SMAD4
protein-codingSMAD family member 4, the group of SMAD family
Gene summary
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]
- MADH4
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~56.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0017380
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008278
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008278
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0008278
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0019625
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015924
Submitter: ClinGen
SMAD4 was first reported in relation to autosomal dominant pulmonary arterial hypertension (PAH) in 2011 (Nasim et al., PMID:21898662) in a cohort of PAH patients without BMPR2 variants and screened for variants in SMAD candidate genes. In total, four SMAD4 variants (missense, non-canonical splice, and in frame deletion) have been reported (PMIDs: 21898662, 31727138). However, none of the variants were scorable. The relationship between SMAD4 and PAH is supported by SMAD4 biochemical function in rats with pulmonary hypertension (PMID:18367643). However, the gene-disease relationship betwen SMAD4 and PAH is classified as disputed due to insufficient genetic evidence over multiple years of research. This classification was approved by the ClinGen PH Gene Curation Expert Panel on 8/30/2022 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0007688
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007688
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0008276
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0008278
Submitter: ClinGen
The SMAD4 gene encodes for the SMAD4 protein, belonging to the SMAD family of transcription factor proteins. SMAD4 plays a pivotal role in signal transduction of the transforming growth factor beta superfamily cytokines by mediating transcriptional activation of target genes. Variants in SMAD4 are linked to 4 different phenotypes: juvenile polyposis with hereditary hemorrhagic telangiectasia (HHT) syndrome, Myhre syndrome, pancreatic cancer (somatic), juvenile intestinal polyposis. We curated SMAD4 for juvenile polyposis with hereditary hemorrhagic telangiectasia syndrome. SMAD4 was first reported in relation to juvenile polyposis–HHT syndrome in 2004 (Gallione et al, PMID 15031030) in seven unrelated families or individuals displaying both juvenile polyposis and hereditary haemorrhagic telangiectasia phenotypes. Seven different variants, 4 missense, 1 stop and 2 deletions leading to frameshift, were described in the enrolled individuals. Common phenotypes were arteriovenous malformation, juvenile polyposis and telangiectasia. Epistaxis was common as well as anemia and digital clubbing. At least 17 unique variants have been reported in humans, comprising missense, stop and frameshift variants. Evidence supporting this gene-disease relationship includes genetic evidences (case-level data) and experimental evidences (non-human model organisms). Summary of Case Level Data: 12 POINTS Variants in this gene have been reported in at least 24 probands in 7 publications (PMIDs: 9582123, 15235019, 15031030, 16613914, 32944796, 30210120, 22331366) leading to a score of 12 for genetic evidence. More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence has been reached. The mechanism for disease is heterozygous loss of function. Summary of Experimental Data: 4 POINTS This gene-disease association is supported by evidences of non-human model organisms, indeed two SMAD4 conditional knock out murine models have been described, both recapitulate most of the juvenile polyposis–HHT phenotypes including anemia and arteriovenous malformations in the brain, gastrointestinal tract, and skin (PMID 30571376) and formation of arteriovenous malformations in the neonate retina (PMID 29460088). In summary, we found definitive association of SMAD4 with juvenile polyposis–HHT syndrome. This classification was approved by the ClinGen Hemostasis Thrombosis Working Group on 12/16/2020 (SOP Version 8). The curation was updated on 2/22/2023 to include cases of classic Juveline polyposis with guidance from the Hereditary Cancer GCEP (SOP Version 9)
Inheritance Pattern: AD
Disease ID:MONDO:0007688
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008276
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008278
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0019180
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007688
Submitter: ClinGen
*SMAD4* has been implicated in autosomal dominant Myhre syndrome (MONDO:0007688), generalized juvenile polyposis/juvenile polyposis coli (MONDO:0008276), and juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (MONDO:0008278). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in molecular mechanisms and phenotypic variability among these disorders. Therefore, each of the disease entities listed above was curated separately. The current curation is for Myhre syndrome. *SMAD4* was first reported in relation to autosomal dominant Myhre syndrome in 2011 (Le Goff et al., PMID: 22158539). Individuals with Myhre syndrome present with short stature, typical facial appearance, hearing loss, laryngotracheal stenosis, skeletal abnormalities, cardiovascular abnormalities, developmental delay, mild-to-moderate intellectual disability, and autistic behavior in a minority of patients (PMIDs: 22158539, 27302097). Congenital hearts defects are reported in 40-60% of affected individuals, with persistent ductus arteriosus, mitral/aortic valve defects, tetralogy of Fallot and ventricular septal defects being the most common (PMIDs: 27302097, 38779990). Myhre syndrome is caused by one of four *SMAD4* missense variants [c.1498A>G (p.Ile500Val); c.1499T>C (p.Ile500Thr); c.1500A>G (p.Ile500Met); and c.1486C>T (p.Arg496Cys)] (PMIDs: 22158539, 27302097, 28406602). Over 55 Myhre syndrome patients with a *de novo* *SMAD4* pathogenic variant have been reported in the literature (PMIDs: 22158539, 26636501, 27302097, 31654632); only 9 probands were scored in this curation because the maximum score for genetic evidence (12 points) has been reached. Only one inherited variant has been reported in a patient with Myhre syndrome (PMID: 31595668). The mechanism of pathogenicity is gain of function (PMID: 22158539). *SMAD4* encodes a transcription factor that regulates bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFβ) signaling. Experimental evidence supporting this gene-disease relationship includes functional assays in patient fibroblasts and cell culture models, expression studies, and model organisms (PMIDs: 16023633, 22158539, 29695415). In summary, *SMAD4* is definitively associated with autosomal dominant Myhre syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel (GCEP) on December 1, 2021 (SOP Version 8). This curation was re-evaluated by the ClinGen Congenital Heart Disease GCEP on October 29, 2025. The classification and SOP did not change, but additional information about congenital heart defects was added to the evidence summary.
Inheritance Pattern: AD
Disease ID:MONDO:0007688
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Endocrine; Gastrointestinal; Hematologic; Oncologic
Intervention: Audiologic/Otolaryngologic; Cardiovascular; Gastrointestinal; Hematologic; Oncologic
Rationale: Individuals with HHT and JPS/HHT may have a variety of vascular complications, including arteriovenous malformations, aortic dilatation, and bleeding diatheses, and surveillance and early intervention related to manifestations (eg, related to thromboembolism or hepatic disease) may decrease morbidity and mortality; In JPS and JPS/HHT, surveillance and early diagnosis/treatment of malignancy (eg, colon cancer) may be beneficial; In Myhre syndrome, individuals may manifest with multisystemic features, including hearing impairment (for which appropriate interventions may be beneficial related to speech and language development) as well as cardiovascular anomalies (eg, cardiomyopathy, hypertension), and appropriate surveillance may allow prompt diagnosis and treatment
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SMAD4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005359.6. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 5 | 507 | 54 | 567 | |
| missense | 8 | 34 | 962 | 41 | 2 | 1047 |
| nonsense | 68 | 10 | 7 | 85 | ||
| start loss | 6 | 6 | ||||
| frameshift | 143 | 27 | 19 | 1 | 190 | |
| splice donor/acceptor (+/-2bp) | 9 | 28 | 10 | 1 | 48 | |
| Total | 228 | 100 | 1009 | 550 | 56 | 1943 |
Highest pathogenic variant AF is 0.000020748035
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005350.1 | 11 | MANE Select | |
| Ensembl | ENSP00000341551.3 | 11 | MANE Select | |
| RefSeq | NP_001393970.1 | 11 | Standard | |
| RefSeq | NP_001393971.1 | 11 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| smad4a | Danio rerio | Structure: neuroectoderm Quality: wholly dorsalized abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Chronic myeloid leukemia - Homo sapiens (human)
- Gastric cancer - Homo sapiens (human)
