Is SMAD4 p.Pro293= (c.879T>A) pathogenic?

SMAD4 p.Pro293= (c.879T>A) is classified Benign/Likely benign in SMAD4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-20). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with SMAD4 p.Pro293= (c.879T>A)?

SMAD4 p.Pro293= (c.879T>A) is associated with hereditary neoplastic syndrome, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, juvenile polyposis syndrome (ClinVar).

How common is SMAD4 p.Pro293= (c.879T>A) in the general population?

SMAD4 p.Pro293= (c.879T>A) is absent from gnomAD v4.1 (gnomAD).

SMAD4 p.Pro293=

c.879T>A · rs1453195015 · VCV1764692

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5	GERP 2.9, phastCons 1
Overall
CADD	12.01	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SMAD4
Protein: p.Pro293=
Coding: c.879T>A
MANE Select: NM_005359
dbSNP: rs1453195015
Type: single nucleotide variant
Location: chr18:51058431 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.56 · 14 PDB
Residue 293: 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.Pro293Ser Uncertain significance ★★ ⚠ same residue
SMAD4 p.Pro293His Uncertain significance ★ ⚠ same residue
SMAD4 p.Pro293Arg 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-pro293 (accessed [today's date]).

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