SIM1 p.Glu396=
c.1188A>G · rs149770773 · VCV3039955
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0162%, 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 0.14 | GERP -4.3, phastCons 0.99 |
| Overall | ||
| CADD | 6.671 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0162%
European (non-Finnish) · 187/1,152,504 alleles
Filtering AF
0.0142%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0136%
Overall
0.0126%
197/1,565,664 alleles · ultra-rare
exomes 194/1,413,446 · genomes 3/152,218 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.0162% | 6,163 |
| Remaining individualsnot grpmax-eligible | 0.0116% | 8,605 |
| Finnishnot grpmax-eligible | 0.00319% | 31,365 |
| African / African-American | 0.00136% | 73,496 |
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.Glu396=
- Coding
- c.1188A>G
- MANE Select
- NM_005068
- dbSNP
- rs149770773
- Type
- single nucleotide variant
- Location
- chr6:100393869 (GRCh38)
- Gene constraint
- LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 60.70
- Residue 396
- the single-minded c-terminal domain; the 'disordered' region
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-glu396 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown