SIM1 p.Ser594=
c.1782C>T · rs759371897 · VCV796934
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0107%, afr)
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 2.5 | GERP -1.2, phastCons 1 |
| Overall | ||
| CADD | 7.005 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0107%
African / African-American · 8/74,898 alleles
Filtering AF
0.00528%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00381%
Overall
0.000743%
12/1,614,022 alleles · ultra-rare
exomes 6/1,461,874 · genomes 6/152,148 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.0107% | 9,362 |
| Admixed American | 0.00167% | 60,002 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,490 |
| European (non-Finnish) | 0.000169% | 590,009 |
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.Ser594=
- Coding
- c.1782C>T
- MANE Select
- NM_005068
- dbSNP
- rs759371897
- Type
- single nucleotide variant
- Location
- chr6:100390880 (GRCh38)
- Gene constraint
- LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 60.70
- Residue 594
- 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-ser594 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown