REL
protein-codingREL proto-oncogene, NF-kB subunit, the group of NF-kappa B complex subunits|IPT domain containing
Gene summary
This gene encodes a protein that belongs to the Rel homology domain/immunoglobulin-like fold, plexin, transcription factor (RHD/IPT) family. Members of this family regulate genes involved in apoptosis, inflammation, the immune response, and oncogenic processes. This proto-oncogene plays a role in the survival and proliferation of B lymphocytes. Mutation or amplification of this gene is associated with B-cell lymphomas, including Hodgkin's lymphoma. Single nucleotide polymorphisms in this gene are associated with susceptibility to ulcerative colitis and rheumatoid arthritis. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2014]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~50.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0030498
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0030498
Submitter: ClinGen
*REL* was first reported in relation to immunodeficiency 92 in a single patient in 2019 (Beaussant-Cohen S, et al., 2019, PMID: 31103457). A second patient was reported in Lévy R, et al., 2021 (PMID: 34623332) and both patients were homozygous for splice variants with a proposed loss of function mechanism. Experimentally, this gene-disease relationship is supported by its expression pattern and biochemical function. c-Rel, the protein product of *REL*, is strongly expressed by control EBV-B cells and was detected in all leukocyte subsets from healthy donors, the highest levels being recorded for γδ T cells, naive CD19+ B cells, CD16+ monocytes, and CD141+ conventional DCs (PMID: 34623332). c-Rel is a transcription factor in the NF-κB family, critical for T and B cell function, it binds to the promoters of genes that encode cytokines important for immunity against infectious pathogens, including IL-2, IFN-γ, IL-12, IL-21, and IL-23 (PMID: 22207895) with significant functional alteration observed in patients (PMID: 34623332). Furthermore, Rel-deficient mice have impaired T and B cell proliferation, hypogammaglobulinemia, and impaired cytokine production (PMID: 7649478, 10221648). The patients' combined immunodeficiency mirrors the defects in T cell activation, B cell proliferation, innate immunity and humoral immunity seen in c-Rel-deficient mice. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the SCID/CID GCEP on 2023 Mar 16. It was reevaluated on 2025 Nov 24. As a result of this reevaluation, no new evidence was identified and the classification did not change.
Inheritance Pattern: AR
Disease ID:MONDO:0030498
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious;
Intervention: Allergy/Immunology/Infectious;
Rationale: The condition involves increased risk of severe and early-onset 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 REL variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001291746.2. 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 | 84 | 1 | 85 | |||
| missense | 81 | 10 | 91 | |||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 2 | 3 | |||
| splice donor/acceptor (+/-2bp) | 2 | 1 | 1 | 4 | ||
| Total | 4 | 1 | 83 | 95 | 1 | 184 |
Highest pathogenic variant AF is 0.000010151419
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001278675.1 | 10 | MANE Select | |
| Ensembl | ENSP00000377989.4 | 10 | MANE Select | |
| RefSeq | NP_001424954.1 | 9 | Standard | |
| RefSeq | NP_002899.1 | 11 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| rel | Danio rerio | Structure: trunk Quality: curved abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Ras signaling pathway - Homo sapiens (human)
- Viral carcinogenesis - Homo sapiens (human)
- Transcriptional misregulation in cancer - Homo sapiens (human)
- Tacrolimus/Cyclosporine Pathway, Pharmacodynamics
- IL-1 signaling pathway
Biological Process
- negative regulation of transcription by RNA polymerase II
- inflammatory response
- I-kappaB kinase/NF-kappaB signaling
- negative regulation of gene expression
- negative regulation of interferon-beta production
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
- DNA-binding transcription activator activity, RNA polymerase II-specific
- chromatin binding
Cellular Component
- nucleus
- nucleoplasm
- transcription factor complex
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000295025
- Coding exons
- 11
- Length
- 50090
- Individuals with no LoFs
- 125730
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 10
- Defined
- 125740
- p
- 0.0000398
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.76 | 243 | 333 | 0.729 | 0.0000170 | 4069 |
| Missense (PolyPhen) | 58 | 135.09 | 0.42935 | 1635 | ||
| Synonymous | 0.400 | 112 | 118 | 0.953 | 0.00000634 | 1172 |
| Loss of Function | 4.51 | 2 | 27.5 | 0.0727 | 0.00000149 | 357 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00017 | 0.00016 | rare |
| 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: Proto-oncogene that may play a role in differentiation and lymphopoiesis. 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. The NF-kappa-B heterodimer RELA/p65-c-Rel is a transcriptional activator.;
Recessive Scores
- pRec
- 0.362
Intolerance Scores
- LoFtool
- 0.286
- RVIS EVS
- -0.69
- RVIS percentile EVS
- 15.12
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.567
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |