Is SMAD3 p.Pro136= (c.408T>C) pathogenic?

SMAD3 p.Pro136= (c.408T>C) is classified Likely benign in SMAD3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-04-18). Very rare (popmax 0.000169%, nfe); Associated with aneurysm-osteoarthritis syndrome.

What condition is associated with SMAD3 p.Pro136= (c.408T>C)?

SMAD3 p.Pro136= (c.408T>C) is associated with aneurysm-osteoarthritis syndrome, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SMAD3 p.Pro136= (c.408T>C) in the general population?

SMAD3 p.Pro136= (c.408T>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is Aneurysm-osteoarthritis syndrome inherited?

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

SMAD3 p.Pro136=

c.408T>C · rs1256814354 · VCV918287

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

aneurysm-osteoarthritis syndrome

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 0.64	GERP 1.9, phastCons 1
Overall
CADD	12.34	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,010 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,928 alleles · very rare exomes 1/1,461,888 · genomes 1/152,040 · 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.Pro136=
Coding: c.408T>C
MANE Select: NM_005902
dbSNP: rs1256814354
Type: single nucleotide variant
Location: chr15:67165260 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.21 · 12 PDB
Residue 136: the mh1 domain

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

Disease context

aneurysm-osteoarthritis syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial thoracic aortic aneurysm and aortic dissection

For Aneurysm-osteoarthritis syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

SMAD3 p.Pro136Ser 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
SMAD3 c.658+1G>A Likely pathogenic ★★ same condition
SMAD3 c.871+1G>A 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-pro136 (accessed [today's date]).

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