SMAD6 p.Pro397=
c.1191C>T · rs551875695 · VCV471747
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 6 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0493%, mid)
Conditions
2
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 -12 | GERP -5.4 |
| Overall | ||
| CADD | 4.424 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0493%
Middle Eastern · 3/6,084 alleles
Filtering AF
0.0134%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0104%
Overall
0.0103%
165/1,608,492 alleles · ultra-rare
exomes 153/1,456,314 · genomes 12/152,178 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0493% | 2,028 |
| European (non-Finnish) | 0.0127% | 7,864 |
| Remaining individualsnot grpmax-eligible | 0.00641% | 15,597 |
| Ashkenazi Jewishnot grpmax-eligible | 0.00338% | 29,564 |
| Admixed American | 0.00333% | 29,988 |
| South Asian | 0.00329% | 30,359 |
| African / African-American | 0.00267% | 37,446 |
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.Pro397=
- Coding
- c.1191C>T
- MANE Select
- NM_005585
- dbSNP
- rs551875695
- Type
- single nucleotide variant
- Location
- chr15:66781235 (GRCh38)
- Gene constraint
- LOEUF 1.996 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 72.34
- Residue 397
- the mh2 domain; 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); a UniProt-annotated variant site (risk factor for rus); a UniProt-annotated variant site (risk factor for crs7); a UniProt-annotated variant site (likely risk factor for rus and crs7); a UniProt-annotated variant site (risk factor for radioulnar synostosis, pectus carinatum and macrocephaly)
Similar variants
- SMAD6 p.Pro397His Uncertain significance ★★ ⚠ same residue
- SMAD6 p.Pro397Leu 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-pro397 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown