SIM1 p.Leu582=
c.1744T>C · rs761882778 · VCV3055150
Likely benign
No assertion criteria
Classification
Likely benign
ClinVar
Review
No assertion criteria ☆☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0373%, sas)
Conditions
1
SIM1-related disorder
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 1.1 | GERP -2.5, phastCons 0.99 |
| Overall | ||
| CADD | 5.07 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0373%
South Asian · 34/91,076 alleles
Filtering AF
0.0274%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.024%
Overall
0.00223%
36/1,613,978 alleles · ultra-rare
exomes 35/1,461,884 · genomes 1/152,094 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.0373% | 2,679 |
| Remaining individualsnot grpmax-eligible | 0.0032% | 31,245 |
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.Leu582=
- Coding
- c.1744T>C
- MANE Select
- NM_005068
- dbSNP
- rs761882778
- Type
- single nucleotide variant
- Location
- chr6:100390918 (GRCh38)
- Gene constraint
- LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 60.70
- Residue 582
- the single-minded c-terminal domain
Disease context
SIM1-related disorder
Similar variants
- SIM1 p.Arg374Trp Uncertain significance ★★ ⚠ same condition
- SIM1 p.Ser199Cys Uncertain significance ★★ same condition
- SIM1 p.Gly480Ter Likely pathogenic ★ same condition
- SIM1 c.-468+6T>A Uncertain significance ★ same condition
- SIM1 p.Ala484Ser Uncertain significance ★ ⚠ same condition
- SIM1 p.Asn608Asp Uncertain significance ★ ⚠ same condition
- SIM1 p.Lys287Arg Uncertain significance ★ ⚠ same condition
- SIM1 p.Pro30Ala Uncertain significance ★ ⚠ same condition
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-leu582 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown