REL

Summary

REL (REL proto-oncogene, NF-kB subunit, HGNC:9954) is a protein-coding gene on chromosome 2p16.1, encoding Proto-oncogene c-Rel (Q04864). Proto-oncogene that may play a role in differentiation and lymphopoiesis.

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.

Source: NCBI Gene 5966 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 92 (Strong, GenCC)
• GWAS associations: 28
• Clinical variants (ClinVar): 264 total — 6 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 22
• Druggable target: yes
• Transcription factor: yes — 126 downstream targets (CollecTRI)
• MANE Select transcript: NM_001291746

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9954
Approved symbol	REL
Name	REL proto-oncogene, NF-kB subunit
Location	2p16.1
Locus type	gene with protein product
Status	Approved
Aliases	I-Rel, c-Rel, HIVEN86A
Ensembl gene	ENSG00000162924
Ensembl biotype	protein_coding
OMIM	164910
Entrez	5966

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 9 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000295025, ENST00000394479, ENST00000642725, ENST00000699191, ENST00000699192, ENST00000699193, ENST00000699194, ENST00000699195, ENST00000878076, ENST00000878077, ENST00000878078, ENST00000949522, ENST00000949523

RefSeq mRNA: 2 — MANE Select: NM_001291746 NM_001291746, NM_002908

CCDS: CCDS1864, CCDS74515

Canonical transcript exons

ENST00000394479 — 10 exons

Exon	Start	End
ENSE00001069884	60920041	60920109
ENSE00001069886	60918394	60918606
ENSE00001069888	60920574	60920642
ENSE00001069892	60900992	60901083
ENSE00001069898	60916877	60917017
ENSE00001069901	60918191	60918295
ENSE00001069902	60894397	60894545
ENSE00001163551	60891683	60891825
ENSE00003975925	60921763	60931612
ENSE00003975927	60881574	60881850

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 87.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.6595 / max 1254.3178, expressed in 1767 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
20454	22.9638	1611
20452	7.6021	1483
20456	2.5763	438
20455	1.9665	545
20457	1.3909	199
20453	0.4609	258
202203	0.2212	82
20461	0.2198	95
20451	0.1298	56
20462	0.1281	45

Top tissues by expression

281 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	87.20	gold quality
bone marrow	UBERON:0002371	86.43	gold quality
secondary oocyte	CL:0000655	86.37	gold quality
oocyte	CL:0000023	86.18	gold quality
bone marrow cell	CL:0002092	86.10	gold quality
monocyte	CL:0000576	85.66	gold quality
mononuclear cell	CL:0000842	85.58	gold quality
leukocyte	CL:0000738	85.12	gold quality
colonic epithelium	UBERON:0000397	84.79	gold quality
mucosa of urinary bladder	UBERON:0001259	84.32	gold quality
penis	UBERON:0000989	83.85	gold quality
cartilage tissue	UBERON:0002418	83.72	gold quality
superficial temporal artery	UBERON:0001614	83.67	gold quality
vermiform appendix	UBERON:0001154	82.99	gold quality
nipple	UBERON:0002030	82.85	gold quality
lower lobe of lung	UBERON:0008949	82.69	gold quality
mucosa of paranasal sinus	UBERON:0005030	82.65	gold quality
tonsil	UBERON:0002372	82.15	gold quality
caecum	UBERON:0001153	81.11	gold quality
blood	UBERON:0000178	80.56	gold quality
skin of hip	UBERON:0001554	80.48	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.23	gold quality
jejunal mucosa	UBERON:0000399	79.55	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.49	gold quality
lymph node	UBERON:0000029	79.39	gold quality
urinary bladder	UBERON:0001255	79.31	gold quality
oral cavity	UBERON:0000167	79.27	gold quality
gall bladder	UBERON:0002110	78.22	gold quality
mammary duct	UBERON:0001765	77.97	gold quality
upper leg skin	UBERON:0004262	77.84	gold quality

Single-cell (SCXA)

Detected in 17 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	131.69
E-MTAB-8142	yes	100.44
E-GEOD-84465	yes	38.18
E-MTAB-9467	yes	28.88
E-CURD-122	yes	24.89
E-MTAB-6678	yes	24.16
E-CURD-46	yes	21.84
E-MTAB-9221	yes	19.20
E-MTAB-9543	yes	10.78
E-GEOD-135922	yes	10.03
E-HCAD-10	yes	7.94
E-CURD-112	yes	5.07
E-HCAD-36	no	3084.52
E-MTAB-11011	no	2547.12
E-GEOD-137537	no	1773.64

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

126 targets.

Target	Regulation
ALCAM	Activation
ALOX12	Repression
AQP2
ATP11C
BCL2	Activation
BCL2A1	Activation
BCL2L1	Activation
BIRC2	Activation
BIRC3	Activation
BTK
C4B
CCL2	Activation
CCL20	Activation
CCL4	Activation
CCL5	Unknown
CCNE1	Repression
CD28
CD40
CD40LG	Unknown
CD74
CD8A
CDKN1A	Activation
CEBPD	Activation
CLSPN	Unknown
CNTN2
CR2
CRP	Unknown
CSF1	Repression
CSF2	Activation
CSRP1	Activation

JASPAR motifs

Motif	Name	Family
MA0101.1	REL	NF-kappaB-related factors

JASPAR matrix evidence (PMIDs): PMID:1406630

Upstream regulators (CollecTRI, top): E2F4, MYC, NFAT5, NFKB, NOTCH1, RBPJ, REL, SP1, SPI1, STAT3

miRNA regulators (miRDB)

219 targeting REL, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-LET-7B-3P	100.00	74.08	3913
HSA-MIR-5692A	100.00	74.40	6850
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996

Literature-anchored findings (GeneRIF, showing 40)

• REL rather than BCL11A may be the target of the 2p13 alterations in classical Hodgkin Lymphoma. (PMID:11830502)
• REL has an important pathologic role in Hodgkin’s lymphoma (PMID:12478664)
• The correlation of structural aberrations of the REL locus & nuclear c-Rel accumulation in Reed-Sternberg cells qualifies REL as a target gene of the frequent gains in 2p in cHL. REL aberrations contribute to constitutive NF-kappa B/Rel activation in cHL. (PMID:12511414)
• calmodulin binds c-Rel and RelA after their release from I kappa B and can inhibit nuclear import of c-Rel while letting RelA translocate to the nucleus and act on its target genes (PMID:12556500)
• v-REL has a role in NF-kappaB-regulated cell death (PMID:12588973)
• Deletion of either C-terminal transactivation subdomains enhances the in viitro transforming activity of REL in chicken spleen cells. (PMID:14534540)
• REL amplification may not be causative in diffuse large B-cell lymphoma (PMID:14615382)
• Rel/NF-kappaB factors could take part in the occurrence of senescence by generating an oxidative stress. (PMID:14744759)
• Alterations between v-Rel and c-Rel locate within the Rel homology region (RHR) of the family that might confer functional differences. (PMID:14961076)
• significantly higher positivity of c-REL protein expression in Reed-Sternberg cells in classic Hodgkin lymphoma was seen compared with positivity of lymphocytic and histiocytic (L&H) cells in nodular lymphocyte predominant Hodgkin lymphoma (PMID:15551733)
• Data show that specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal differentiation. (PMID:15578091)
• Impaired nuclear translocation of c-Rel may determine an impaired Th1 cytokine response in atopic dermatitis. (PMID:15660915)
• DLBCL subtypes had a robust NFKB target gene signature that partially overlapped that of MLBCL. In this series of MLBCLs and DLBCLs, NFKB activation was not associated with amplification of the cREL locus, suggesting alternative pathogenetic mechanisms. (PMID:15870177)
• low levels of c-Rel are the underlying cause of aberrant CD23 expression in non-X-linked hyper-IgM syndrome B cells (PMID:16896156)
• c-Rel, like AR, is a part of the nucleoprotein complex regulating the androgen-responsive prostate-specific antigen (PSA) promoter (PMID:17011549)
• The frequent genomic overrepresentation of REL in primary mediastinal B-cell lymphoma does not necessarily trigger an increased transcription/translation of REL. (PMID:17243160)
• c-Rel((1-300)) binding to C/EBPbeta increases the affinity of C/EBPbeta for the C/EBP binding site at -53 on the CRP promoter (PMID:17335903)
• VEGF is expressed not only by reactive cells, but also by neoplastic cells, and NF-kappaB activation is uncommon in angioimmunoblastic lymphoma, as suggested by frequent exclusively cytoplasmic c-REL localization (PMID:18006812)
• activation of PKCtheta inhibits the FOXO3a/ERalpha/p27(Kip1) axis that normally maintains an epithelial cell phenotype and induces c-Rel target genes, thereby promoting proliferation, survival, and more invasive breast cancer. (PMID:18037997)
• Coexpression of c-Rel and CK2 or DMBA induce Slug and maammary cancer invasiveness. (PMID:18089804)
• High levels of DeltaNp63alpha interact with activated c-Rel in keratinocytes and squamous cell cancer, thereby promoting uncontrolled proliferation, a key alteration in the pathogenesis of cancers. (PMID:18593911)
• RELDelta9 splice variant is preferentially expressed in lymphoma, suggesting that the REL transcript lacking exon 9 could serve as a marker for certain types of lymphoid tumors. (PMID:18695674)
• results do not support a role for IKK-mediated phosphorylation as means for regulating the activity of REL in vivo (PMID:19110719)
• Both TNFAIP3 (A20, at the protein level) and REL are key mediators in the nuclear factor kappa B (NF-kappaB) inflammatory signalling pathway. (PMID:19240061)
• A genome-wide association study of rheumatoid arthritis in 2,418 cases and 4,504 controls from North America identified an association at the REL locus, encoding c-Rel, on chromosome 2p13. (PMID:19503088)
• a genetic increase in the activity of the NF-kappaB subunit c-Rel results in protection against cell death in human islets–nuclear factor-kappaB subunit c-Rel. (PMID:19706790)
• The REL locus is associated with rheumatoid arthritis susceptibility in the UK population (PMID:19945995)
• The kinetics of NFkappaB subunit activation are partly responsible for the observed pattern of acute inflammation in the adenoviral-infected cornea. (PMID:20038977)
• c-Rel, but not nuclear factor-kappa B1 (NFKB1), is required for development of transgenic regulatory T cell progenitors. (PMID:20228198)
• CXCR2 signaling is critical in transgenic mice with C-rel-deficient/NFkappaB1-deficient/heterozygous Rela+/- neutrophilia causing spontaneous inflammation. (PMID:20519647)
• characterize the prevalence of REL, BCL11A, and MYCN gains in a consecutive CLL series at the time of diagnosis; (ii) define the prognostic relevance of REL, BCL11A, and MYCN gains in CLL. (PMID:20575024)
• the described effect of REL rs13031237 on the predisposition for rheumatoid arthritis was re-evaluated in a large case-control data set of 23 711 individuals and showed a modest increase in rheumatoid arthritis risk. (PMID:20876593)
• Three new susceptibility loci at 2p16.1 (rs1432295, REL, 8q24.21 (rs2019960, PVT1 and 10p14 (rs501764, GATA3). (PMID:21037568)
• Thus, dectin-1 and dectin-2 control adaptive T(H)-17 immunity to fungi via Malt1-dependent activation of c-Rel. (PMID:21283787)
• IL-23 induction by beta-glucans is due to activation of c-Rel associated with Ser-10-histone H3 phosphorylation in the il23a promoter mediated by MAPK and SAPK or PKA, and inhibition of il12a transcription (PMID:21402701)
• Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL, and CARD9. (PMID:21425313)
• Data show that Foxp3 directly or as part of a multimeric complex engages with the NF-kappaB component c-Rel. (PMID:21490927)
• TAK1-c-Rel and IRF4 pathways play distinct roles in the maintenance of IL-9-producing Th17 phenotype of HTLV-1-transformed cells (PMID:21498517)
• IRF-4 was shown to enhance the c-Rel-dependent binding and activation of the interleukin-4 (IL-4) promoter region. IL-2 production was also enhanced by exogenously-expressed IRF-4 and c-Rel. (PMID:21890374)
• By a novel, reversible dynamic mechanism TNF-alpha-induced c-REL/DeltaNp63alpha interactions inactivate tumor suppressor TAp73 function, promoting TNF-alpha resistance & cell survival in cancers with mtTP53. (PMID:21933882)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rel	ENSDARG00000055276
mus_musculus	Rel	ENSMUSG00000020275
rattus_norvegicus	Rel	ENSRNOG00000054437
drosophila_melanogaster	Dif	FBGN0011274
drosophila_melanogaster	dl	FBGN0260632

