordingly, the residue swap could weaken the tertiary structure assembly of the protein. Due to the missing N-terminal part of the SynGAP model, the effect could be largely underestimated or missing. Notably, the doubly protonated and positively charged form of histidine was not simulated here. | ||||||||
| c.1552T>C | Y518H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y518H is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, and ESM1b. Predictions that are inconclusive are Foldetta, AlphaMissense‑Optimized, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for Y518H, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -9.797 | Likely Pathogenic | 0.943 | Likely Pathogenic | Ambiguous | 0.496 | Likely Benign | 2.39 | Destabilizing | 0.4 | 0.82 | Ambiguous | 1.61 | Ambiguous | 1.31 | Destabilizing | -4.74 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.08 | Tolerated | 0 | 2 | -1.9 | -26.03 | ||||||||||||||||||||||
| c.1558T>C | S520P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a pathogenic outcome, while premPS remains inconclusive. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Overall, the evidence strongly supports a pathogenic impact for S520P, 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 Pathogenic | GAP | Uncertain | 1 | -12.707 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.855 | Likely Pathogenic | 3.72 | Destabilizing | 0.8 | 8.86 | Destabilizing | 6.29 | Destabilizing | 0.83 | Ambiguous | -4.57 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||
| c.1559C>T | S520F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520F is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include Rosetta, Foldetta, and premPS. Those that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX gives an uncertain result. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, whereas Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign impact. Overall, the majority of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -12.541 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.833 | Likely Pathogenic | -1.20 | Ambiguous | 0.4 | 0.39 | Likely Benign | -0.41 | Likely Benign | 0.25 | Likely Benign | -5.57 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.36 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -2 | -3 | 3.6 | 60.10 | ||||||||||||||||||||
| c.155C>T | S52L 2D AISynGAP1 missense variant S52L is listed in ClinVar with an uncertain significance and is present in the gnomAD database (ID 6‑33423564‑C‑T). 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 AlphaMissense‑Default; ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also favors benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the collective evidence points to a likely benign effect, which does not contradict the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Uncertain | 1 | 6-33423564-C-T | 1 | 6.20e-7 | -7.199 | In-Between | 0.688 | Likely Pathogenic | Likely Benign | 0.087 | Likely Benign | -1.41 | Neutral | 0.829 | Possibly Damaging | 0.706 | Possibly Damaging | 4.10 | Benign | 0.00 | Affected | 4.32 | 1 | -3 | -2 | 4.6 | 26.08 | ||||||||||||||||||||||||||||
| c.1579G>T | D527Y 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant D527Y is listed in ClinVar with an uncertain significance (ClinVar ID 1698369.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: the single benign prediction from premPS versus a consensus of pathogenic predictions from the remaining 12 tools (REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Protein‑stability calculations from FoldX and Rosetta are also uncertain. Overall, the preponderance of evidence indicates that D527Y is most likely pathogenic, which does not contradict the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -15.386 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.905 | Likely Pathogenic | -0.77 | Ambiguous | 0.2 | 1.89 | Ambiguous | 0.56 | Ambiguous | -0.14 | Likely Benign | -8.79 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -2.41 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -4 | -3 | 2.2 | 48.09 | 270.9 | -45.7 | 0.1 | 0.1 | -0.1 | 0.0 | X | Potentially Pathogenic | Asp527 is located on an α-α loop between the two α-helices (res. Gly502-Tyr518 and Ala533-Val560). In the WT simulations, the carboxylate group of the Asp527 side chain forms hydrogen bonds with the backbone atoms of loop residues (e.g., Ile529, Lys530) facing the membrane surface. In the variant simulations, Tyr527 is a bulkier residue that faces away from the loop and stacks with Phe646 in a nearby α-helix (res. Ser614-Ser668). Regardless, no negative structural effects are observed during the variant simulations. However, due to its location near the SynGAP-membrane interface, the effect of the residue swap cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||
| c.1586T>C | I529T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I529T is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Benign” call. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the majority of evidence points to a benign effect, and this is consistent with the ClinVar “Uncertain” classification—there is no contradiction between the predictions and the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Uncertain | 1 | -0.539 | Likely Benign | 0.336 | Likely Benign | Likely Benign | 0.343 | Likely Benign | 0.22 | Likely Benign | 0.2 | 0.16 | Likely Benign | 0.19 | Likely Benign | 0.17 | Likely Benign | 0.24 | Neutral | 0.872 | Possibly Damaging | 0.820 | Possibly Damaging | -1.23 | Pathogenic | 0.55 | Tolerated | 3.37 | 35 | 0 | -1 | -5.2 | -12.05 | 207.2 | 29.8 | 0.2 | 0.0 | 0.2 | 0.1 | X | Potentially Benign | Ile529 is located on an α-α loop between the two α-helices (res. Gly502-Tyr518 and Ala533-Val560). In the WT simulations, the sec-butyl side chain of Ile529 faces the membrane interface and shows no specific interactions. In the variant simulations, the hydroxyl group of Thr529 forms a hydrogen bond with the carboxylate side chain of Asp527, but no negative structural changes are observed. However, due to its location near the SynGAP-membrane interface, the effect of the residue swap cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||
| c.1600T>C | S534P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534P is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438843‑T‑C). Functional prediction tools that report a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The high‑accuracy assessments are consistent with a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Based on the aggregate predictions, the variant 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 | GAP | Uncertain | 1 | 6-33438843-T-C | 3 | 1.86e-6 | -5.056 | Likely Benign | 0.265 | Likely Benign | Likely Benign | 0.203 | Likely Benign | -0.40 | Likely Benign | 0.2 | 0.35 | Likely Benign | -0.03 | Likely Benign | 0.47 | Likely Benign | -3.81 | Deleterious | 0.993 | Probably Damaging | 0.993 | Probably Damaging | 3.32 | Benign | 0.05 | Affected | 3.37 | 35 | -1 | 1 | -0.8 | 10.04 | |||||||||||||||||
| c.1606T>G | L536V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L536V is listed in ClinVar (ID 1690714.0) with an uncertain significance designation and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic verdict. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. No evidence from FoldX or Rosetta alone is available. Overall, the majority of evidence points toward a pathogenic effect, which does not contradict the ClinVar uncertain status but suggests a higher likelihood of pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -9.014 | Likely Pathogenic | 0.269 | Likely Benign | Likely Benign | 0.586 | Likely Pathogenic | 1.25 | Ambiguous | 0.3 | 1.22 | Ambiguous | 1.24 | Ambiguous | 1.20 | Destabilizing | -2.81 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | -1.34 | Pathogenic | 0.09 | Tolerated | 3.37 | 34 | 2 | 1 | 0.4 | -14.03 | 204.7 | 26.4 | 0.2 | 0.0 | -0.2 | 0.2 | X | Potentially Benign | Leu536 is located on an α-helix (res. Ala533-Val560) at the membrane interface. The iso-butyl group of Leu536 interacts with nearby hydrophobic residues in the preceding loop (e.g., Val526, Pro528, Cys531). In the variant simulations, the iso-propyl side chain of Val536 forms similar hydrophobic interactions as Leu536 in the WT, causing no negative structural effects. | |||||||||||
| c.1621G>C | A541P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A541P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include only SIFT, whereas the remaining tools—REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenicity. No predictions are inconclusive or missing. Overall, the collective evidence points to a pathogenic effect for A541P, which is in contrast to the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -14.733 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.594 | Likely Pathogenic | 2.47 | Destabilizing | 0.3 | 7.26 | Destabilizing | 4.87 | Destabilizing | 0.86 | Ambiguous | -3.16 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.34 | Pathogenic | 0.07 | Tolerated | 3.37 | 35 | 1 | -1 | -3.4 | 26.04 | 170.4 | -11.2 | 0.1 | 0.0 | 0.1 | 0.0 | X | Potentially Pathogenic | Ala541 is located on the outer surface of an α-helix (res. Ala533-Val560). The methyl group of Ala541 is on the surface and does not form any interactions. Proline lacks a free backbone amide group, and thus, Pro541 is unable to form a hydrogen bond with the carbonyl group of Ala537 in the variant simulations. Consequently, Pro541 disrupts the continuity of the secondary structure element, causing the α-helix to bend slightly in the variant simulations. | |||||||||||
| c.1622C>G | A541G 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant A541G is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438865‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default, and ESM1b) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also inconclusive. Overall, the balance of evidence leans toward a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Uncertain | 1 | 6-33438865-C-G | 2 | 1.24e-6 | -7.233 | In-Between | 0.341 | Ambiguous | Likely Benign | 0.421 | Likely Benign | 0.67 | Ambiguous | 0.0 | 0.94 | Ambiguous | 0.81 | Ambiguous | 0.76 | Ambiguous | -1.48 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.31 | Pathogenic | 0.57 | Tolerated | 3.37 | 35 | 1 | 0 | -2.2 | -14.03 | 170.1 | 23.6 | 0.0 | 0.0 | 0.0 | 0.0 | X | Potentially Pathogenic | Ala541 is located on the outer surface of an α-helix (res. Ala533-Val560). The methyl group of Ala541 is on the surface and does not form any interactions. Glycine, known as an “α-helix breaker,” weakens the integrity of the helix. Indeed, in the variant simulations, the hydrogen bond formation between Gly541 and the backbone carbonyl of Ala537 is disrupted. | |||||||||
| c.1631G>A | R544Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R544Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33438874‑G‑A). Prediction tools that classify the change as benign include FoldX, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Foldetta and Rosetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, which is not contradictory to the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | 6-33438874-G-A | 1 | 6.20e-7 | -10.281 | Likely Pathogenic | 0.596 | Likely Pathogenic | Likely Benign | 0.542 | Likely Pathogenic | 0.19 | Likely Benign | 0.2 | 0.87 | Ambiguous | 0.53 | Ambiguous | 1.40 | Destabilizing | -2.41 | Neutral | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.40 | Pathogenic | 0.09 | Tolerated | 3.37 | 35 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||
| c.1631G>C | R544P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R544P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Across the available in‑silico predictors, none indicate a benign effect; all 13 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. Consequently, the variant is most likely pathogenic based on current predictions, which contradicts the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 2 | -16.905 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.762 | Likely Pathogenic | 4.70 | Destabilizing | 0.1 | 4.19 | Destabilizing | 4.45 | Destabilizing | 1.14 | Destabilizing | -4.88 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.48 | Pathogenic | 0.05 | Affected | 3.37 | 35 | 0 | -2 | 2.9 | -59.07 | 192.0 | 123.8 | 0.1 | 0.0 | -0.3 | 0.0 | X | X | Potentially Pathogenic | Arg544 is located in the middle of an α-helix (res. Ala533-Val560). In the WT simulations, the guanidinium side chain of Arg544 forms a salt bridge with the carboxylate groups of Glu548 on the same α-helix, and with Glu651 and Glu656 on an opposing α-helix (res. Glu666-Asp644). In the variant simulations, the pyrrolidine side chain of Pro544 cannot form any of the salt bridges that Arg544 does in the WT, potentially weakening the tertiary structure assembly. Additionally, Pro544 lacks the amide group, and thus, unlike Arg544 in the WT, is unable to form a hydrogen bond with the carbonyl of Gln540. This disruption breaks the continuity of the secondary structure element, causing the α-helix to bend slightly in the variant simulations. These negative structural effects could be more pronounced during protein folding and are likely to be undermined in the MD simulations. | ||||||||||
| c.1635G>A | M545I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M545I is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions arise from FoldX, Rosetta, and SIFT, whereas pathogenic predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default; premPS remains inconclusive. High‑accuracy methods provide mixed evidence: AlphaMissense‑Optimized indicates pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also suggests likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Overall, the preponderance of conventional tools and the SGM Consensus lean toward pathogenicity, whereas the Foldetta result is an outlier. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict its ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -8.348 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.592 | Likely Pathogenic | 0.47 | Likely Benign | 0.1 | 0.14 | Likely Benign | 0.31 | Likely Benign | 0.63 | Ambiguous | -3.61 | Deleterious | 0.935 | Possibly Damaging | 0.941 | Probably Damaging | -1.27 | Pathogenic | 0.28 | Tolerated | 3.37 | 35 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||
| c.1639T>C | C547R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C547R is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while no tool in the dataset predicts a benign outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Based on the unanimous computational evidence, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -16.967 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.900 | Likely Pathogenic | 7.76 | Destabilizing | 0.8 | 5.83 | Destabilizing | 6.80 | Destabilizing | 1.69 | Destabilizing | -11.60 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.33 | Pathogenic | 0.02 | Affected | 3.37 | 35 | -4 | -3 | -7.0 | 53.05 | 267.4 | -90.3 | 0.0 | 0.0 | -0.1 | 0.1 | X | X | X | X | Potentially Pathogenic | Cys547 is located in an α-helix (res. Ala533-Val560). The thiol side chain of Cys is situated in a hydrophobic inter-helix space, where it packs hydrophobically with other residues such as Ile626, Leu551, and Phe652. Additionally, the thiol side chain of Cys547 weakly hydrogen bonds with the carbonyl group of Leu543 in the same α-helix. In the variant simulations, the bulkier, positively charged guanidinium group of Arg547 must rotate out of the hydrophobic space. Consequently, it forms ionic interactions with the carboxylate groups of Glu548 in the same helix and Glu656 in the neighboring α-helix (res. Glu666-Asp644). This causes the two helices to slightly separate, significantly affecting the secondary structure integrity of the latter helix. These negative structural effects could be more pronounced during protein folding and are likely to be undermined in the MD simulations. | ||||||||
| c.163C>A | Q55K 2D  AIThe SynGAP1 missense variant Q55K is listed in ClinVar (ID 520688.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33423572‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments 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 not in conflict with the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 2 | 6-33423572-C-A | 24 | 1.49e-5 | -5.840 | Likely Benign | 0.612 | Likely Pathogenic | Likely Benign | 0.085 | Likely Benign | -1.21 | Neutral | 0.140 | Benign | 0.184 | Benign | 3.91 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||
| c.1651C>A | L551M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L551M is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438894‑C‑A). Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, PROVEAN, SIFT, and AlphaMissense‑Optimized, while those that predict pathogenicity are REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Two tools report an uncertain outcome: premPS and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of predictions lean toward a benign effect, and this does not contradict the ClinVar “Uncertain” classification. Thus, the variant is most likely benign based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Uncertain | 1 | 6-33438894-C-A | 7 | 4.34e-6 | -9.937 | Likely Pathogenic | 0.480 | Ambiguous | Likely Benign | 0.544 | Likely Pathogenic | -0.07 | Likely Benign | 0.1 | 0.13 | Likely Benign | 0.03 | Likely Benign | 0.71 | Ambiguous | -0.56 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.48 | Pathogenic | 0.06 | Tolerated | 3.37 | 35 | 4 | 2 | -1.9 | 18.03 | 246.5 | -18.6 | 0.0 | 0.0 | 0.3 | 0.0 | X | Potentially Benign | L551 is located on an α-helix (res. Ala533-Val560). The iso-butyl side chain of Leu551 hydrophobically packs with nearby hydrophobic residues such as Cys547, Phe652, Leu633, and Ile630 in the inter-helix space. In the variant simulations, the thioether side chain of Met551 can maintain similar hydrophobic interactions as Leu551 in the WT, thus causing no negative effect on the protein structure during the simulations. | |||||||||
| c.1658A>C | K553T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K553T is listed in ClinVar with an uncertain significance (ClinVar ID 2007142.0) and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include Rosetta and SIFT, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, both polyPhen‑2 HumDiv and HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Uncertain results are reported by FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as inconclusive. Overall, the consensus of the available predictions indicates that K553T is most likely pathogenic, which does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -15.328 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.761 | Likely Pathogenic | 1.06 | Ambiguous | 0.2 | 0.48 | Likely Benign | 0.77 | Ambiguous | 0.79 | Ambiguous | -5.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.34 | Pathogenic | 0.14 | Tolerated | 3.37 | 35 | 0 | -1 | 3.2 | -27.07 | 218.2 | -10.7 | 0.0 | 0.0 | -0.2 | 0.5 | X | Potentially Pathogenic | Lys533 is located on an α-helix (res. Ala533-Val560). In the WT simulations, Lys533 packs against Phe513, and its amino side chain occasionally forms an ionic interaction with the carboxylate group of Glu512 from an opposing α-helix (res. Gln503-Tyr518). In the variant simulations, Thr533 is unable to reproduce these interactions, potentially weakening the integrity of the tertiary structure. Additionally, Thr533 forms a hydrogen bond with the backbone carbonyl group of Leu549 in the same helix, which could potentially weaken the secondary structure. Regardless, the residue swap does not cause significant structural effects based on the simulations. | |||||||||||
| c.1663G>A | V555I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V555I is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Only FATHMM predicts a pathogenic outcome, while FoldX, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect, 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 | GAP | Uncertain | 1 | -4.544 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.253 | Likely Benign | -0.82 | Ambiguous | 0.0 | -0.41 | Likely Benign | -0.62 | Ambiguous | -0.55 | Ambiguous | 0.45 | Neutral | 0.002 | Benign | 0.002 | Benign | -1.26 | Pathogenic | 1.00 | Tolerated | 4 | 3 | 0.3 | 14.03 | ||||||||||||||||||||||
| c.1667A>G | N556S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N556S (ClinVar ID 941099.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33438910‑A‑G). Functional prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta predicts a benign effect. No other high‑accuracy or folding‑stability methods provide additional evidence. Overall, the majority of predictions support 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. | GAP | Uncertain | 1 | 6-33438910-A-G | 3 | 1.86e-6 | -6.576 | Likely Benign | 0.197 | Likely Benign | Likely Benign | 0.449 | Likely Benign | 0.52 | Ambiguous | 0.1 | 0.14 | Likely Benign | 0.33 | Likely Benign | 0.16 | Likely Benign | -3.60 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | -1.22 | Pathogenic | 0.14 | Tolerated | 3.37 | 35 | 1 | 1 | 2.7 | -27.03 | 198.8 | 31.0 | 0.0 | 0.0 | -0.5 | 0.2 | X | Potentially Benign | Asn556 is located on the outer surface of an α-helix (res. Ala533-Val560). The carboxamide group of Asn556 forms hydrogen bonds with nearby residues such as Lys553 and Cys552. It also forms a hydrogen bond with the backbone carbonyl group of Cys552, which weakens the α-helix integrity. In the variant simulations, the hydroxyl group of Ser556 forms a more stable hydrogen bond with the backbone carbonyl oxygen of the same helix residue, Cys552, compared to Asn556 in the WT. Serine has a slightly lower propensity to reside in an α-helix than asparagine, which may exacerbate the negative effect on the α-helix integrity. However, the residue swap does not cause negative structural effects during the simulations. | |||||||||
| c.1673A>G | H558R 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant H558R is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from AlphaMissense‑Optimized, Rosetta, SIFT, and polyPhen‑2 HumVar, while pathogenic predictions arise from REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and FATHMM. Four tools give inconclusive results: AlphaMissense‑Default, SGM‑Consensus, FoldX, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign effect, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains uncertain. Overall, the majority of evidence points toward a pathogenic impact, which does not conflict with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -14.445 | Likely Pathogenic | 0.554 | Ambiguous | Likely Benign | 0.587 | Likely Pathogenic | -1.14 | Ambiguous | 0.1 | -0.23 | Likely Benign | -0.69 | Ambiguous | 1.03 | Destabilizing | -4.94 | Deleterious | 0.677 | Possibly Damaging | 0.239 | Benign | -1.24 | Pathogenic | 0.14 | Tolerated | 3.37 | 35 | 0 | 2 | -1.3 | 19.05 | ||||||||||||||||||||
| c.1678G>A | V560M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V560M missense variant is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6-33440730-G-A). Functional prediction tools that agree on a benign effect include FoldX, Foldetta, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Uncertain predictions come from Rosetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of high‑confidence tools predict a benign impact, with only one consensus pathogenic prediction. Therefore, the variant is most likely benign based on current computational evidence, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Uncertain | 2 | 6-33440730-G-A | 15 | 9.50e-6 | -9.598 | Likely Pathogenic | 0.517 | Ambiguous | Likely Benign | 0.520 | Likely Pathogenic | -0.33 | Likely Benign | 0.1 | 0.88 | Ambiguous | 0.28 | Likely Benign | 0.72 | Ambiguous | -2.42 | Neutral | 0.999 | Probably Damaging | 0.863 | Possibly Damaging | -1.25 | Pathogenic | 0.14 | Tolerated | 3.37 | 35 | 2 | 1 | -2.3 | 32.06 | 234.9 | -52.6 | 0.0 | 0.0 | -0.1 | 0.1 | X | Potentially Benign | Val560 is located on the surface at the end of an α-helix (res. Ala533-Val560). The iso-propyl group of Val560 favorably packs against Asp508 of the opposing α-helix (res. Gln503-Glu519). However, in the variant simulations, the bulkier thioether side chain of Met560 does not form equally favorable inter-helix interactions. Regardless, no negative structural effects are observed during the simulations. | |||||||||
| c.169C>T | L57F 2D AIThe SynGAP1 missense variant L57F (ClinVar ID 1973575.0) is listed as “Uncertain” in ClinVar and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion aligns with the ClinVar “Uncertain” status, as it does not contradict the current classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 2 | -5.096 | Likely Benign | 0.459 | Ambiguous | Likely Benign | 0.051 | Likely Benign | -0.78 | Neutral | 0.824 | Possibly Damaging | 0.879 | Possibly Damaging | 3.96 | Benign | 0.00 | Affected | 4.32 | 1 | 2 | 0 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||