- TGF-beta signaling pathway - Homo sapiens (human)
- Adherens junction - Homo sapiens (human)
- AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)
Biological Process
- negative regulation of transcription by RNA polymerase II
- ovarian follicle development
- branching involved in ureteric bud morphogenesis
- response to hypoxia
- in utero embryonic development
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- proximal promoter sequence-specific DNA binding
- RNA polymerase II transcription factor binding
- DNA-binding transcription activator activity, RNA polymerase II-specific
Cellular Component
- nuclear chromatin
- nucleus
- nucleoplasm
- transcription factor complex
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000342988
- Coding exons
- 11
- Length
- 117006
- Individuals with no LoFs
- 125743
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 4
- Defined
- 125747
- p
- 0.0000159
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.13 | 107 | 312 | 0.342 | 0.0000164 | 3624 |
| Missense (PolyPhen) | 20 | 121.97 | 0.16398 | 1446 | ||
| Synonymous | 0.579 | 103 | 111 | 0.930 | 0.00000623 | 1069 |
| Loss of Function | 4.59 | 2 | 28.4 | 0.0705 | 0.00000138 | 334 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions (By similarity). Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling (PubMed:25514493). Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator. {ECO:0000250, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:25514493, ECO:0000269|PubMed:9389648}.;
- Disease
- DISEASE: Pancreatic cancer (PNCA) [MIM:260350]: A malignant neoplasm of the pancreas. Tumors can arise from both the exocrine and endocrine portions of the pancreas, but 95% of them develop from the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue. {ECO:0000269|PubMed:8553070}. Note=The gene represented in this entry may be involved in disease pathogenesis.; DISEASE: Juvenile polyposis syndrome (JPS) [MIM:174900]: Autosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. The lesions are typified by a smooth histological appearance, predominant stroma, cystic spaces and lack of a smooth muscle core. Multiple juvenile polyps usually occur in a number of Mendelian disorders. Sometimes, these polyps occur without associated features as in JPS; here, polyps tend to occur in the large bowel and are associated with an increased risk of colon and other gastrointestinal cancers. {ECO:0000269|PubMed:12417513, ECO:0000269|PubMed:9811934}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (JP/HHT) [MIM:175050]: JP/HHT syndrome phenotype consists of the coexistence of juvenile polyposis (JIP) and hereditary hemorrhagic telangiectasia (HHT) [MIM:187300] in a single individual. JIP and HHT are autosomal dominant disorders with distinct and non-overlapping clinical features. The former, an inherited gastrointestinal malignancy predisposition, is caused by mutations in SMAD4 or BMPR1A, and the latter is a vascular malformation disorder caused by mutations in ENG or ACVRL1. All four genes encode proteins involved in the transforming-growth- factor-signaling pathway. Although there are reports of patients and families with phenotypes of both disorders combined, the genetic etiology of this association is unknown. {ECO:0000269|PubMed:15031030}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269|PubMed:16959974}. Note=The disease may be caused by mutations affecting the gene represented in this entry.; DISEASE: Note=SMAD4 variants may be associated with susceptibility to pulmonary hypertension, a disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs. {ECO:0000269|PubMed:21898662}.; DISEASE: Myhre syndrome (MYHRS) [MIM:139210]: A syndrome characterized by pre- and postnatal growth deficiency, mental retardation, generalized muscle hypertrophy and striking muscular build, decreased joint mobility, cryptorchidism, and unusual facies. Dysmorphic facial features include microcephaly, midface hypoplasia, prognathism, and blepharophimosis. Typical skeletal anomalies are short stature, square body shape, broad ribs, iliac hypoplasia, brachydactyly, flattened vertebrae, and thickened calvaria. Other features, such as congenital heart disease, may also occur. {ECO:0000269|PubMed:22158539, ECO:0000269|PubMed:22243968}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.796
Intolerance Scores
- LoFtool
- 0.116
- RVIS EVS
- -0.32
- RVIS percentile EVS
- 31.69
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Indispensability pred.
- E
- Indispensability score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |