Is SMAD3 p.Pro161= (c.483C>T) pathogenic?

SMAD3 p.Pro161= (c.483C>T) is classified Benign/Likely benign in SMAD3 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-26). Rare (popmax 0.112%, afr); Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is SMAD3 p.Pro161= (c.483C>T) in the general population?

SMAD3 p.Pro161= (c.483C>T) is rare (popmax 0.112%, afr) (gnomAD).

SMAD3 p.Pro161=

Q: What condition is associated with SMAD3 p.Pro161= (c.483C>T)?

SMAD3 p.Pro161= (c.483C>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.483C>T · rs202203039 · VCV387889

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.112%, afr)

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.1	GERP -3.7
Overall
CADD	12.06	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.112% African / African-American · 84/75,066 alleles

Filtering AF 0.0926% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0854%

Overall 0.0083% 134/1,614,234 alleles · rare exomes 83/1,461,890 · genomes 51/152,344 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.112%	894
Remaining individualsnot grpmax-eligible	0.0192%	5,209
Admixed American	0.015%	6,669
East Asian	0.0134%	7,479
South Asian	0.0022%	45,542
European (non-Finnish)	0.00178%	56,193

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.Pro161=
Coding: c.483C>T
MANE Select: NM_005902
dbSNP: rs202203039
Type: single nucleotide variant
Location: chr15:67165335 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.21 · 12 PDB
Residue 161: 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

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.Pro161Leu Uncertain significance ★★ ⚠ same residue
SMAD3 p.Pro161Ser Uncertain significance ★ ⚠ same residue
SMAD3 p.Pro161Thr Uncertain significance ★ ⚠ 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
SMAD3 c.532+1G>C 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-pro161 (accessed [today's date]).

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