Is SMAD4 p.Pro511Ser (c.1531C>T) pathogenic?

SMAD4 p.Pro511Ser (c.1531C>T) is classified Uncertain significance in SMAD4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-15). AlphaMissense: likely pathogenic (0.9734); Very rare (popmax 8.47e-05%, nfe); Associated with juvenile polyposis syndrome.

What condition is associated with SMAD4 p.Pro511Ser (c.1531C>T)?

SMAD4 p.Pro511Ser (c.1531C>T) is associated with juvenile polyposis syndrome, hereditary neoplastic syndrome, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SMAD4 p.Pro511Ser (c.1531C>T) in the general population?

SMAD4 p.Pro511Ser (c.1531C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Juvenile polyposis syndrome inherited?

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

What do computational predictors say about SMAD4 p.Pro511Ser (c.1531C>T)?

AlphaMissense predicts likely pathogenic (score 0.9734) — an in-silico prediction, not a clinical call.

SMAD4 p.Pro511Ser

c.1531C>T · VCV3445862

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9734 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

juvenile polyposis syndrome

Computational evidence

Protein change
AlphaMissense	0.9734	likely pathogenic
REVEL	0.545	indeterminate
SaProt	LLR -14.04	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.1, phastCons 1
Regional constraint	o/e 0.30	constrained · MANE · 19 kb · p 2.2e-34 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,006 alleles

Overall 6.2e-05% 1/1,614,144 alleles · very rare exomes 1/1,461,856 · genomes 0/152,288 · 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.Pro511Ser
Coding: c.1531C>T
MANE Select: NM_005359
Type: single nucleotide variant
Location: chr18:51078339 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.56 · 14 PDB
Residue 511: the mh2 domain

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

Disease context

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

Also linked: hereditary neoplastic syndrome familial thoracic aortic aneurysm and aortic dissection

For Juvenile polyposis syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

SMAD4 p.Pro511Leu Uncertain significance ★★ ⚠ same residue
SMAD4 p.Pro511= Benign/Likely benign ★★ 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
SMAD4 c.249+1G>T 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-pro511ser (accessed [today's date]).

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