RELB
protein-codingRELB proto-oncogene, NF-kB subunit, the group of NF-kappa B complex subunits|IPT domain containing
Gene summary
Enables RNA polymerase II cis-regulatory region sequence-specific DNA binding activity and protein kinase binding activity. Involved in lymphocyte differentiation and negative regulation of interferon-beta production. Located in centrosome; chromatin; and nucleoplasm. Part of nucleus and transcription repressor complex. Implicated in breast cancer and immunodeficiency 53. Biomarker of breast cancer and transitional cell carcinoma. [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 ~36.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: Unknown
Disease ID:MONDO:0054696
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0054696
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0054696
Submitter: ClinGen
Biallelic germline variants in RELB were first reported in relationship to combined immunodeficiency (CID) in a consanguineous family in 2015 (Merico et al., 2015; DOI: 10.14785/lpsn-2015-0005). Subsequent reports have described affected individuals presenting with a dysplastic thymus, abnormal T-cell repertoire, dysfunctional T and B cells, autoimmune manifestations and susceptibility to opportunistic infections (PMID: 26385063, 33791233). In total, there have been a reported seven loss-of-function (LOF) variants (four truncating and three missense) across multiple probands (PMID:26385063, 33083013, 33791233, 36402602, 39231201). Heterozygous carriers do not manifest clinical symptoms. RelB is a key component of the alternative NF-κB signaling pathway, functioning as a heterodimer with p52 to regulate lymphoid organogenesis, dendritic cell maturation, and thymic development. LOF variants in RELB lead to the reduction or absence of RelB protein and impairment of the alternative NF-κB signaling pathway. Functional studies using patient-derived cells demonstrate significant reductions in RELB RNA and protein levels, alongside alterations in T- and B-cell activation, proliferation, and cytokine production (Merico et al., 2015; PMID: 26385063, 39231201). Mouse models of RelB deficiency, including conditional knockout systems, recapitulate key features observed in probands, such as defects in medullary thymic epithelial cells and impaired regulatory T-cell development, often manifesting in autoimmunity (PMID: 28385374, 7845467). Notably, hematopoietic stem cell transplant (HSCT) has been reported to rescue lymphocyte function and improve clinical outcomes (PMID: 28552761, 39231201). In summary, there is definitive evidence to support this gene-disease relationship. This association 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 SCID-CID Working Group on 5/21/2026.
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious
Intervention: Allergy/Immunology/Infectious
Rationale: Individuals have been described with recurrent respiratory and other infections, and awareness may allow preventative measures and early and aggressive treatment of infections; HSCT has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to RELB variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006509.4. 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 | 6 | 163 | 3 | 172 | ||
| missense | 246 | 4 | 250 | |||
| nonsense | 1 | 1 | 3 | 5 | ||
| start loss | 1 | 1 | ||||
| frameshift | 3 | 3 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 5 | 6 | |||
| Total | 1 | 2 | 264 | 167 | 3 | 437 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006500.2 | 12 | MANE Select | |
| Ensembl | ENSP00000221452.7 | 12 | MANE Select | |
| RefSeq | NP_001398016.1 | 11 | Standard | |
| Ensembl | ENSP00000423287.1 | 11 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- HTLV-I infection - Homo sapiens (human)
- C-type lectin receptor signaling pathway - Homo sapiens (human)
- MAPK signaling pathway - Homo sapiens (human)
- Osteoclast differentiation - Homo sapiens (human)
- NF-kappa B signaling pathway - Homo sapiens (human)
Biological Process
- negative regulation of transcription by RNA polymerase II
- stimulatory C-type lectin receptor signaling pathway
- inflammatory response
- I-kappaB kinase/NF-kappaB signaling
- antigen processing and presentation
Molecular Function
- RNA polymerase II regulatory region sequence-specific DNA binding
- RNA polymerase II distal enhancer sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- chromatin binding
- DNA-binding transcription factor activity
Cellular Component
- nucleus
- nucleoplasm
- centrosome
- cytosol
- transcriptional repressor complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000221452
- Coding exons
- 12
- Length
- 36765
- Individuals with no LoFs
- 124361
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 124363
- p
- 0.00000804
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.28 | 240 | 362 | 0.663 | 0.0000252 | 3654 |
| Missense (PolyPhen) | 58 | 125 | 0.464 | 1270 | ||
| Synonymous | -0.0838 | 169 | 168 | 1.01 | 0.0000131 | 1232 |
| Loss of Function | 4.16 | 2 | 24.0 | 0.0832 | 0.00000126 | 273 |
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 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000019 | 0.000018 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: NF-kappa-B is a pleiotropic transcription factor which is present in almost all cell types and is involved in many biological processed such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF- kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF- kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric RelB-p50 and RelB-p52 complexes are transcriptional activators. RELB neither associates with DNA nor with RELA/p65 or REL. Stimulates promoter activity in the presence of NFKB2/p49. As a member of the NUPR1/RELB/IER3 survival pathway, may provide pancreatic ductal adenocarcinoma with remarkable resistance to cell stress, such as starvation or gemcitabine treatment. Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-ARNTL/BMAL1 heterodimer in a CRY1/CRY2 independent manner. Increased repression of the heterodimer is seen in the presence of NFKB2/p52. Is required for both T and B lymphocyte maturation and function (PubMed:26385063). {ECO:0000269|PubMed:1732739, ECO:0000269|PubMed:22565310, ECO:0000269|PubMed:26385063, ECO:0000269|PubMed:7925301, ECO:0000269|PubMed:8441398}.;
- Disease
- DISEASE: Immunodeficiency 53 (IMD53) [MIM:617585]: An autosomal recessive primary immunodeficiency apparent from early infancy and resulting in recurrent infections, severe autoimmune skin disease rheumatoid arthritis, and failure to thrive. Immunologic workup shows increased CD4+/CD8+ ratio, impaired T-cell proliferative response to multiple antigen, T-cell developmental and functional defects, and impaired ability to produce specific immunoglobulins. {ECO:0000269|PubMed:26385063}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.487
Intolerance Scores
- LoFtool
- 0.0582
- RVIS EVS
- -1
- RVIS percentile EVS
- 8.32
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.839
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |