SMAD6 p.Pro89=
c.267C>A · rs896888252 · VCV2453899
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00408%, nfe)
Conditions
1
aortic valve disease 2
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 4.4 | GERP -1, phastCons 1 |
| Overall | ||
| CADD | 13.68 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00408%
European (non-Finnish) · 40/979,448 alleles
Filtering AF
0.00308%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00271%
Overall
0.00335%
41/1,222,112 alleles · very rare
exomes 40/1,070,844 · genomes 1/151,268 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.00408% | 24,486 |
| Remaining individualsnot grpmax-eligible | 0.00225% | 44,382 |
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
- SMAD6
- Protein
- p.Pro89=
- Coding
- c.267C>A
- MANE Select
- NM_005585
- dbSNP
- rs896888252
- Type
- single nucleotide variant
- Location
- chr15:66703525 (GRCh38)
- Gene constraint
- LOEUF 1.996 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 72.34
- Residue 89
- a UniProt-annotated variant site (in aovd2); a UniProt-annotated variant site (likely risk factor for crs7); a UniProt-annotated variant site (risk factor for radioulnar synostosis and macrocephaly); the 'disordered' region
Similar variants
- SMAD6 p.Pro89Leu Uncertain significance ★★ ⚠ same residue
- SMAD6 p.Pro89fs Uncertain significance ★ same residue
- SMAD6 p.Gln218Ter Pathogenic/Likely pathogenic ★★ same condition
- SMAD6 p.Tyr264Ter Pathogenic/Likely pathogenic ★★ same condition
- SMAD6 c.817+4A>G Uncertain significance ★★ same condition
- SMAD6 p.Ala100Pro Uncertain significance ★★ ⚠ same condition
- SMAD6 p.Ala100Thr Uncertain significance ★★ ⚠ same condition
- SMAD6 p.Ala134Thr 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/smad6-p-pro89 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown