Is SMAD3 p.Val331= (c.993C>T) pathogenic?

SMAD3 p.Val331= (c.993C>T) is classified Likely benign in SMAD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-30). Very rare (popmax 8.47e-05%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is SMAD3 p.Val331= (c.993C>T) in the general population?

SMAD3 p.Val331= (c.993C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

SMAD3 p.Val331=

Q: What condition is associated with SMAD3 p.Val331= (c.993C>T)?

SMAD3 p.Val331= (c.993C>T) is associated with familial thoracic aortic aneurysm and aortic dissection, aneurysm-osteoarthritis syndrome (ClinVar).

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.993C>T · rs2505300946 · VCV3074694

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

familial thoracic aortic aneurysm and aortic dissection

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 4	GERP -3.7, phastCons 1
Overall
CADD	13.03	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,034 alleles

Overall 6.2e-05% 1/1,613,142 alleles · very rare exomes 1/1,460,762 · genomes 0/152,380 · 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: SMAD3
Protein: p.Val331=
Coding: c.993C>T
MANE Select: NM_005902
dbSNP: rs2505300946
Type: single nucleotide variant
Location: chr15:67184848 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.21 · 12 PDB
Residue 331: the mh2 domain

Full SMAD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: aneurysm-osteoarthritis syndrome

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

SMAD3 p.Val331Phe Likely pathogenic ★★ same residue
SMAD3 p.Val331Ile Uncertain significance ★★ ⚠ same residue
SMAD3 p.Val331Asp Uncertain significance ★ ⚠ same residue
SMAD3 p.Val331fs Pathogenic ★★ same residue
SMAD3 c.1009+1G>A Likely pathogenic ★★ same condition
SMAD3 c.1009+2T>A Likely pathogenic ★★ same condition
SMAD3 c.1010-1G>C Pathogenic/Likely pathogenic ★★ same condition
SMAD3 c.401-6G>A Pathogenic/Likely pathogenic ★★ 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/smad3-p-val331 (accessed [today's date]).

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