SMAD2
protein-codingSMAD family member 2, the group of SMAD family
Gene summary
The protein encoded by this gene belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein mediates the signal of the transforming growth factor (TGF)-beta, and thus regulates multiple cellular processes, such as cell proliferation, apoptosis, and differentiation. This protein is recruited to the TGF-beta receptors through its interaction with the SMAD anchor for receptor activation (SARA) protein. In response to TGF-beta signal, this protein is phosphorylated by the TGF-beta receptors. The phosphorylation induces the dissociation of this protein with SARA and the association with the family member SMAD4. The association with SMAD4 is important for the translocation of this protein into the nucleus, where it binds to target promoters and forms a transcription repressor complex with other cofactors. This protein can also be phosphorylated by activin type 1 receptor kinase, and mediates the signal from the activin. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, May 2012]
- MADH2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~122.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0859213
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0859213
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0030500
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0030500
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0005453
Submitter: ClinGen
SMAD2 was first reported in relation to autosomal dominant congenital heart disease in 2017 (Jin et al., PMID 28991257). At least 9 rare variants (4 missense, 5 loss-of-function) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. SMAD2 has been noted to be associated with the following disease entities: atrial septal defect, ventricular septal defect, dextrocardia, atrial isomerism, double-outlet right ventricle, unbalanced complete atrioventricular canal, unbalanced right-dominant complete atrioventricular canal, pulmonary stenosis, pulmonary atresia, mitral atresia and hypoplastic left ventricle (OMIM 619657). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern. Therefore, these disease entities have been lumped into one disease entity, Autosomal Dominant SMAD2-related Congenital Heart Disorders with or without Heterotaxy. Variants in this gene have been reported in at least 9 probands in 9 publications (PMIDs 28991257, 36803080, 30157302, 30622330, 29786156, 34328347), using an allele frequency threshold of 1x10-5. This gene-disease relationship is supported by animal models, expression studies, and functional assays. Expression studies confirmed that SMAD2 is expressed during mouse embryogenesis (PMID 24064296). Multiple mouse models of congenital heart disease had abnormal SMAD2 expression and/or phosphorylation (PMIDs 15528466, 33801433, 18952608, 26821812, 35894043). Hypomorphic alleles of Smad2 resulted in impaired mouse embryo formation (PMID 12432092), while overexpression led to increased cardiac differentiation (PMID 27818139). In summary, there is strong evidence to support this gene-disease relationship. The association has been replicated over time, supporting a definitive gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 11/6/23 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0018954
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0859213
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0030500
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0005453
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0030500
Submitter: ClinGen
Variants in *SMAD2* have been reported in individuals with the following disease entities: congenital heart disease, Loeys-Dietz syndrome, and thoracic aortic aneurysm and dissection. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in molecular mechanism and phenotypic variability. Therefore, Loeys-Dietz syndrome 6 (MIM: 619656) and familial thoracic aortic aneurysm and dissection (FTAAD) have been lumped into one disease entity, whereas Congenital heart defects, multiple types, 8, with or without heterotaxy (MIM: 619657) remains separate. This current curation will be for the lumped disease entity of *SMAD2*-related autosomal dominant Loeys-Dietz syndrome and thoracic aortic aneurysm and dissection. The split curation for *SMAD2*-related autosomal dominant congenital heart disorder has been assessed separately by the ClinGen Congenital Heart Disease GCEP. *SMAD2* was first reported in relation to autosomal dominant inheritance of Loeys-Dietz syndrome (LDS) and thoracic aortic aneurysm and dissection (TAAD) in 2015 when Micha *et al.* described individuals carrying heterozygous *SMAD2* variants affected by aneurysms and dissections in the vertebral arteries and thoracic aorta while also presenting with tall stature, hip dysplasia, ptosis, scoliosis, high palate, and osteoarthrosis (PMID: 26247899). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Fourteen variants (nine missense, three nonsense, and two frameshift) that have been reported in sixteen probands from five publications (PMIDs: 26247899, 28283438, 29967133, 30157302, 31915033) and five ClinVar submissions (ClinVar IDs: SCV002581277.2, SCV004501205.2, SCV005729311.1, SCV004399167.2, SCV006083335.1) are included in this curation. The nine missense variants reported in patients with arterial or aortic aneurysms are primarily localized to the MH2 domain while the null variants are distributed across all three domains of *SMAD2*. Only probands with aneurysm or dissection were considered for this curation. This gene-disease association is also supported by protein interaction, animal model, and expression studies. *SMAD2* is ubiquitously expressed in tissues with high expression in aorta and skin tissue (PMID: 23715323, dbGaP Accession phs000424.v10.p2). Using a transgenic mouse model, Xie *et al.* reported Smad2 deficiency in neural crest cells (NCC) caused reduction in differentiated vascular smooth muscle cell layers along with distortion and thinning of elastic lamina, resulting in thinner vessel walls within carotid arteries of Smad2 NCC-specific knockout mice (PMID: 23817199). Furthermore, coimmunoprecipitation assays by Marcias-Silva *et al.* showed *SMAD2* interacts with *TGFBR1*, a gene previously determined to be Definitively associated with Loeys-Dietz syndrome and familial thoracic aortic aneurysm and dissections (PMID: 8980228, 9311995). Using isogenic induced pluripotent stem cells (iPSC) models with heterozygous or homozygous loss-of-function and missense *SMAD2* variants, Ward *et al.* in 2025 (PMID: 40028843) showed *SMAD2*-mutant iPSCs reduced SMAD2 protein expression and reduced expression of target genes in the TGF‐beta/BMP pathway. However, the variants used in these SMAD2 mutant iPSC models were only reported in patients with clinical presentations of congenital heart disease with no indication of aortopathy (PMID: 40028843). In contrast, Smad2 mRNA upregulation as well as increased phosphorylated Smad2 have been shown in aneurysmal vascular smooth muscle cells (PMID: 19224541). Fukuda *et al.* (2018, PMID: 29682117) reported increased phosphorylated Smad2 immunostaining in aortic tissues of individuals with thoracic aortic aneurysms while Micha *et al.* (2015, PMID: 26247899) reported increased levels of both phosphorylated Smad2 and phosphorylated Smad3 in cultured dermal fibroblasts from individuals with *SMAD2* missense variants and affected by arterial aneurysms and dissections. However, the direct functional impact of pathogenic variants in *SMAD2* on the TGF-beta-signaling Smad2 pathway in aneurysms is unclear. Therefore, the mechanism of pathogenicity of *SMAD2*-related LDS with thoracic aortic aneurysm and dissection remains to be unclear. In summary, there is definitive evidence to support the relationship between *SMAD2* and autosomal dominant Loeys Dietz Syndrome with thoracic aortic aneurysm and dissection. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Heritable Thoracic Aortic Aneurysm and Dissection subgroup of the Hereditary Cardiovascular Disease GCEP on August 1st, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0030500
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0019625
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0859213
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Gastrointestinal; Musculoskeletal
Intervention: Cardiovascular
Rationale: Loeys-Dietz syndrome can involve cardiovascular sequelae, including aortic aneurysms and dissection, and awareness may allow early detection and medical and surgical management; Congenital heart defects, multiple types, 8, with or without heterotaxy can involve congenital heart anomalies, and awareness may allow early detection and management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SMAD2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005901.6. 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 | 3 | 149 | 2 | 154 | ||
| missense | 6 | 8 | 190 | 204 | ||
| nonsense | 6 | 4 | 2 | 12 | ||
| start loss | 0 | |||||
| frameshift | 8 | 4 | 4 | 16 | ||
| splice donor/acceptor (+/-2bp) | 3 | 4 | 2 | 9 | ||
| Total | 23 | 20 | 201 | 149 | 2 | 395 |
Highest pathogenic variant AF is 0.0000013692515
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005892.1 | 10 | MANE Select | |
| Ensembl | ENSP00000262160.6 | 10 | MANE Select | |
| RefSeq | NP_001003652.1 | 10 | Standard | |
| RefSeq | NP_001129409.1 | 9 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| smad2 | Danio rerio | Structure: neuron Quality: degenerate abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Gastric cancer - Homo sapiens (human)
- Relaxin signaling pathway - 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
- ureteric bud development
- in utero embryonic development
- endoderm formation
- mesoderm formation
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription activator activity, RNA polymerase II-specific
- DNA binding
- chromatin binding
Cellular Component
- nuclear chromatin
- nucleus
- nucleoplasm
- transcription factor complex
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000402690
- Coding exons
- 10
- Length
- 99594
- Individuals with no LoFs
- 125736
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 4
- Defined
- 125740
- p
- 0.0000159
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.66 | 88 | 251 | 0.350 | 0.0000132 | 3033 |
| Missense (PolyPhen) | 16 | 87.809 | 0.18221 | 1154 | ||
| Synonymous | -0.656 | 98 | 90.1 | 1.09 | 0.00000500 | 890 |
| Loss of Function | 4.57 | 3 | 30.0 | 0.100 | 0.00000181 | 313 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000026 | 0.000026 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD2/SMAD4 complex, activates transcription. May act as a tumor suppressor in colorectal carcinoma. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator. {ECO:0000269|PubMed:16751101, ECO:0000269|PubMed:16862174, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:19289081, ECO:0000269|PubMed:9892009}.;
Recessive Scores
- pRec
- 0.844
Intolerance Scores
- LoFtool
- 0.173
- RVIS EVS
- -0.38
- RVIS percentile EVS
- 27.42
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Low | Low |
| Primary Immunodeficiency | Medium | Low | Medium |
| Cancer | Medium | Medium | Medium |