| c.1702G>T | V568L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V568L is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Among the available in‑silico predictors, eight tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic effect, whereas three tools (FoldX, Foldetta, and polyPhen‑2 HumVar) predict a benign outcome; the remaining three (Rosetta, premPS, AlphaMissense‑Optimized) are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as benign. Overall, the preponderance of evidence points to a pathogenic impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -9.503 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | 0.651 | Likely Pathogenic | -0.30 | Likely Benign | 0.3 | 0.57 | Ambiguous | 0.14 | Likely Benign | 0.56 | Ambiguous | -2.69 | Deleterious | 0.511 | Possibly Damaging | 0.147 | Benign | -1.23 | Pathogenic | 0.04 | Affected | 3.37 | 35 | 1 | 2 | -0.4 | 14.03 | ||||||||||||||||||||
| c.1712C>T | S571L 2D 3DClick to see structure in 3D Viewer AISynGAP1 S571L is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33440764‑C‑T). Prediction tools cluster into two groups: benign predictions come from premPS and AlphaMissense‑Optimized, while the remaining nine tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—indicate pathogenicity. High‑accuracy assessments further show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic (a majority vote of pathogenic predictions from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain due to conflicting FoldX‑MD and Rosetta outputs. Overall, the preponderance of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | 6-33440764-C-T | 1 | 6.23e-7 | -11.651 | Likely Pathogenic | 0.660 | Likely Pathogenic | Likely Benign | 0.841 | Likely Pathogenic | -1.53 | Ambiguous | 0.1 | -1.05 | Ambiguous | -1.29 | Ambiguous | 0.27 | Likely Benign | -5.61 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | -1.25 | Pathogenic | 0.04 | Affected | 3.37 | 35 | -2 | -3 | 4.6 | 26.08 | |||||||||||||||||
| c.1714T>G | W572G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W572G is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Based on the uniform pathogenic predictions from both general and high‑accuracy tools, the variant is most likely pathogenic, a conclusion that contradicts its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -17.692 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.900 | Likely Pathogenic | 6.57 | Destabilizing | 0.2 | 7.57 | Destabilizing | 7.07 | Destabilizing | 1.83 | Destabilizing | -11.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.24 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -7 | -2 | 0.5 | -129.16 | 195.2 | 127.9 | 0.0 | 0.0 | -1.0 | 0.0 | X | Potentially Pathogenic | The introduced residue Gly572, located in an α-helix (res. Arg563-Glu578), is considerably smaller than the tryptophan it replaced. The indole ring of the Trp572 side chain lies in a hydrophobic inter-helix space, where it makes extensive hydrophobic interactions with nearby residues such as Met470, Phe569, Leu588, and Ile589. In the variant simulations, all these favorable packing interactions are completely removed, as the introduced residue Gly572 essentially lacks a side chain altogether. Although not observed in the simulations, the residue swap could also weaken the integrity of the helix (res. Arg563-Glu578), as glycine is known as an “α-helix breaker.” Overall, the residue swap is highly likely to cause critical protein folding problems that are underestimated based on the effects seen in the variant simulations. | |||||||||||
| c.172A>G | M58V 2D AIThe SynGAP1 missense variant M58V is listed in ClinVar (ID 2962156.0) with an uncertain significance status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The high‑accuracy consensus from AlphaMissense‑Optimized, SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta (protein‑folding stability) is available only for the first two; Foldetta data are missing. The SGM Consensus, based on a majority of benign predictions, indicates a likely benign outcome. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -2.211 | Likely Benign | 0.688 | Likely Pathogenic | Likely Benign | 0.160 | Likely Benign | -0.71 | Neutral | 0.006 | Benign | 0.091 | Benign | 4.19 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||||||||||
| c.1736G>A | R579Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R579Q is listed in ClinVar with an uncertain significance (ClinVar ID 3964539.0) and is present in gnomAD (variant ID 6‑33440788‑G‑A). Prediction tools that classify the variant as benign include SIFT and AlphaMissense‑Optimized, whereas the majority of other in‑silico predictors (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict it to be pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized reports a benign effect, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an inconclusive result. FoldX and Rosetta individually report uncertain effects. Overall, the preponderance of evidence from both general and high‑accuracy tools indicates that R579Q is most likely pathogenic, which is consistent with its ClinVar status of uncertain significance rather than a benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | 6-33440788-G-A | 18 | 1.12e-5 | -9.193 | Likely Pathogenic | 0.690 | Likely Pathogenic | Likely Benign | 0.673 | Likely Pathogenic | 0.65 | Ambiguous | 0.1 | 0.70 | Ambiguous | 0.68 | Ambiguous | 1.13 | Destabilizing | -3.31 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.34 | Pathogenic | 0.06 | Tolerated | 3.37 | 34 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||
| c.1738G>A | G580S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G580S is listed in ClinVar with an “Uncertain” status (ClinVar ID 1487029.0) and is present in the gnomAD database (gnomAD ID 6‑33440790‑G‑A). Among the available in‑silico predictors, the majority (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) indicate a pathogenic effect, whereas only SIFT predicts a benign outcome. Predictions that are inconclusive or uncertain include Rosetta, Foldetta, premPS, AlphaMissense‑Optimized, and the SGM‑Consensus (which is derived from the pathogenic majority of the four contributing tools). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain (combining a pathogenic FoldX result with an uncertain Rosetta result). Overall, the preponderance 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 | GAP | Uncertain | 1 | 6-33440790-G-A | 1 | 6.20e-7 | -10.788 | Likely Pathogenic | 0.861 | Likely Pathogenic | Ambiguous | 0.644 | Likely Pathogenic | 2.84 | Destabilizing | 0.2 | 0.59 | Ambiguous | 1.72 | Ambiguous | 0.87 | Ambiguous | -5.73 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.23 | Pathogenic | 0.07 | Tolerated | 3.37 | 34 | 1 | 0 | -0.4 | 30.03 | 233.9 | -49.3 | 0.8 | 0.0 | 0.6 | 0.1 | X | Potentially Benign | Gly580 is located on the outer surface in a short α-α loop turn connecting two α-helices (res. Arg563-Glu578, res. Glu582-Phe608) in the WT simulations. In the variant simulations, the side chain of Ser580 faces outward, and its hydroxyl group does not make any new or additional interactions compared to Gly580 in the WT simulations that could affect the protein structure. | ||||||||
| c.1741C>T | R581W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R581W is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include only Rosetta, whereas the remaining pathogenic‑predicating tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—consistently classify the variant as deleterious. Uncertain or inconclusive results come from FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain”; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Pathogenic”; and Foldetta remains “Uncertain.” Overall, the preponderance of evidence points to a pathogenic impact, which contrasts with the ClinVar designation of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 2 | -12.855 | Likely Pathogenic | 0.920 | Likely Pathogenic | Ambiguous | 0.678 | Likely Pathogenic | 1.32 | Ambiguous | 0.1 | -0.32 | Likely Benign | 0.50 | Ambiguous | 0.68 | Ambiguous | -6.79 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.37 | Pathogenic | 0.01 | Affected | 3.37 | 34 | 2 | -3 | 3.6 | 30.03 | 257.8 | 36.0 | 0.1 | 0.1 | 0.1 | 0.3 | X | X | Potentially Pathogenic | Arg581 is located on a short α-α loop between two α helices (res. Arg563-Glu578 and res. Glu582-Ser604). In the WT simulations, the guanidinium group of Arg581 forms salt bridges with the carboxylate groups of Asp583 within the same helix, as well as with Glu478 and/or Glu480 in a slightly α-helical loop (res. Glu478-Thr488) preceding another α helix (res. Ala461-Phe476).In the variant simulations, the neutral indole ring of the Trp581 side chain cannot form any of these salt bridges. Instead, it packs hydrophobically against Met477 and Ile587 without forming any direct hydrogen bonds. The tendency of the loop (res. Asp477-Thr488) to acquire an α-helical structure seems to marginally increase, potentially due to Trp581's inability to coordinate stable hydrogen bonds with the loop residues (e.g., Glu478-Arg581 salt bridge). Additionally, the residue swap could weaken the tertiary structure assembly and negatively affect the overall protein folding process. | ||||||||||
| c.1752C>G | I584M 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant I584M is listed in ClinVar with an uncertain significance (ClinVar ID 1301269.0) and is present in gnomAD (6‑33440804‑C‑G). Consensus from multiple in‑silico predictors shows a split: benign calls come from REVEL, FoldX, Rosetta, Foldetta, SIFT, and AlphaMissense‑Optimized, whereas pathogenic calls arise from premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b, FATHMM, and PROVEAN, is pathogenic. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized predicts benign, but SGM Consensus is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign. Overall, the majority of tools favor pathogenicity, and the high‑accuracy consensus leans pathogenic, indicating the variant is most likely pathogenic, 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 Pathogenic | GAP | Uncertain | 2 | 6-33440804-C-G | 1 | 6.20e-7 | -10.119 | Likely Pathogenic | 0.419 | Ambiguous | Likely Benign | 0.478 | Likely Benign | 0.11 | Likely Benign | 0.1 | 0.46 | Likely Benign | 0.29 | Likely Benign | 1.16 | Destabilizing | -2.62 | Deleterious | 0.983 | Probably Damaging | 0.925 | Probably Damaging | -1.25 | Pathogenic | 0.12 | Tolerated | 3.37 | 34 | 2 | 1 | -2.6 | 18.03 | 247.5 | -20.3 | -0.1 | 0.3 | -0.1 | 0.1 | X | Potentially Benign | A hydrophobic residue, Ile584, located in an α helix (res. Glu582-Met603), is swapped for another hydrophobic residue, Met584. The sec-butyl hydrocarbon side chain of Ile584 packs hydrophobically with residues in an inter-helix hydrophobic space (e.g., Leu588, Met477, Val473, and Ile483).In the variant simulations, the thioether hydrophobic side chain of Met584 maintains similar interactions as Ile584 in the WT, as it is roughly the same size and fits well within the hydrophobic space. Thus, the residue swap does not appear to cause any negative effects on the protein structure. | ||||||||
| c.1760G>C | R587T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R587T is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include SIFT and AlphaMissense‑Optimized, whereas a majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic outcome. Uncertain predictions from FoldX, Rosetta, Foldetta, and premPS are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for R587T, 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 | GAP | Uncertain | 1 | -9.697 | Likely Pathogenic | 0.784 | Likely Pathogenic | Likely Benign | 0.603 | Likely Pathogenic | 1.14 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.94 | Ambiguous | 0.98 | Ambiguous | -4.71 | Deleterious | 0.998 | Probably Damaging | 0.847 | Possibly Damaging | -1.19 | Pathogenic | 0.08 | Tolerated | 3.37 | 35 | -1 | -1 | 3.8 | -55.08 | 227.2 | 87.4 | 0.0 | 0.0 | 0.5 | 0.1 | X | Potentially Pathogenic | The guanidinium group of Arg587, located on an α helix (res. Glu582-Met603), is constantly rotating and breaking/forming multiple hydrogen bonds and/or salt bridges at the surface intersection of α helices in the WT simulations. The positively charged Arg587 side chain can form a salt bridge with either the carboxylate group of Asp583 or Asp586 in the same helix, or with Glu480 on the opposing short helical loop structure (res. Glu480-Leu482).Importantly, the Arg587 side chain also hydrogen bonds with the backbone carbonyl groups of Ala634 and Asn635, as well as the carboxamide group of Asn635 at the end of another α helix (res. Asp616-Phe636). However, in the variant simulations, the neutral hydroxyl group of the Thr587 side chain is unable to form these salt bridges. Due to its smaller size, it also does not form the hydrogen bonds that the Arg587 side chain could. Instead, the hydroxyl group of Thr587 hydrogen bonds with the backbone carbonyl group of Asp583, which could weaken the integrity of the α helix, although this is not observed in the simulations.Overall, the residue swap could weaken the tertiary structure assembly and negatively affect the overall protein folding process. | |||||||||||
| c.1763T>C | L588P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L588P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -14.771 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.932 | Likely Pathogenic | 5.61 | Destabilizing | 0.5 | 12.91 | Destabilizing | 9.26 | Destabilizing | 2.33 | Destabilizing | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.42 | Pathogenic | 0.00 | Affected | 3.38 | 34 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||
| c.1767C>G | I589M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I589M is listed in ClinVar with an uncertain significance (ClinVar ID 964298.0) and is not reported in gnomAD. Functional prediction tools that provide a definitive call overwhelmingly predict a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all indicate pathogenicity, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely pathogenic outcome. Tools that are inconclusive—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—are listed as uncertain and do not influence the overall assessment. High‑accuracy methods specifically show AlphaMissense‑Optimized as uncertain, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the majority of available predictions support a pathogenic effect, which is consistent with the ClinVar uncertain designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -12.225 | Likely Pathogenic | 0.926 | Likely Pathogenic | Ambiguous | 0.830 | Likely Pathogenic | 0.74 | Ambiguous | 0.2 | 1.54 | Ambiguous | 1.14 | Ambiguous | 1.33 | Destabilizing | -2.99 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.94 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 2 | 1 | -2.6 | 18.03 | 267.6 | -24.5 | 0.0 | 0.0 | -0.1 | 0.1 | X | Potentially Benign | A hydrophobic residue, Ile589, located in an α helix (res. Glu582-Met603), is swapped for another hydrophobic residue, methionine. The sec-butyl hydrocarbon side chain of Ile589 packs favourably with multiple residues in the inter-helix hydrophobic space (e.g., Phe569, Ile667, and Leu664).Although the S-methyl thioether group of the Met589 side chain in the variant is longer than the branched side chain of isoleucine, it stacks favourably with the aromatic phenol ring. Additionally, the polar sulphur atom forms a weak hydrogen bond with the guanidinium group of Arg573, which in turn forms a salt bridge with the carboxylate group of Asp586.Overall, the hydrophobic packing in the inter-helix space does not appear to be disrupted in the variant simulations. | |||||||||||
| c.1771G>C | A591P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A591P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely converge on a pathogenic effect: pathogenic predictions come from FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (Likely Pathogenic). Benign predictions are limited to REVEL and FATHMM. High‑accuracy assessments reinforce the pathogenic view: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenic. Consequently, the variant is most likely pathogenic, a conclusion that contrasts with its ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -14.479 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.404 | Likely Benign | 3.78 | Destabilizing | 0.3 | 7.29 | Destabilizing | 5.54 | Destabilizing | 1.45 | Destabilizing | -4.41 | Deleterious | 0.995 | Probably Damaging | 0.853 | Possibly Damaging | 3.35 | Benign | 0.01 | Affected | 3.37 | 35 | 1 | -1 | -3.4 | 26.04 | 191.5 | -10.1 | 0.2 | 0.1 | 0.4 | 0.1 | X | Potentially Pathogenic | The methyl group of the Ala591 side chain, located in the middle of an α helix (res. Glu582-Met603), packs against hydrophobic residues (e.g., Ile483, Phe484) of an opposing partially helical loop (res. Phe476-Asn487).In the variant simulations, Pro591 lacks a free backbone amide group and, therefore, cannot form a hydrogen bond with the backbone carbonyl of Arg587 as Ala591 does in the WT. This notably weakens the α helix integrity and compromises the continuity of the helix. In reality, the effect on the structure during protein folding could be more severe. | |||||||||||
| c.1778T>A | L593H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L593H is listed in ClinVar with an uncertain significance and is not present in gnomAD. In silico predictors that classify the variant as benign include only FATHMM. All other evaluated tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic effect. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No prediction or stability result is missing or inconclusive. Overall, the variant is most likely pathogenic based on the consensus of predictions, and this assessment does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -16.504 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.812 | Likely Pathogenic | 2.52 | Destabilizing | 0.2 | 2.32 | Destabilizing | 2.42 | Destabilizing | 2.75 | Destabilizing | -6.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.77 | Benign | 0.00 | Affected | 3.37 | 35 | -2 | -3 | -7.0 | 23.98 | 222.0 | 20.7 | 0.0 | 0.0 | 0.2 | 0.0 | X | X | Potentially Pathogenic | The iso-propyl side chain of Leu593, located in an α helix (res. Glu582-Met603), packs favourably with multiple hydrophobic residues in the inter-helix space (e.g., Leu598, Ile589, Phe594, Phe561).In the variant simulations, His593 retains a similar packing arrangement via its aromatic imidazole ring. However, the polar nitrogen atoms introduce hydrogen bond donors and acceptors into the previously hydrophobic space. The epsilon protonated nitrogen of His593 forms a stable hydrogen bond with the phenol group of the Tyr505 side chain in an α helix (res. Gln503-Tyr518).While the residue swap could affect the tertiary assembly and the underlying protein folding process, it is difficult to determine if the mutation would be tolerated based solely on the variant simulations. | ||||||||||
| c.1778T>C | L593P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L593P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic outcome. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, a conclusion that contradicts its current ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -13.961 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.777 | Likely Pathogenic | 5.75 | Destabilizing | 0.9 | 10.77 | Destabilizing | 8.26 | Destabilizing | 2.43 | Destabilizing | -6.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.77 | Benign | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||
| c.1784T>A | L595Q 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant L595Q is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized—predict a pathogenic effect, and the SGM‑Consensus score indicates a likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized returns a pathogenic prediction, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a likely pathogenic result, while Foldetta’s stability analysis is inconclusive. Overall, the majority of computational evidence points to a pathogenic effect, which does not contradict the ClinVar designation of uncertain significance but suggests a higher likelihood of pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -15.101 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.733 | Likely Pathogenic | 0.79 | Ambiguous | 0.1 | 1.40 | Ambiguous | 1.10 | Ambiguous | 1.99 | Destabilizing | -5.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.75 | Benign | 0.00 | Affected | 3.37 | 35 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||
| c.1784T>C | L595P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L595P is listed in ClinVar with an “Uncertain” status (ClinVar ID 3172762.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -11.856 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.747 | Likely Pathogenic | 2.09 | Destabilizing | 0.8 | 5.88 | Destabilizing | 3.99 | Destabilizing | 1.78 | Destabilizing | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.72 | Benign | 0.00 | Affected | 3.37 | 35 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||
| c.1787G>T | R596L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 R596L missense variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect are Foldetta and premPS, whereas the remaining pathogenic‑predicting tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all indicate a deleterious impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (derived from the same four high‑confidence predictors) also indicates likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Overall, the preponderance of evidence points to a pathogenic effect for R596L, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -13.197 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.756 | Likely Pathogenic | 1.51 | Ambiguous | 0.3 | -0.58 | Ambiguous | 0.47 | Likely Benign | -0.02 | Likely Benign | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -3 | -2 | 8.3 | -43.03 | 234.2 | 63.4 | -0.1 | 0.0 | -0.5 | 0.6 | X | X | Potentially Pathogenic | The guanidinium group of Arg596, located in an α helix (res. Glu582-Met603), forms a salt bridge with the carboxylate group of Glu495 from another α helix (res. Leu489-Glu519). In the WT simulations, the side chain of Arg596 hydrogen bonds with the backbone carbonyl groups of Asn487, Glu486, Arg485, and Phe484. Additionally, Arg596 can hydrogen bond with the carboxamide group of the Asn487 side chain on an opposing loop that links two α helices (res. Ala461-Arg475, res. Leu489-Glu519).However, in the variant simulations, the branched hydrocarbon side chain of Leu596 cannot form any of the hydrogen bonds or salt bridges maintained by the considerably bulkier and positively charged Arg596 side chain. Instead, Leu596 packs hydrophobically with the phenyl ring of Phe484 in the linker loop or residues from the opposing helix (e.g., Ile494, Thr491).Thus, the residue swap could affect the tertiary structure assembly more profoundly than observed in the simulations. Notably, Arg596 plays a key role in positioning the aforementioned loop, which is crucial for the placement of the “arginine finger” or the Arg485 side chain during RasGTPase activation. | 10.1016/j.ajhg.2020.11.011 | |||||||||
| c.1789T>C | F597L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F597L is listed in ClinVar with an uncertain significance (ClinVar ID 3658115.0) and is not reported in gnomAD. Prediction tools that classify the variant as benign include only SIFT, whereas the remaining tools—SGM‑Consensus, REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. The high‑accuracy AlphaMissense‑Optimized score is pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for F597L, which is consistent with its ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -10.173 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.929 | Likely Pathogenic | 0.74 | Ambiguous | 0.1 | 2.12 | Destabilizing | 1.43 | Ambiguous | 1.20 | Destabilizing | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -2.06 | Pathogenic | 0.13 | Tolerated | 2 | 0 | 1.0 | -34.02 | ||||||||||||||||||||||
| c.1792C>G | L598V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L598V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as inconclusive. Overall, the majority of evidence points to a pathogenic impact, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -10.002 | Likely Pathogenic | 0.578 | Likely Pathogenic | Likely Benign | 0.221 | Likely Benign | 1.89 | Ambiguous | 0.1 | 1.58 | Ambiguous | 1.74 | Ambiguous | 1.01 | Destabilizing | -2.92 | Deleterious | 0.944 | Possibly Damaging | 0.786 | Possibly Damaging | 3.21 | Benign | 0.02 | Affected | 3.37 | 35 | 2 | 1 | 0.4 | -14.03 | 218.4 | 29.6 | 0.0 | 0.0 | 0.8 | 0.0 | X | Potentially Benign | The iso-butyl side chain of Leu598, located on an α helix (res. Glu582-Met603), packs hydrophobically with other hydrophobic residues in the inter-helix space (e.g., Ile602, Phe594, Ile510).In the variant simulations, Val598, which has similar size and physicochemical properties to leucine, resides in the inter-helix hydrophobic space in a similar manner to Leu598 in the WT. This causes no negative effects on the protein structure. | |||||||||||
| c.1802C>T | A601V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A601V is listed in ClinVar (ID 968190.0) with an uncertain clinical significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from Rosetta and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score. Four tools (FoldX, Foldetta, premPS, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect, which is consistent with the ClinVar designation of uncertain significance rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -10.447 | Likely Pathogenic | 0.853 | Likely Pathogenic | Ambiguous | 0.535 | Likely Pathogenic | 1.64 | Ambiguous | 0.1 | 0.35 | Likely Benign | 1.00 | Ambiguous | 0.81 | Ambiguous | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 2.74 | Benign | 0.03 | Affected | 3.37 | 35 | 0 | 0 | 2.4 | 28.05 | 228.5 | -45.5 | 0.0 | 0.0 | 0.4 | 0.5 | X | Potentially Benign | The methyl side chain of Ala601, located on an α helix (res. Glu582-Met603), packs hydrophobically against other hydrophobic residues in the inter-helix space (e.g., Phe597, Leu598, Leu506, Phe608).In the variant simulations, Val601, which has similar size and physicochemical properties to alanine, resides in the inter-helix hydrophobic space in a similar manner to Ala601 in the WT, causing no apparent negative effect on the protein structure. However, the effect of the residue swap on the SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||
| c.1811C>T | S604L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S604L is listed in ClinVar with an “Uncertain” status (ClinVar ID 1055027.0) and is present in gnomAD (ID 6‑33440863‑C‑T). Prediction tools that agree on a benign effect are premPS and FATHMM. Tools that predict a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | 6-33440863-C-T | 6 | 3.72e-6 | -14.683 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.639 | Likely Pathogenic | -0.94 | Ambiguous | 0.1 | -1.24 | Ambiguous | -1.09 | Ambiguous | -0.31 | Likely Benign | -5.97 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | 3.37 | 35 | -3 | -2 | 4.6 | 26.08 | 234.0 | -49.6 | 0.0 | 0.1 | 0.3 | 0.5 | X | X | Potentially Pathogenic | Ser604 is located in a short turn between an α helix (res. Glu582-Met603) and a short α helical section (res. Ser606-Phe608). In the WT simulations, the hydroxyl side chain of Ser604 periodically hydrogen bonds with the backbone carbonyl groups of other α helix residues (e.g., Pro600, Met603). Serine weakens the α helix secondary structure, and thus, Ser604 along with Pro605 breaks the α helix, facilitating the turn in the WT structure.In contrast, in the variant simulations, Leu604 forms a few hydrophobic interactions (e.g., Leu607, Phe608). More importantly, the helix end is more stable than with Ser604 in the WT. The residue swap could have a more profound effect on the actual folding process, for example, by preventing the bending at the α helix end, than what the simulations suggest.Moreover, Ser604 directly hydrogen bonds with Ras residues Ser65 and Ala66 in the WT SynGAP-Ras complex. The hydrophobic leucine cannot maintain these interactions with Ras at the GAP-Ras interface. Thus, the effect of the residue swap on the complex formation with the GTPase cannot be fully explored in the solvent-only simulations. | |||||||
| c.1813C>T | P605S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P605S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All evaluated in‑silico predictors classify the change as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, which contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -10.830 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.718 | Likely Pathogenic | 3.40 | Destabilizing | 0.1 | 3.34 | Destabilizing | 3.37 | Destabilizing | 1.00 | Destabilizing | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.70 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 1 | -1 | 0.8 | -10.04 | 213.8 | -15.4 | -0.3 | 0.2 | 0.2 | 0.1 | X | X | Potentially Pathogenic | Pro605 is located in a short turn between an α helix (res. Glu582-Met603) and a short α helical section (res. Ser606-Phe608). The pyrrolidine side chain of Pro605 packs hydrophobically with nearby hydrophobic residues (e.g., Ile514, Leu623, Leu610) in the inter-helix space. Additionally, proline lacks a free backbone amide group, which breaks the α helix and facilitates the turn in the WT structure.In the variant simulations, the hydroxyl side chain of Ser605 forms hydrogen bonds with the backbone carbonyl groups of Ala601 and Ile602. Importantly, the helix end is more stable than with Pro605 in the WT. Indeed, proline is a more effective secondary structure breaker compared to serine.Thus, the residue swap could have a more profound effect on the actual folding process, for example, by preventing the bending at the α helix end, than what the simulations suggest. Moreover, due to its location at the GAP-Ras interface, the residue swap could affect the GAP-Ras association. | ||||||||||
| c.1814C>G | P605R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P605R is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while premPS remains inconclusive. Grouping by consensus, the benign category is empty and the pathogenic category contains all available predictions. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields pathogenic; and Foldetta, integrating FoldX‑MD and Rosetta outputs, reports a destabilizing, pathogenic effect. Consequently, the variant is most likely pathogenic, which does not contradict its current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -13.745 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.845 | Likely Pathogenic | 8.71 | Destabilizing | 2.5 | 6.46 | Destabilizing | 7.59 | Destabilizing | 0.92 | Ambiguous | -8.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.69 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0 | -2 | -2.9 | 59.07 | 281.7 | -118.1 | -0.2 | 0.0 | 0.5 | 0.1 | X | X | X | X | Potentially Pathogenic | Pro605 is located in a short turn between an α helix (res. Glu582-Met603) and a short α helical section (res. Ser606-Phe608). The pyrrolidine side chain of Pro605 packs hydrophobically with nearby hydrophobic residues (e.g., Ile514, Leu623, Leu610) in the inter-helix space. Additionally, proline lacks a free backbone amide group, which breaks the α helix and facilitates the turn in the WT structure.In the variant simulations, the guanidinium side chain of Arg605 is bulkier than proline, and its positively charged guanidinium group faces mostly hydrophobic residues (e.g., Ile514, Leu623, Leu610). As a result, it needs to rotate away from the hydrophobic niche. The residue swap could have a more profound effect on the actual folding process, for example, by preventing the bending at the α helix end.Moreover, due to its location at the GAP-Ras interface, the residue swap could affect the GAP-Ras association. | ||||||||