Paralogs (4): NFKB2 (ENSG00000077150), RELB (ENSG00000104856), NFKB1 (ENSG00000109320), RELA (ENSG00000173039)

Protein

Protein identifiers

Proto-oncogene c-Rel — Q04864 (reviewed: Q04864)

All UniProt accessions (4): A0A8V8TMU9, A0A8V8TMW2, A0A8V8TPL7, Q04864

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. Component of the NF-kappa-B p65-c-Rel complex. Component of the NF-kappa-B p50-c-Rel complex. Component of the NF-kappa-B p52-c-Rel complex. Homodimer; component of the NF-kappa-B c-Rel-c-Rel complex. Interacts with NKIRAS1. Interacts with NFKBIB. Interacts with NFKBIE.

Subcellular location. Nucleus.

Disease relevance. Immunodeficiency 92 (IMD92) [MIM:619652] An autosomal recessive disorder characterized by recurrent bacterial, viral, fungal, or parasitic infections appearing in infancy or early childhood. Patient lymphocytes show defects in both T- and B-cell proliferation, cytokine secretion, and overall function, and there is also evidence of dysfunction of NK, certain antigen-presenting cells, and myeloid subsets. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q04864-1	1	yes
Q04864-2	2

RefSeq proteins (2): NP_001278675, NP_002899 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000451	NFkB/Dor	Family
IPR002909	IPT_dom	Domain
IPR008967	p53-like_TF_DNA-bd_sf	Homologous_superfamily
IPR011539	RHD_DNA_bind_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR014756	Ig_E-set	Homologous_superfamily
IPR030492	RHD_CS	Conserved_site
IPR032397	RHD_dimer	Domain
IPR033926	IPT_NFkappaB	Domain
IPR037059	RHD_DNA_bind_dom_sf	Homologous_superfamily
IPR042845	RHD-n_c-Rel	Domain

Pfam: PF00554, PF16179

UniProt features (12 total): modified residue 3, region of interest 2, compositionally biased region 2, initiator methionine 1, chain 1, splice variant 1, domain 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q04864-F1	66.46	0.42

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 503, 2, 267

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1169091	Activation of NF-kappaB in B cells

MSigDB gene sets: 406 (showing top): CREL_01, IIZUKA_LIVER_CANCER_EARLY_RECURRENCE, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, HOFMANN_CELL_LYMPHOMA_UP, MODULE_45, GOZGIT_ESR1_TARGETS_DN, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_NEGATIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, BROWNE_HCMV_INFECTION_16HR_UP, RACCACAR_AML_Q6, BROWNE_HCMV_INFECTION_12HR_UP, NAGASHIMA_NRG1_SIGNALING_UP, NFKB_Q6

