Is SMAD4 p.Pro10= (c.30A>T) pathogenic?

SMAD4 p.Pro10= (c.30A>T) is classified Benign/Likely benign in SMAD4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-11). Very rare (popmax 0.00167%, amr); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with SMAD4 p.Pro10= (c.30A>T)?

SMAD4 p.Pro10= (c.30A>T) is associated with familial thoracic aortic aneurysm and aortic dissection, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, hereditary neoplastic syndrome (ClinVar).

How common is SMAD4 p.Pro10= (c.30A>T) in the general population?

SMAD4 p.Pro10= (c.30A>T) is very rare (popmax 0.00167%, amr) (gnomAD).

SMAD4 p.Pro10=

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.30A>T · rs761044209 · VCV1665722

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

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 2	GERP -2.3, phastCons 1
Overall
CADD	8.879	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,032 alleles

Overall 6.2e-05% 1/1,613,866 alleles · very rare exomes 1/1,461,514 · genomes 0/152,352 · 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: SMAD4
Protein: p.Pro10=
Coding: c.30A>T
MANE Select: NM_005359
dbSNP: rs761044209
Type: single nucleotide variant
Location: chr18:51047076 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.56 · 14 PDB
Residue 10: the 'mediates interaction with zbtb7a' region

Full SMAD4 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: juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome hereditary neoplastic syndrome juvenile polyposis syndrome

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

SMAD4 p.Pro10Leu Uncertain significance ★★ ⚠ same residue
SMAD4 p.Pro10Ala Uncertain significance ★ ⚠ same residue
SMAD4 p.Pro10Ser Uncertain significance ★ ⚠ same residue
SMAD4 c.1140-1G>A Pathogenic ★★ same condition
SMAD4 c.1308+1G>A Pathogenic/Likely pathogenic ★★ same condition
SMAD4 c.1308+2T>G Likely pathogenic ★★ same condition
SMAD4 c.1309-1G>A Pathogenic/Likely pathogenic ★★ same condition
SMAD4 c.1447+2T>C 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/smad4-p-pro10 (accessed [today's date]).

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