SIM1 p.Ile762Met
c.2286A>G · VCV4055996
Uncertain significance
Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
AlphaMissense
likely pathogenic
0.6168 · ACMG-weighted
gnomAD v4.1
Absent
absent from gnomAD v4.1
Missense predictors
1/2 damaging
AlphaMissense, SaProt · REVEL indeterminate
Computational evidence
| Protein change | ||
| AlphaMissense | 0.6168 | likely pathogenic |
|---|---|---|
| REVEL | 0.303 | indeterminate |
| SaProt | LLR -6.65 | tolerated |
| ⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 3.5 | GERP 1.3, phastCons 1 |
| Regional constraint | o/e 1.07 | unconstrained · MANE · 31 kb · p 0.14 · regional, not allelic |
| Overall | ||
| CADD | 22.7 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
gnomAD v4.1 · exomes + genomes
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- SIM1
- Protein
- p.Ile762Met
- Coding
- c.2286A>G
- MANE Select
- NM_005068
- Type
- single nucleotide variant
- Location
- chr6:100390376 (GRCh38)
- Gene constraint
- LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 60.70
- Residue 762
- the single-minded c-terminal domain
Similar variants
- SIM1 p.Cys434Ter Pathogenic ★★ same type
- SIM1 p.Ala495Gly Uncertain significance ★★ ⚠ same type
- SIM1 p.Arg374Trp Uncertain significance ★★ ⚠ same type
- SIM1 p.Arg548Gln Uncertain significance ★★ ⚠ same type
- SIM1 p.Arg550His Uncertain significance ★★ ⚠ same type
- SIM1 p.Cys605Tyr Uncertain significance ★★ ⚠ same type
- SIM1 p.Gln704Leu Uncertain significance ★★ ⚠ same type
- SIM1 p.Glu552Lys Uncertain significance ★★ ⚠ same type
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/sim1-p-ile762met (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown