Is SMAD3 p.Pro137= (c.411T>A) pathogenic?

SMAD3 p.Pro137= (c.411T>A) is classified Likely benign in SMAD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-13). Absent from gnomAD v4.1; Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with SMAD3 p.Pro137= (c.411T>A)?

SMAD3 p.Pro137= (c.411T>A) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SMAD3 p.Pro137= (c.411T>A) in the general population?

SMAD3 p.Pro137= (c.411T>A) is absent from gnomAD v4.1 (gnomAD).

SMAD3 p.Pro137=

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.411T>A · rs2505213022 · VCV2854984

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 -1.7	GERP -3.7
Overall
CADD	5.919	PHRED · no single calibrated threshold — expert panels disagree

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.Pro137=
Coding: c.411T>A
MANE Select: NM_005902
dbSNP: rs2505213022
Type: single nucleotide variant
Location: chr15:67165263 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.21 · 12 PDB
Residue 137: the 'linker' region

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 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
SMAD3 c.532+1G>C Likely pathogenic ★★ same condition
SMAD3 c.658+1G>A Likely pathogenic ★★ same condition
SMAD3 c.871+1G>A Pathogenic ★★ same condition
SMAD3 p.Ala112Val 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-pro137 (accessed [today's date]).

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