| c.1819C>G | L607V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L607V is listed in ClinVar with an uncertain significance (ClinVar ID 1450275.0) and is present in gnomAD (ID 6‑33440871‑C‑G). Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized reports benign, whereas the SGM‑Consensus, derived from the majority of pathogenic predictions, indicates pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive and therefore not considered evidence. Overall, the preponderance of computational evidence points to a pathogenic effect for L607V, a conclusion that contrasts with the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 2 | 6-33440871-C-G | 2 | 1.24e-6 | -11.190 | Likely Pathogenic | 0.637 | Likely Pathogenic | Likely Benign | 0.715 | Likely Pathogenic | 1.04 | Ambiguous | 0.2 | 1.36 | Ambiguous | 1.20 | Ambiguous | 0.90 | Ambiguous | -2.99 | Deleterious | 0.985 | Probably Damaging | 0.992 | Probably Damaging | -1.50 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 2 | 1 | 0.4 | -14.03 | 216.3 | 28.1 | 0.1 | 0.0 | 0.9 | 0.2 | X | Potentially Benign | Leu607 is located in a short helical region (res. Ser606-Phe608) within an α-α loop connecting two α helices (res. Glu582-Met603 and res. Glu617-Asn635). In the WT simulations, the iso-butyl side chain of Leu607 does not interact with any other residues, but it could potentially interact directly with Ras due to its location at the GAP domain.In the variant simulations, Val607, which has similar size and physicochemical properties to leucine, does not cause any negative effects on the protein structure. However, due to its location at the GAP-Ras interface, the residue swap could affect the complex formation with the GTPase, but this cannot be investigated using solvent-only simulations. | ||||||||
| c.182A>C | E61A 2D  AIThe SynGAP1 missense variant E61A is listed in ClinVar (ID 3767543.0) 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‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while 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 current ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -5.235 | Likely Benign | 0.453 | Ambiguous | Likely Benign | 0.074 | Likely Benign | -1.52 | Neutral | 0.458 | Possibly Damaging | 0.678 | Possibly Damaging | 4.12 | Benign | 0.00 | Affected | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||
| c.1832T>C | M611T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M611T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33440884‑T‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. Four tools (FoldX, Rosetta, Foldetta, premPS) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact, and this does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Uncertain | 1 | 6-33440884-T-C | 1 | 6.19e-7 | -5.696 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.240 | Likely Benign | 1.98 | Ambiguous | 0.2 | 0.94 | Ambiguous | 1.46 | Ambiguous | 0.87 | Ambiguous | -2.40 | Neutral | 0.034 | Benign | 0.038 | Benign | -1.19 | Pathogenic | 0.29 | Tolerated | 3.37 | 35 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||
| c.1835A>C | Q612P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q612P is listed in ClinVar (ID 3660462.0) with an uncertain significance annotation and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from REVEL, PolyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, PROVEAN, and the SGM Consensus score (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). The high‑accuracy AlphaMissense‑Optimized predicts benign, whereas the SGM Consensus predicts likely pathogenic; Foldetta, a folding‑stability method combining FoldX‑MD and Rosetta outputs, returns an uncertain result and is therefore not factored into the consensus. Overall, the majority of evidence supports a pathogenic effect, which contrasts with the ClinVar uncertain classification. Thus, based on current predictions, the variant is most likely pathogenic, contradicting the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -9.684 | Likely Pathogenic | 0.673 | Likely Pathogenic | Likely Benign | 0.671 | Likely Pathogenic | -0.19 | Likely Benign | 0.3 | 3.06 | Destabilizing | 1.44 | Ambiguous | 0.56 | Ambiguous | -5.84 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.31 | Pathogenic | 0.19 | Tolerated | 0 | -1 | 1.9 | -31.01 | ||||||||||||||||||||||
| c.1851G>T | E617D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E617D is listed in ClinVar with an uncertain significance (ID 2584916.0) and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score all indicate benign or likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic impact, while Rosetta remains inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. Overall, the preponderance of evidence supports a benign classification, which does not contradict the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | Uncertain | 1 | -1.349 | Likely Benign | 0.241 | Likely Benign | Likely Benign | 0.322 | Likely Benign | 0.12 | Likely Benign | 0.1 | 0.80 | Ambiguous | 0.46 | Likely Benign | 0.07 | Likely Benign | -0.01 | Neutral | 0.994 | Probably Damaging | 0.979 | Probably Damaging | -1.35 | Pathogenic | 0.88 | Tolerated | 3.37 | 35 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||
| c.1855A>T | T619S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T619S is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated algorithms—SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized reports a benign outcome, whereas the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, yields an uncertain result. Overall, the majority of evidence points to a pathogenic effect for T619S, and this conclusion does not contradict the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -8.608 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 0.602 | Likely Pathogenic | 1.09 | Ambiguous | 0.2 | 1.35 | Ambiguous | 1.22 | Ambiguous | 0.85 | Ambiguous | -3.42 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.30 | Pathogenic | 0.05 | Affected | 3.37 | 35 | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||
| c.1873C>G | L625V 2D AISynGAP1 missense variant L625V is listed in ClinVar with an uncertain significance (ClinVar ID 3392716.0) 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 premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic effect, which does not contradict the ClinVar uncertain status but suggests a higher likelihood of pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -11.319 | Likely Pathogenic | 0.833 | Likely Pathogenic | Ambiguous | 0.480 | Likely Benign | 1.80 | Ambiguous | 0.7 | 1.69 | Ambiguous | 1.75 | Ambiguous | 1.42 | Destabilizing | -2.96 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 3.07 | Benign | 0.01 | Affected | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||
| c.1877T>C | I626T 2D AISynGAP1 missense variant I626T is listed in ClinVar with an uncertain significance (ClinVar ID 3359331.0) and is not reported in gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions are returned by REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FATHMM predicts a benign outcome, while AlphaMissense‑Optimized is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Overall, the consensus of the majority of tools points to a pathogenic effect, contradicting the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -10.420 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 0.640 | Likely Pathogenic | 2.94 | Destabilizing | 0.1 | 2.70 | Destabilizing | 2.82 | Destabilizing | 2.23 | Destabilizing | -4.18 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.04 | Benign | 0.00 | Affected | 0 | -1 | -5.2 | -12.05 | ||||||||||||||||||||||
| c.187G>A | E63K 2D AIThe SynGAP1 E63K missense variant (ClinVar ID 2830630.0) is listed as “Uncertain” and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default all predict a pathogenic outcome. AlphaMissense‑Optimized is inconclusive, 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 the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. Overall, the high‑accuracy consensus leans toward a benign effect, and this assessment does not contradict the ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -4.976 | Likely Benign | 0.894 | Likely Pathogenic | Ambiguous | 0.103 | Likely Benign | -0.70 | Neutral | 0.458 | Possibly Damaging | 0.678 | Possibly Damaging | 3.98 | Benign | 0.00 | Affected | 4.32 | 1 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||
| c.187G>C | E63Q 2D  AIThe SynGAP1 missense variant E63Q is listed in ClinVar (ID 2132335.0) 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. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (majority of the four high‑accuracy tools) 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 preponderance of predictions points to a benign effect, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Uncertain | 1 | -4.038 | Likely Benign | 0.687 | Likely Pathogenic | Likely Benign | 0.078 | Likely Benign | -0.85 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 4.32 | 1 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
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