SIM1 p.Ile761=
c.2283A>C · rs371924273 · VCV3043346
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0159%, nfe)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 5 | GERP -0.029, phastCons 1 |
| Overall | ||
| CADD | 8.421 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0159%
European (non-Finnish) · 187/1,179,680 alleles
Filtering AF
0.0139%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0133%
Overall
0.0119%
192/1,613,184 alleles · ultra-rare
exomes 176/1,460,972 · genomes 16/152,212 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.0159% | 6,308 |
| Remaining individualsnot grpmax-eligible | 0.00641% | 15,610 |
| Admixed American | 0.00167% | 59,886 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- SIM1
- Protein
- p.Ile761=
- Coding
- c.2283A>C
- MANE Select
- NM_005068
- dbSNP
- rs371924273
- Type
- single nucleotide variant
- Location
- chr6:100390379 (GRCh38)
- Gene constraint
- LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 60.70
- Residue 761
- the single-minded c-terminal domain
Similar variants
- SIM1 p.Ile761Leu Uncertain significance ★ same residue
- 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
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-ile761 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown