Is SMAD6 p.Phe366= (c.1098C>T) pathogenic?

SMAD6 p.Phe366= (c.1098C>T) is classified Likely benign in SMAD6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-19). Very rare (popmax 0.00892%, eas); Associated with aortic valve disease 2.

What condition is associated with SMAD6 p.Phe366= (c.1098C>T)?

SMAD6 p.Phe366= (c.1098C>T) is associated with aortic valve disease 2 (ClinVar).

How common is SMAD6 p.Phe366= (c.1098C>T) in the general population?

SMAD6 p.Phe366= (c.1098C>T) is very rare (popmax 0.00892%, eas) (gnomAD).

SMAD6 p.Phe366=

c.1098C>T · VCV4702646

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Conditions

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 2.7	GERP 2.7, phastCons 1
Overall
CADD	10.65	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00892% East Asian · 4/44,858 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000249% 4/1,608,404 alleles · very rare exomes 3/1,456,050 · genomes 1/152,354 · 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.Phe366=
Coding: c.1098C>T
MANE Select: NM_005585
Type: single nucleotide variant
Location: chr15:66781142 (GRCh38)
Gene constraint: LOEUF 1.996 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.34
Residue 366: 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)

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

Similar variants

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
SMAD6 p.Ala135Thr Uncertain significance ★★ ⚠ same condition
SMAD6 p.Ala161Ser 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-phe366 (accessed [today's date]).

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