SMAD4

Chr 18AD

SMAD family member 4

Also known as: DPC4, JIP, MADH4, MYHRS

NCBI Gene: 4089ENSG00000141646UniProt: Q13485

This gene encodes a member of the Smad family of signal transduction proteins. Smad proteins are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to transforming growth factor (TGF)-beta signaling. The product of this gene forms homomeric complexes and heteromeric complexes with other activated Smad proteins, which then accumulate in the nucleus and regulate the transcription of target genes. This protein binds to DNA and recognizes an 8-bp palindromic sequence (GTCTAGAC) called the Smad-binding element (SBE). The protein acts as a tumor suppressor and inhibits epithelial cell proliferation. It may also have an inhibitory effect on tumors by reducing angiogenesis and increasing blood vessel hyperpermeability. The encoded protein is a crucial component of the bone morphogenetic protein signaling pathway. The Smad proteins are subject to complex regulation by post-translational modifications. Mutations or deletions in this gene have been shown to result in pancreatic cancer, juvenile polyposis syndrome, and hereditary hemorrhagic telangiectasia syndrome. [provided by RefSeq, May 2022]

Primary Disease Associations & Inheritance

Juvenile polyposis/hereditary hemorrhagic telangiectasia syndromeMIM #175050
AD
Myhre syndromeMIM #139210
AD
Pancreatic cancer, somaticMIM #260350
Polyposis, juvenile intestinalMIM #174900
AD
UniProtColorectal cancer
674
ClinVar variants
78
Pathogenic / LP
1.00
pLI score· haploinsufficient
6
Active trials
Clinical Summary— SMAD4
🧬
Gene-Disease Validity (ClinGen)
pulmonary arterial hypertension · ADDisputed

Disputed — evidence questions this relationship

3 total gene-disease associations curated

⚡
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.
📋
ClinVar Variants
78 Pathogenic / Likely Pathogenic· 290 VUS of 674 total submissions
💊
Clinical Trials
6 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.07 (0.03–0.22)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.34 (0.29–0.40)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.93
0≤1.21.6
LoF obs/exp: 2 / 28.4Missense obs/exp: 107 / 312.5Syn Z: 0.58

ClinVar Variant Classifications

674 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic62
Likely Pathogenic16
VUS290
Likely Benign230
Benign56
Conflicting20
62
Pathogenic
16
Likely Pathogenic
290
VUS
230
Likely Benign
56
Benign
20
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
34
1
27
0
62
Likely Pathogenic
8
1
7
0
16
VUS
4
255
29
2
290
Likely Benign
1
2
86
141
230
Benign
0
0
7
49
56
Conflicting
—20
Total47259156192674

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.

Gene2Phenotype Curations

SMAD4-related juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

definitive
ADLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure
Dev. DisordersSkinCancer
G2P ↗

SMAD4-related Myhre syndrome

definitive
ADGain Of FunctionAltered Gene Product Structure
Dev. DisordersSkinSkeletal
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

MIM #175050

Molecular basis of disorder known

Autosomal dominant

Myhre syndrome

MIM #139210

Molecular basis of disorder known

Autosomal dominant

Pancreatic cancer, somatic

MIM #260350

Molecular basis of disorder known

Polyposis, juvenile intestinal

MIM #174900

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — SMAD4
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia.
Shovlin CL et al.·Blood
2020
PRMT5 methylating SMAD4 activates TGF-β signaling and promotes colorectal cancer metastasis.
Liu A et al.·Oncogene
2023
Diverse roles of TGF-β/Smads in renal fibrosis and inflammation.
Lan HY·Int J Biol Sci
2011Review
Curaçao diagnostic criteria for hereditary hemorrhagic telangiectasia is highly predictive of a pathogenic variant in ENG or ACVRL1 (HHT1 and HHT2).
McDonald J et al.·Genet Med
2020
SMAD4 and KRAS Status Shapes Cancer Cell-Stromal Cross-Talk and Therapeutic Response in Pancreatic Cancer.
Lloyd EG et al.·Cancer Res
2025
[Colorectal oncogenesis].
Laurent-Puig P et al.·Bull Cancer
2010Review
Phosphorylation of FOXN3 by NEK6 promotes pulmonary fibrosis through Smad signaling.
Yu J et al.·Nat Commun
2025
Myhre syndrome in adulthood: clinical variability and emerging genotype-phenotype correlations.
Vanbelleghem E et al.·Eur J Hum Genet
2024
Hereditary hemorrhagic telangiectasia: A pediatric-focused review.
Ortman C et al.·Semin Pediatr Neurol
2024Review
Localisation of PGK1 determines metabolic phenotype to balance metastasis and proliferation in patients with SMAD4-negative pancreatic cancer.
Liang C et al.·Gut
2020Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Clinical impact of the methylation status of SMAD4 and AKR1B1 genes in a liquid biopsy sample as a prognostic marker for breast cancer.
Swellam M et al.·Sci Rep
2026🔓 Open Access
Resistance-exercise-induced stress intervenes in TGF-β signaling by cooperatively downregulating nuclear αB-crystallin and SMAD4 in human skeletal muscle fibers.
Schaaf K et al.·FEBS J
2026
Resveratrol targeting Smad4 via a concentration-dependent biphasic effect regulates stem cells-mediated regeneration.
Zhou Z et al.·Exp Mol Pathol
2026
Unraveling the Mechanistic Spectrum of Myhre Syndrome: SMAD4 Signaling Disruption, Skeletal Phenotypes, and Translational Innovation.
Zhu M et al.·Am J Med Genet C Semin Med Genet
2026
Cancer-associated fibroblast signature and SMAD4 mutation in resistance to adjuvant chemotherapy in stage III colon cancer patients.
Franken IA et al.·Eur J Cancer
2026Cohort
Top 5 resultsSearch Europe PMC ↗

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
Metastatic Colorectal Cancer

Cetuximab and Envafolimab Plus mFOLFOXIRI as First-line Treatment for RAS/BRAF Wild-type, MSS, Unresectable Left-side Metastatic Colorectal Cancer

RECRUITING
NCT05959356Phase PHASE2Sun Yat-sen UniversityStarted 2023-11-09
Cetuximab + Envafolimab + mFOLFOXIRICetuximab + mFOLFOX6
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
Hereditary Hemorrhagic Telangiectasia

Cardiac Evaluation in Hereditary Hemorrhagic Telangiectasia

NOT YET RECRUITING
NCT07101575Fondazione Policlinico Universitario Agostino Gemelli IRCCSStarted 2025-08-05
Transthoracic echocardiography
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
Pancreas Cancer

Prospective Cohort Study of Pancreatic Cancer Patients Treated With Proton Beam Therapy

ENROLLING BY INVITATION
NCT04466189National Cancer Center, KoreaStarted 2018-09-21

External Resources

Links to major genomics databases and tools