GO Biological Process (11): inflammatory response (GO:0006954), canonical NF-kappaB signal transduction (GO:0007249), negative regulation of gene expression (GO:0010629), negative regulation of interferon-beta production (GO:0032688), response to cytokine (GO:0034097), non-canonical NF-kappaB signal transduction (GO:0038061), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), innate immune response (GO:0045087), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of cytokine production (GO:0001818), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (7): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), NF-kappaB complex (GO:0071159)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Downstream signaling events of B Cell Receptor (BCR)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
intracellular signaling cassette	2
regulation of gene expression	2
regulation of transcription by RNA polymerase II	2
defense response	1
gene expression	1
negative regulation of macromolecule biosynthetic process	1
negative regulation of type I interferon production	1
interferon-beta production	1
regulation of interferon-beta production	1
response to peptide	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
immune response	1
defense response to symbiont	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
cytokine production	1
regulation of cytokine production	1
negative regulation of gene expression	1
negative regulation of multicellular organismal process	1
DNA-templated transcription	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
transcription cis-regulatory region binding	1
regulation of DNA-templated transcription	1
transcription regulator activity	1
nucleic acid binding	1
binding	1
DNA binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

4804 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
REL	NFKBIA	P25963	999
REL	NFKBIB	Q15653	995
REL	NFKBIE	O00221	992
REL	CD40	P25942	992
REL	NFKB1	P19838	987
REL	NFKB2	Q00653	987
REL	RELB	Q01201	985
REL	RELA	Q04206	984
REL	BCL3	P20749	936
REL	CHUK	O15111	933
REL	IKBKB	O14920	909
REL	TNF	P01375	884
REL	CREB1	P16220	852
REL	ANK2	Q01484	844
REL	ANK1	P16157	840

IntAct

656 interactions, top by confidence:

A	B	Type	Score
REL	GADD45G	psi-mi:“MI:0915”(physical association)	0.670
REL	CDKN2C	psi-mi:“MI:0915”(physical association)	0.670
PLEKHN1	REL	psi-mi:“MI:0915”(physical association)	0.670
REL	EFHC1	psi-mi:“MI:0915”(physical association)	0.670
REL	LGALS14	psi-mi:“MI:0915”(physical association)	0.670
PIH1D2	REL	psi-mi:“MI:0915”(physical association)	0.670
REL	VPS25	psi-mi:“MI:0915”(physical association)	0.670
REL	EGLN3	psi-mi:“MI:0915”(physical association)	0.670
CGGBP1	REL	psi-mi:“MI:0915”(physical association)	0.670
REL	EXOSC1	psi-mi:“MI:0915”(physical association)	0.670
REL	DYNC1LI1	psi-mi:“MI:0915”(physical association)	0.670
CDKN2C	REL	psi-mi:“MI:0915”(physical association)	0.670
REL	NECAP1	psi-mi:“MI:0915”(physical association)	0.560
	REL	psi-mi:“MI:0915”(physical association)	0.560
CENPX	REL	psi-mi:“MI:0915”(physical association)	0.560
REL	CCNJL	psi-mi:“MI:0915”(physical association)	0.560
REL	HIP1	psi-mi:“MI:0915”(physical association)	0.560
REL	SDCBP	psi-mi:“MI:0915”(physical association)	0.560
REL	ACOT8	psi-mi:“MI:0915”(physical association)	0.560
HAT1	REL	psi-mi:“MI:0915”(physical association)	0.560
REL	EPHB6	psi-mi:“MI:0915”(physical association)	0.560
EIF3D	REL	psi-mi:“MI:0915”(physical association)	0.560
REL	NCK2	psi-mi:“MI:0915”(physical association)	0.560
REL	EIF4E2	psi-mi:“MI:0915”(physical association)	0.560
STK16	REL	psi-mi:“MI:0915”(physical association)	0.560
REL	SEC31A	psi-mi:“MI:0915”(physical association)	0.560
REL	ARIH2	psi-mi:“MI:0915”(physical association)	0.560
POLR1A	REL	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (538): REL (Two-hybrid), REL (Two-hybrid), REL (Two-hybrid), REL (Two-hybrid), REL (Two-hybrid), REL (Two-hybrid), REL (Two-hybrid), REL (Two-hybrid), REL (Two-hybrid), REL (Two-hybrid), REL (Two-hybrid), REL (Two-hybrid), REL (Two-hybrid), REL (Two-hybrid), REL (Two-hybrid)

