TAB2
protein-codingTGF-beta activated kinase 1 (MAP3K7) binding protein 2, the group of Zinc fingers RANBP2-type
Gene summary
The protein encoded by this gene is an activator of MAP3K7/TAK1, which is required for for the IL-1 induced activation of nuclear factor kappaB and MAPK8/JNK. This protein forms a kinase complex with TRAF6, MAP3K7 and TAB1, and it thus serves as an adaptor that links MAP3K7 and TRAF6. This protein, along with TAB1 and MAP3K7, also participates in the signal transduction induced by TNFSF11/RANKl through the activation of the receptor activator of NF-kappaB (TNFRSF11A/RANK), which may regulate the development and function of osteoclasts. Studies of the related mouse protein indicate that it functions to protect against liver damage caused by chemical stressors. Mutations in this gene cause congenital heart defects, multiple types, 2 (CHTD2). Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]
- MAP3K7IP2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~193.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014000
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014000
Submitter: ClinGen
*TAB2* was first reported in relation to autosomal dominant congenital heart disease in 2010 (Thienpoint et al, PMID 20493459). At least 14 rare variants (2 missense, 12 loss-of-function) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. *TAB2* has been noted to be associated with the following disease entities: atrial septal defect, bicuspid aortic valve, valvular dysplasia, valvular stenosis, and ventricular septal defect (OMIM 160710). 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, *TAB2*-related syndromic congenital heart disease. Variants in this gene have been reported in at least 14 probands in 6 publications (PMIDs 20493459, 27452334, 28386937, 34741306, 34456334, 34995729), using an allele frequency threshold of 1x10-5. This gene-disease relationship is supported by expression studies, animal models, and cellular models. Expression studies confirmed that TAB2 is expressed during zebrafish embryogenesis and human development (PMID 20493459). Zebrafish depletion of tab2 by morpholino led to early cardiac dysfunction and disrupted development (PMID 20493459). Human induced pluripotent stem cell models of cardiac development demonstrated disorganized sarcomeric structure in *TAB2*-deficient cells (PMID 39905300). In summary, *TAB2* is definitively associated with autosomal dominant **TAB2*-related syndromic congenital heart disease. 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 Congenital Heart Disease GCEP on the meeting date January 5th, 2026 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0014000
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014000
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013025
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014000
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0016460
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014000
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular
Intervention: Cardiovascular
Rationale: While some reported cardiac malformations may be readily clinically ascertained, other reported types may be more subtle, and targeted surveillance (eg, with echocardiography and electrocardiography) for findings that have been reported as including bicuspid aortic valve and aortic dilatation, left ventricular outflow obstruction, subaortic stenosis, and atrial fibrillation, may allow early medical and/or surgical management, which may decrease morbidity and mortality
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TAB2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001292034.3. 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 | 5 | 61 | 3 | 69 | ||
| missense | 2 | 3 | 202 | 5 | 212 | |
| nonsense | 16 | 15 | 31 | |||
| start loss | 0 | |||||
| frameshift | 31 | 16 | 1 | 48 | ||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 2 | 5 | ||
| Total | 50 | 36 | 210 | 66 | 3 | 365 |
Highest pathogenic variant AF is 0.0000041045287
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001278963.1 | 6 | MANE Select | |
| Ensembl | ENSP00000490618.1 | 6 | MANE Select | |
| RefSeq | NP_001278964.1 | 6 | Standard | |
| RefSeq | NP_001356435.1 | 6 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| tab2 | Danio rerio | Structure: pericardial cavity Quality: increased size abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- TNF signaling pathway - Homo sapiens (human)
- Toll-like receptor signaling pathway - Homo sapiens (human)
- NOD-like receptor signaling pathway - Homo sapiens (human)
- MAPK signaling pathway - Homo sapiens (human)
- Leishmaniasis - Homo sapiens (human)
Biological Process
- activation of MAPK activity
- stimulatory C-type lectin receptor signaling pathway
- MyD88-dependent toll-like receptor signaling pathway
- I-kappaB kinase/NF-kappaB signaling
- JNK cascade
Molecular Function
- protein binding
- metal ion binding
- K63-linked polyubiquitin modification-dependent protein binding
Cellular Component
- nucleoplasm
- cytosol
- plasma membrane
- endosome membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000367456
- Coding exons
- 6
- Length
- 192973
- Individuals with no LoFs
- 125742
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 125745
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.61 | 272 | 358 | 0.760 | 0.0000190 | 4555 |
| Missense (PolyPhen) | 82 | 147.34 | 0.55655 | 1787 | ||
| Synonymous | -0.934 | 136 | 123 | 1.11 | 0.00000611 | 1381 |
| Loss of Function | 5.11 | 0 | 30.4 | 0.00 | 0.00000216 | 308 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Adapter linking MAP3K7/TAK1 and TRAF6. Promotes MAP3K7 activation in the IL1 signaling pathway. The binding of 'Lys-63'- linked polyubiquitin chains to TAB2 promotes autophosphorylation of MAP3K7 at 'Thr-187'. Involved in heart development. {ECO:0000269|PubMed:10882101, ECO:0000269|PubMed:11460167, ECO:0000269|PubMed:20493459}.;
- Disease
- DISEASE: Congenital heart defects, multiple types, 2 (CHTD2) [MIM:614980]: A disease characterized by congenital developmental abnormalities involving structures of the heart. CHTD2 patients have left ventricular outflow tract obstruction, subaortic stenosis, residual aortic regurgitation, atrial fibrillation, bicuspid aortic valve and aortic dilation. {ECO:0000269|PubMed:20493459}. Note=The disease is caused by mutations affecting the gene represented in this entry. A chromosomal aberration involving TAB2 has been found in a family with congenital heart disease. Translocation t(2;6)(q21;q25).;
Recessive Scores
- pRec
- 0.227
Intolerance Scores
- LoFtool
- 0.123
- RVIS EVS
- -1.11
- RVIS percentile EVS
- 6.72
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.539
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |