Is SMAD3 p.Val331Asp (c.992T>A) pathogenic?

SMAD3 p.Val331Asp (c.992T>A) is classified Uncertain significance in SMAD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-10-13). AlphaMissense: likely pathogenic (1); Absent from gnomAD v4.1; Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with SMAD3 p.Val331Asp (c.992T>A)?

SMAD3 p.Val331Asp (c.992T>A) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SMAD3 p.Val331Asp (c.992T>A) in the general population?

SMAD3 p.Val331Asp (c.992T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SMAD3 p.Val331Asp (c.992T>A)?

AlphaMissense predicts likely pathogenic (score 1) — an in-silico prediction, not a clinical call.

SMAD3 p.Val331Asp

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.992T>A · rs1555414028 · VCV520187

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

1 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	1	likely pathogenic
REVEL	0.993	strongly pathogenic-leaning
SaProt	LLR -15.97	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.42	unconstrained · MANE · 20 kb · p 8.3e-22 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SMAD3
Protein: p.Val331Asp
Coding: c.992T>A
MANE Select: NM_005902
dbSNP: rs1555414028
Type: single nucleotide variant
Location: chr15:67184847 (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

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.Val331= Likely benign ★★ 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-val331asp (accessed [today's date]).

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