ESM2 similar proteins: A0A1D5NVS8, A0A1L8H0H2, A0AVK6, A0JME2, A2A891, D2HNW6, D3ZGB1, D4A4D7, D4A666, E1B7L7, E1BE02, E1BKK0, F1LMN3, F1QZ88, F6YVB9, F7EA39, F8VPJ6, O70546, O94916, P0C090, P15307, P79944, Q04864, Q14B70, Q2KHR2, Q53TQ3, Q58FA4, Q5RIX9, Q5RJA1, Q5ZKW8, Q5ZQU2, Q66JJ0, Q66JY2, Q69ZF8, Q6E2N3, Q6EUW1, Q6S7F2, Q7Z353, Q8C7R7, Q8CHP6

Diamond homologs: O00592, O57604, Q04864, Q28645, Q52S86, Q8CAE9, Q9NZ53, Q9R0M4, Q9WTQ2, O73630, P01125, P01126, P15307, P15330, P16236, P19838, P20749, P25799, P51509, P51510, P98149, P98150, P98152, Q00653, Q01201, Q03017, Q04206, Q04207, Q04861, Q04863, Q04865, Q08353, Q5ZXN6, Q63369, Q6F3J0, Q7TQN4, Q91974, Q94527, Q9WTK5, A2ARS0

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
IKBKE	up-regulates	REL	phosphorylation
TBK1	up-regulates	REL	phosphorylation
REL	“up-regulates quantity by expression”	CSRP1	“transcriptional regulation”
IKBKB	“up-regulates activity”	REL	phosphorylation
REL	“form complex”	REL/RELA	binding
TNF	up-regulates	REL

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

264 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	1
Uncertain significance	87
Likely benign	142
Benign	12

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1327625	NM_001291746.2(REL):c.535+1G>A	Pathogenic
1327626	NM_001291746.2(REL):c.395-1G>A	Pathogenic
2709063	NM_001291746.2(REL):c.910_911del (p.Cys304fs)	Pathogenic
2744659	NM_001291746.2(REL):c.923-140C>G	Pathogenic
2781196	NM_001291746.2(REL):c.923-184_923-183del	Pathogenic
4736334	NM_001291746.2(REL):c.88C>T (p.Arg30Ter)	Pathogenic
2824163	NM_001291746.2(REL):c.922+1G>A	Likely pathogenic

SpliceAI

1548 predictions. Top by Δscore:

Variant	Effect	Δscore
2:60881848:CCGGT:C	donor_loss	1.0000
2:60881851:G:GG	donor_gain	1.0000
2:60881851:GTG:G	donor_loss	1.0000
2:60881852:T:A	donor_loss	1.0000
2:60891682:GGT:G	acceptor_gain	1.0000
2:60891682:GGTGC:G	acceptor_gain	1.0000
2:60891821:TCCAG:T	donor_loss	1.0000
2:60891822:CCAG:C	donor_loss	1.0000
2:60891823:CAGG:C	donor_loss	1.0000
2:60891824:AG:A	donor_loss	1.0000
2:60891825:GG:G	donor_loss	1.0000
2:60891826:GT:G	donor_loss	1.0000
2:60891827:T:G	donor_loss	1.0000
2:60894392:TTCA:T	acceptor_loss	1.0000
2:60894393:TCA:T	acceptor_loss	1.0000
2:60894395:A:AG	acceptor_gain	1.0000
2:60894395:A:T	acceptor_loss	1.0000
2:60894396:G:GA	acceptor_gain	1.0000
2:60894396:GA:G	acceptor_gain	1.0000
2:60894396:GAT:G	acceptor_gain	1.0000
2:60894396:GATT:G	acceptor_gain	1.0000
2:60894541:TTGTT:T	donor_gain	1.0000
2:60894542:TGTT:T	donor_gain	1.0000
2:60894543:GTT:G	donor_gain	1.0000
2:60894543:GTTG:G	donor_gain	1.0000
2:60894544:TT:T	donor_gain	1.0000
2:60894544:TTGT:T	donor_gain	1.0000
2:60894545:TG:T	donor_loss	1.0000
2:60894546:G:GG	donor_gain	1.0000
2:60894546:GTA:G	donor_loss	1.0000

