Is SMAD3 p.Pro211= (c.633G>A) pathogenic?

SMAD3 p.Pro211= (c.633G>A) is classified Conflicting classifications of pathogenicity in SMAD3 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-12-18). Ultra-rare (popmax 0.0154%, sas); Associated with aneurysm-osteoarthritis syndrome.

What condition is associated with SMAD3 p.Pro211= (c.633G>A)?

SMAD3 p.Pro211= (c.633G>A) is associated with aneurysm-osteoarthritis syndrome, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SMAD3 p.Pro211= (c.633G>A) in the general population?

SMAD3 p.Pro211= (c.633G>A) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

How is Aneurysm-osteoarthritis syndrome inherited?

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

SMAD3 p.Pro211=

c.633G>A · rs776009102 · VCV744945

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Conditions

aneurysm-osteoarthritis syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.32	donor loss, 25 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.36	GERP 1.4, phastCons 0.98
Overall
CADD	9.603	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0154% South Asian · 14/91,082 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.0018% 29/1,613,808 alleles · ultra-rare exomes 27/1,461,636 · genomes 2/152,172 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0154%	6,506
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
East Asian	0.00223%	44,894
African / African-American	0.00133%	74,910
European (non-Finnish)	0.00102%	98,322

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.Pro211=
Coding: c.633G>A
MANE Select: NM_005902
dbSNP: rs776009102
Type: single nucleotide variant
Location: chr15:67170579 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.21 · 12 PDB
Residue 211: the 'linker' region

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.Pro211Leu Uncertain significance ★★ ⚠ same residue
SMAD3 p.Pro211Ala 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

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-pro211 (accessed [today's date]).

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