Is SMAD4 p.Pro313= (c.939C>T) pathogenic?

SMAD4 p.Pro313= (c.939C>T) is classified Benign/Likely benign in SMAD4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-01). Very rare (popmax 8.49e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with SMAD4 p.Pro313= (c.939C>T)?

SMAD4 p.Pro313= (c.939C>T) is associated with hereditary neoplastic syndrome, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, juvenile polyposis syndrome (ClinVar).

How common is SMAD4 p.Pro313= (c.939C>T) in the general population?

SMAD4 p.Pro313= (c.939C>T) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

SMAD4 p.Pro313=

c.939C>T · rs1305282354 · VCV486452

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Conditions

hereditary neoplastic 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 1.4	GERP 0.22, phastCons 1
Overall
CADD	10.11	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,178,170 alleles

Overall 6.2e-05% 1/1,611,972 alleles · very rare exomes 1/1,459,700 · genomes 0/152,272 · 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.Pro313=
Coding: c.939C>T
MANE Select: NM_005359
dbSNP: rs1305282354
Type: single nucleotide variant
Location: chr18:51059900 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.56 · 14 PDB
Residue 313: the 'mediates interaction with zbtb7a' region; the 'sad' region

Full SMAD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome juvenile polyposis syndrome familial thoracic aortic aneurysm and aortic dissection

Similar variants

SMAD4 p.Pro313Ala Uncertain significance ★★ ⚠ same residue
SMAD4 p.Pro313Leu Uncertain significance ★★ ⚠ same residue
SMAD4 p.Pro313Thr Uncertain significance ★★ ⚠ same residue
SMAD4 p.Pro313His Uncertain significance ★ ⚠ same residue
SMAD4 p.Pro313fs Pathogenic ★ 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

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-pro313 (accessed [today's date]).

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