AlphaMissense

3887 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:60891719:C:A	P16H	1.000
2:60891736:C:A	R22S	1.000
2:60891736:C:G	R22G	1.000
2:60891736:C:T	R22C	1.000
2:60891739:T:A	F23I	1.000
2:60891739:T:C	F23L	1.000
2:60891739:T:G	F23V	1.000
2:60891740:T:C	F23S	1.000
2:60891740:T:G	F23C	1.000
2:60891741:T:A	F23L	1.000
2:60891741:T:G	F23L	1.000
2:60891742:A:G	R24G	1.000
2:60891743:G:C	R24T	1.000
2:60891743:G:T	R24I	1.000
2:60891744:A:C	R24S	1.000
2:60891744:A:T	R24S	1.000
2:60891745:T:C	Y25H	1.000
2:60891745:T:G	Y25D	1.000
2:60891746:A:G	Y25C	1.000
2:60891751:T:C	C27R	1.000
2:60891754:G:A	E28K	1.000
2:60891755:A:T	E28V	1.000
2:60891756:A:C	E28D	1.000
2:60891756:A:T	E28D	1.000
2:60891757:G:A	G29R	1.000
2:60891757:G:C	G29R	1.000
2:60891757:G:T	G29W	1.000
2:60891758:G:A	G29E	1.000
2:60891769:G:C	G33R	1.000
2:60891769:G:T	G33C	1.000

dbSNP variants (sampled 300 via entrez): RS1000056584 (2:60908877 G>A,C), RS1000079605 (2:60914977 G>A), RS1000119842 (2:60908611 A>G), RS1000168436 (2:60924943 A>C,G), RS1000227308 (2:60930466 A>G), RS1000343602 (2:60919805 C>A), RS1000402097 (2:60900459 CTG>C), RS1000422076 (2:60896890 T>C), RS1000451558 (2:60896179 T>G), RS1000524300 (2:60895904 G>C), RS1000577391 (2:60926603 A>T), RS1000657284 (2:60879956 T>C), RS1000675164 (2:60919792 C>T), RS1000694942 (2:60903233 A>G), RS1000734116 (2:60890417 G>A,T)

Disease associations

OMIM: gene MIM:164910 | disease phenotypes: MIM:619652

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 92	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
immunodeficiency 92	Moderate	AR

Mondo (1): immunodeficiency 92 (MONDO:0030498)

Orphanet (1): Combined immunodeficiency due to c-REL deficiency (Orphanet:697394)

HPO phenotypes

22 total (22 of 22 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001894	Thrombocytosis
HP:0001954	Recurrent fever
HP:0001974	Increased total leukocyte count
HP:0002028	Chronic diarrhea
HP:0002090	Pneumonia
HP:0002240	Hepatomegaly
HP:0002720	Decreased circulating IgA concentration
HP:0002754	Osteomyelitis
HP:0004315	Decreased circulating IgG concentration
HP:0010976	Decreased total B cell count
HP:0011463	Childhood onset
HP:0020087	BCGosis
HP:0030151	Cholangitis
HP:0030388	Decreased class-switched memory B cell proportion
HP:0030991	Sclerosing cholangitis
HP:0031380	Abnormal B cell proliferation
HP:0032247	Persistent CMV viremia
HP:0100633	Esophagitis
HP:0100827	Increased total lymphocyte count
HP:0410028	Recurrent oral herpes
HP:0410297	Partial absence of specific antibody response to tetanus vaccine

GWAS associations

28 associations (top):

Study	Trait	p-value
GCST000420_2	Rheumatoid arthritis	2.000000e-12
GCST000612_18	Celiac disease	4.000000e-13
GCST000624_10	Ulcerative colitis	7.000000e-09
GCST000833_2	Psoriasis	4.000000e-09
GCST000851_2	Hodgkin’s lymphoma	2.000000e-08
GCST000879_48	Crohn’s disease	7.000000e-09
GCST001355_1	Psoriatic arthritis	1.000000e-08
GCST001355_2	Psoriatic arthritis	2.000000e-07
GCST001438_15	Crohn’s disease	5.000000e-09
GCST001725_44	Inflammatory bowel disease	9.000000e-32
GCST002318_101	Rheumatoid arthritis	4.000000e-16
GCST002318_102	Rheumatoid arthritis	2.000000e-15
GCST002480_2	Hodgkin’s lymphoma	3.000000e-06
GCST002738_9	Psoriasis	3.000000e-11
GCST002874_46	Psoriasis	1.000000e-08
GCST002874_68	Psoriasis	2.000000e-10
GCST003268_32	Psoriasis vulgaris	4.000000e-12
GCST003270_5	Psoriatic arthritis	6.000000e-07
GCST005527_4	Psoriasis	2.000000e-17
GCST005568_16	Rheumatoid arthritis (ACPA-positive)	3.000000e-08
GCST005568_27	Rheumatoid arthritis (ACPA-positive)	1.000000e-11
GCST005569_2	Rheumatoid arthritis	1.000000e-09
GCST005569_39	Rheumatoid arthritis	4.000000e-06
GCST006048_43	Rheumatoid arthritis (ACPA-positive)	4.000000e-13
GCST006956_8	Erectile dysfunction	8.000000e-06
GCST006959_147	Rheumatoid arthritis	2.000000e-13
GCST006959_52	Rheumatoid arthritis	5.000000e-14
GCST008644_7	Celiac disease and Rheumatoid arthritis	4.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:1001494	psoriasis vulgaris

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296310 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs13031237	REL		0.00	0
rs3732179	REL		0.00	0
rs842647	REL		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — NF-kappa B TF proteins

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.88	Kd	1334	nM	CHEMBL5653589
5.88	ED50	1334	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149215: Binding affinity to human REL incubated for 45 mins by Kinobead based pull down assay	kd	1.3341	uM

CTD chemical–gene interactions

76 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	affects cotreatment, increases expression, affects localization, affects response to substance, affects binding (+2 more)	5
Doxorubicin	affects localization, decreases expression, affects response to substance	4
Tetradecanoylphorbol Acetate	affects cotreatment, decreases reaction, increases expression, affects localization	3
Arsenic Trioxide	decreases expression	2
Curcumin	decreases reaction, increases expression, increases reaction	2
Oxygen	decreases expression, decreases reaction, increases expression, affects cotreatment	2
Tetrachlorodibenzodioxin	affects expression, increases expression	2
Tretinoin	increases expression	2
Valproic Acid	decreases expression, increases expression	2
4-((alpha-L-rhamnosyloxy)benzyl)isothiocyanate	decreases reaction, increases expression, increases reaction	1
Glupearl 19S	increases expression	1
2-anisidine	affects expression	1
oxybenzone	increases expression	1
triphenyl phosphate	affects expression	1
fucoidan	decreases activity	1
piperine	decreases localization	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
sulforaphane	decreases expression, increases reaction	1
scoparone	affects localization, decreases reaction	1
pyrrolidine dithiocarbamic acid	increases expression, affects cotreatment, decreases reaction	1
4-hydroxy-2-nonenal	decreases expression	1
bathocuproine sulfonate	decreases reaction, increases expression, affects cotreatment	1
nickel sulfate	decreases expression, increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
phenethyl isothiocyanate	decreases reaction, increases expression	1
di-n-butylphosphoric acid	affects expression	1
prolinedithiocarbamate	affects localization, decreases reaction	1
bisindolylmaleimide I	affects binding, decreases reaction, increases reaction	1
perfluorooctane sulfonic acid	decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652257	Binding	Binding affinity to human REL incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8NQ	Abcam HCT 116 REL KO	Cancer cell line	Male
CVCL_B9B2	Abcam MCF-7 REL KO	Cancer cell line	Female
CVCL_B9R2	Abcam A-549 REL KO	Cancer cell line	Male
CVCL_TI74	HAP1 REL (-)	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.