Is SMAD6 p.Arg231Pro (c.692G>C) pathogenic?

SMAD6 p.Arg231Pro (c.692G>C) is classified Conflicting classifications of pathogenicity in SMAD6 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-01-06). AlphaMissense: likely pathogenic (0.9985); Very rare (popmax 0.000278%, nfe); Associated with aortic valve disease 2.

What condition is associated with SMAD6 p.Arg231Pro (c.692G>C)?

SMAD6 p.Arg231Pro (c.692G>C) is associated with aortic valve disease 2, aortic valve disease 1 (ClinVar).

How common is SMAD6 p.Arg231Pro (c.692G>C) in the general population?

SMAD6 p.Arg231Pro (c.692G>C) is very rare (popmax 0.000278%, nfe) (gnomAD).

What do computational predictors say about SMAD6 p.Arg231Pro (c.692G>C)?

AlphaMissense predicts likely pathogenic (score 0.9985) — an in-silico prediction, not a clinical call.

SMAD6 p.Arg231Pro

c.692G>C · rs1419095990 · VCV590963

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9985 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000278%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

aortic valve disease 2

Computational evidence

Protein change
AlphaMissense	0.9985	likely pathogenic · top 4% in SMAD6
REVEL	0.815	moderately pathogenic-leaning
SaProt	LLR -17.29	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.6	GERP -0.62, phastCons 1
Regional constraint	o/e 1.49	unconstrained · MANE · 78 kb · p 4.6e-40 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000278% European (non-Finnish) · 3/1,078,770 alleles

Filtering AF 7.4e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.1e-05%

Overall 0.000213% 3/1,406,920 alleles · very rare exomes 3/1,254,864 · genomes 0/152,056 · joint denominator

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.Arg231Pro
Coding: c.692G>C
MANE Select: NM_005585
dbSNP: rs1419095990
Type: single nucleotide variant
Location: chr15:66703950 (GRCh38)
Gene constraint: LOEUF 1.996 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.34
Residue 231: the mh1 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 (in aovd2; uncertain significance)

Full SMAD6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

aortic valve disease 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: aortic valve disease 1

Similar variants

SMAD6 p.Arg231Cys Uncertain significance ★★ ⚠ same residue
SMAD6 p.Arg231Gly Uncertain significance ★ ⚠ same residue
SMAD6 p.Arg231Ser Uncertain significance ★ ⚠ same residue
SMAD6 p.Arg231fs Likely pathogenic ★ same residue
SMAD6 p.Arg231Leu 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

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-arg231pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown