SMAD4

Chr 18AD

SMAD family member 4

Also known as: DPC4, JIP, MADH4, MYHRS

NCBI Gene: 4089 ENSG00000141646 UniProt: Q13485 OMIM: 600993

The SMAD4 protein is a central mediator of TGF-beta and bone morphogenetic protein (BMP) signaling pathways, forming complexes with other SMAD proteins to regulate gene transcription in the nucleus. Mutations cause autosomal dominant juvenile polyposis syndrome, hereditary hemorrhagic telangiectasia, and Myhre syndrome. This gene is highly constrained against loss-of-function variation (pLI 0.99, LOEUF 0.22), indicating that heterozygous loss is typically not tolerated.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.224 OMIM phenotypes

Clinical Summary— SMAD4

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Gene-Disease Validity (ClinGen)

pulmonary arterial hypertension · ADDisputed

Disputed — evidence questions this relationship

3 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

70 unique Pathogenic / Likely Pathogenic· 285 VUS of 699 total submissions

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Clinical Trials

6 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SMAD4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.22LOEUF

pLI 0.999

Z-score 4.59

OE 0.07 (0.03–0.22)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

4.13Z-score

OE missense 0.34 (0.29–0.40)

107 obs / 312.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.07 (0.03–0.22)

0≤0.351.4

Missense OE0.34 (0.29–0.40)

0≤0.61.4

Synonymous OE0.93

0≤1.21.6

LoF obs/exp: 2 / 28.4Missense obs/exp: 107 / 312.5Syn Z: 0.58

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSMAD4-related juvenile polyposis/hereditary hemorrhagic telangiectasia syndromeLOFAD

definitiveSMAD4-related Myhre syndromeGOFAD

0.3395th %ile

GOF

0.3391th %ile

LOF

0.82top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 79% of P/LP variants are LoF · LOEUF 0.22

GOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFPotentially heritable, autosomal dominant, gain-of-function heterozygous variants of SMAD4 cause a rare developmental disorder, the Myhre syndrome, which is associated with a wide range of developmental and post-developmental phenotypes that we now characterize as a novel segmental progeroid syndromPMID:33428109

LOFThese findings may reveal implications not only towards colonic inflammation in the setting of SMAD4 haploinsufficiency, but for colorectal cancer as well.PMID:23090737

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

699 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic55

Likely Pathogenic15

VUS285

Likely Benign273

Benign57

Conflicting9

Pathogenic

Likely Pathogenic

285

VUS

273

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	48	0	7	0	55
Likely Pathogenic	7	5	3	0	15
VUS	8	242	33	2	285
Likely Benign	2	1	151	119	273
Benign	0	0	9	48	57
Conflicting	—				9
Total	65	248	203	169	694

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SMAD4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

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GeneReview available — SMAD4

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Pancreas Cancer

ctDNA Assay in Patients With Resectable Pancreatic Cancer

RECRUITING

NCT05052671University of OklahomaStarted 2022-05-25

BRCA1 MutationPOLD1 Gene MutationCDKN2A Mutation

An Intervention to Increase Genetic Testing in Families Who May Share a Gene Mutation Related to Cancer Risk and An Intervention to Help Patients and Their Primary Care Providers Stay Up-to-date About Uncertain Genetic Test Results

RECRUITING

NCT05420064Phase NAMemorial Sloan Kettering Cancer CenterStarted 2022-12-01

Intervention Arm At-risk Relative/ARR ContactsMyGene PortalStandard of Care

Lynch SyndromeLi Fraumeni SyndromePTEN Hamartoma Syndrome

Video Capsule Examination in Patients With Lynch Syndrome

RECRUITING

NCT06712095Phase NARoyal Marsden NHS Foundation TrustStarted 2024-03-04

Video capsule investigation

Hereditary Hemorrhagic Telangiectasia

Cardiac Evaluation in Hereditary Hemorrhagic Telangiectasia

NOT YET RECRUITING

NCT07101575Fondazione Policlinico Universitario Agostino Gemelli IRCCSStarted 2025-08-05