SMURF2
protein-codingSMAD specific E3 ubiquitin protein ligase 2, the group of C2 domain containing|HECT domain containing
Gene summary
Enables SMAD binding activity; identical protein binding activity; and ubiquitin protein ligase activity. Involved in several processes, including negative regulation of transforming growth factor beta receptor signaling pathway; positive regulation of ferroptosis; and positive regulation of trophoblast cell migration. Located in nuclear speck. Part of ubiquitin ligase complex. [provided by Alliance of Genome Resources, Jun 2026]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~120.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0100038
Submitter: LiferaOmics
Genetic evidence – Published PMID: 28097321 – Family 1 – one proband. Case-level: Not scored (biallelic missense variant reported; however, second confident candidate variant in AMZ2 identified in same individual; dual molecular finding unresolved) = 0;Segregation = 0;Case-control = 0 Family 1 total = 0 Published genetic evidence total = 0 / 12 Genetic evidence – Our cases Family 1 – One proband. Case-level (biallelic predicted null in AR model; homozygous frameshift; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0;Segregation = 0; Case-control = 0 Family 1 total = 1.0 Our genetic evidence total = 1.0 / 12 Total genetic evidence (published AR + our cases) 0 (published AR) + 1.0 (our case) = 1.0 / 12 Experimental evidence – Published PMID: 11016919 – SMURF2 identified as a HECT-type E3 ubiquitin ligase regulating TGF-β/SMAD signaling. This establishes SMURF2 as a regulator of a core developmental signaling pathway implicated in neurodevelopment, cardiac morphogenesis, and organogenesis. Gene function / biological plausibility = 0.5 (No patient-derived functional data, no phenotype-specific animal recapitulation, and no rescue studies available.) Experimental evidence total = 0.5 / 6 Overall score Genetic evidence = 1.0 Experimental evidence = 0.5 Overall score = 1.5 / 18
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SMURF2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_022739.4. 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 | 7 | 4 | 12 | ||
| missense | 64 | 1 | 1 | 66 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 3 | 3 | ||||
| Total | 0 | 0 | 68 | 8 | 5 | 81 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_073576.1 | 19 | MANE Select | |
| Ensembl | ENSP00000262435.9 | 19 | MANE Select | |
| Ensembl | ENSP00000464432.1 | 4 | Standard | |
| Ensembl | ENSP00000463531.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- TGF-beta signaling pathway - Homo sapiens (human)
- Endocytosis - Homo sapiens (human)
- Ubiquitin mediated proteolysis - Homo sapiens (human)
- Hedgehog signaling pathway - Homo sapiens (human)
- WNT-Ncore
Biological Process
- negative regulation of transcription by RNA polymerase II
- protein polyubiquitination
- ubiquitin-dependent protein catabolic process
- protein ubiquitination
- protein deubiquitination
Molecular Function
- ubiquitin-protein transferase activity
- transforming growth factor beta receptor binding
- protein binding
- identical protein binding
- SMAD binding
Cellular Component
- ubiquitin ligase complex
- nucleus
- nucleoplasm
- cytoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000262435
- Coding exons
- 19
- Length
- 119774
- Individuals with no LoFs
- 125732
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 15
- Defined
- 125747
- p
- 0.0000596
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.90 | 238 | 402 | 0.593 | 0.0000214 | 4906 |
| Missense (PolyPhen) | 79 | 171.47 | 0.46071 | 2084 | ||
| Synonymous | 0.914 | 128 | 142 | 0.902 | 0.00000740 | 1381 |
| Loss of Function | 5.30 | 10 | 50.8 | 0.197 | 0.00000314 | 542 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000031 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00011 | 0.00011 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Interacts with SMAD1 and SMAD7 in order to trigger their ubiquitination and proteasome-dependent degradation. In addition, interaction with SMAD7 activates autocatalytic degradation, which is prevented by interaction with SCYE1. Forms a stable complex with the TGF-beta receptor-mediated phosphorylated SMAD2 and SMAD3. In this way, SMAD2 may recruit substrates, such as SNON, for ubiquitin-mediated degradation. Enhances the inhibitory activity of SMAD7 and reduces the transcriptional activity of SMAD2. Coexpression of SMURF2 with SMAD1 results in considerable decrease in steady-state level of SMAD1 protein and a smaller decrease of SMAD2 level. {ECO:0000269|PubMed:11389444, ECO:0000269|PubMed:12717440}.;
Recessive Scores
- pRec
- 0.183
Intolerance Scores
- LoFtool
- 0.264
- RVIS EVS
- -0.69
- RVIS percentile EVS
- 15.12
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.974
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |