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 (top 5% of genes corpus-wide)
• Clinical variants (ClinVar): 272 total — 6 pathogenic, 1 likely-pathogenic
• Regional missense constraint (gnomAD): 1 of 4 regions constrained (≈2% of expected missense variation)
• GTEx eGene: eQTL in 11 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 99
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.42 (moderately constrained)
• Transcription factor: yes — 126 downstream targets (CollecTRI)
• MANE Select transcript: NM_001291746
• Interaction hub: 3,436 STRING partners (top 2% of genes corpus-wide)

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: 15 — 11 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

MANE Select: ENST00000394479

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2

ENST00000394479, ENST00000295025, ENST00000642725, ENST00000699191, ENST00000699192, ENST00000699193, ENST00000699194, ENST00000699195, ENST00000878076, ENST00000878077, ENST00000878078, ENST00000949522, ENST00000949523, ENST00001122763, ENST00001138285

RefSeq mRNA: 3 — MANE Select: NM_001291746 NM_001291746, NM_001438025, 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.

Highest expression (Bgee): buccal mucosa cell, bone marrow, secondary oocyte, oocyte, bone marrow cell.

Genetic regulation across tissues (GTEx eQTL / sQTL)

REL is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 11 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

12 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	eqtl	3.0e-06	+0.16	2:60841687:C:CA
Cells EBV-transformed lymphocytes	eqtl	1.3e-03	+0.17	2:60998428:A:C
Vagina	sqtl	2.1e-03	-3.01	2:61119377:C:T
Spleen	eqtl	3.0e-03	+0.23	2:60780851:T:C
Brain Cerebellar Hemisphere	eqtl	9.0e-03	+0.27	2:60711897:A:G
Nerve Tibial	eqtl	1.2e-02	+0.46	2:60057689:A:G
Cells Cultured fibroblasts	eqtl	2.2e-02	+0.13	2:61691933:G:A
Adipose Subcutaneous	eqtl	3.2e-02	+0.13	2:60908878:G:A
Adipose Visceral Omentum	eqtl	3.8e-02	+0.20	2:60711897:A:G
Artery Coronary	eqtl	3.8e-02	+0.37	2:60038224:T:C
Whole Blood	eqtl	4.2e-02	-0.07	2:61084119:G:A
Brain Cerebellum	eqtl	4.8e-02	+0.17	2:60712744:C:T

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

showing 100 of 281 tissues 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
mammalian vulva	UBERON:0000997	76.84	gold quality
superior surface of tongue	UBERON:0007371	76.62	gold quality
adrenal tissue	UBERON:0018303	76.51	gold quality
mucosa of sigmoid colon	UBERON:0004993	76.34	gold quality
epithelium of mammary gland	UBERON:0003244	76.11	gold quality
endometrium epithelium	UBERON:0004811	75.74	silver quality
nasal cavity mucosa	UBERON:0001826	75.48	gold quality
lung	UBERON:0002048	75.45	gold quality
skin of abdomen	UBERON:0001416	75.03	gold quality
visceral pleura	UBERON:0002401	75.03	gold quality
cauda epididymis	UBERON:0004360	74.88	gold quality
palpebral conjunctiva	UBERON:0001812	74.86	gold quality
zone of skin	UBERON:0000014	74.83	gold quality
colonic mucosa	UBERON:0000317	74.78	gold quality
bronchial epithelial cell	CL:0002328	74.77	gold quality
calcaneal tendon	UBERON:0003701	74.52	gold quality
trabecular bone tissue	UBERON:0002483	74.34	gold quality
rectum	UBERON:0001052	74.29	gold quality
islet of Langerhans	UBERON:0000006	74.10	gold quality
urethra	UBERON:0000057	74.07	gold quality
skin of leg	UBERON:0001511	73.86	gold quality
epithelium of nasopharynx	UBERON:0001951	73.83	gold quality
esophagus squamous epithelium	UBERON:0006920	73.69	gold quality
duodenum	UBERON:0002114	73.32	gold quality
upper lobe of lung	UBERON:0008948	73.22	gold quality
pleura	UBERON:0000977	73.19	gold quality
nasal cavity epithelium	UBERON:0005384	73.15	gold quality
omental fat pad	UBERON:0010414	73.07	gold quality
parietal pleura	UBERON:0002400	73.06	gold quality
peritoneum	UBERON:0002358	73.05	gold quality
seminal vesicle	UBERON:0000998	72.96	gold quality
upper lobe of left lung	UBERON:0008952	72.89	gold quality
pharyngeal mucosa	UBERON:0000355	72.83	gold quality
adipose tissue of abdominal region	UBERON:0007808	72.71	gold quality
stromal cell of endometrium	CL:0002255	72.47	gold quality
jejunum	UBERON:0002115	72.42	gold quality
right ovary	UBERON:0002118	71.88	gold quality
right lung	UBERON:0002167	71.78	gold quality
epithelium of esophagus	UBERON:0001976	71.71	gold quality
left ovary	UBERON:0002119	71.64	gold quality
vagina	UBERON:0000996	71.63	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	71.45	gold quality
esophagus mucosa	UBERON:0002469	71.16	gold quality
ovary	UBERON:0000992	71.10	gold quality
bronchus	UBERON:0002185	71.07	gold quality
uterine cervix	UBERON:0000002	71.02	gold quality
epithelium of bronchus	UBERON:0002031	70.98	gold quality
pancreas	UBERON:0001264	70.95	gold quality
endothelial cell	CL:0000115	70.91	gold quality
granulocyte	CL:0000094	70.56	gold quality
mammary gland	UBERON:0001911	70.51	gold quality
thoracic mammary gland	UBERON:0005200	70.45	gold quality
parotid gland	UBERON:0001831	70.32	gold quality
subcutaneous adipose tissue	UBERON:0002190	70.20	gold quality
connective tissue	UBERON:0002384	69.85	gold quality
spleen	UBERON:0002106	69.84	gold quality
adipose tissue	UBERON:0001013	69.79	gold quality
smooth muscle tissue	UBERON:0001135	69.79	gold quality
liver	UBERON:0002107	69.67	gold quality
caput epididymis	UBERON:0004358	69.55	gold quality
left uterine tube	UBERON:0001303	69.53	gold quality
trachea	UBERON:0003126	69.52	gold quality
oviduct epithelium	UBERON:0004804	69.44	gold quality
female reproductive system	UBERON:0000474	69.43	gold quality
small intestine	UBERON:0002108	69.34	gold quality
fallopian tube	UBERON:0003889	69.29	gold quality
corpus epididymis	UBERON:0004359	69.13	gold quality
decidua	UBERON:0002450	68.88	gold quality
lower esophagus mucosa	UBERON:0035834	68.88	gold quality
endometrium	UBERON:0001295	68.85	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

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	35.3	low
Postcentral gyrus	tissue	23.0
Nucleus accumbens	tissue	21.1
Choroid plexus	tissue	20.5
Hippocampus	tissue	20.5	medium
Locus coeruleus	tissue	18.6
Tonsil	tissue	15.3	high
Olfactory bulb	tissue	15.2
Lymph node	tissue	14.7	high
Appendix	tissue	13.4	medium
Urinary bladder	tissue	12.5	medium
Amygdala	tissue	12.5
Cerebellum	tissue	12.2	medium
Cerebral cortex	tissue	12.0	medium
Insular cortex	tissue	12.0
Basal ganglia	tissue	11.3	medium
Corpus callosum	tissue	11.3
Retrosplenial and cingulate cortex	tissue	11.2
Periaqueductal gray	tissue	11.0
Retrosplenial cortex	tissue	11.0
Hippocampal formation	tissue	10.9
Temporal cortex	tissue	10.9
Septum	tissue	10.7
Entorhinal cortex	tissue	10.6
Ventral forebrain	tissue	10.4
Prefrontal cortex	tissue	10.3
Spleen	tissue	10.3	low
Occipital cortex	tissue	10.3
Putamen	tissue	10.0
Spinal cord	tissue	9.8
Motor cortex	tissue	9.7
Hypothalamus	tissue	9.7
Substantia nigra	tissue	9.4
Somatosensory cortex	tissue	9.3
Midbrain	tissue	8.9
Medulla oblongata	tissue	8.7
Thymus	tissue	8.7
Thalamus	tissue	8.2
Retina	tissue	7.9
Superior colliculi	tissue	7.9
Pons	tissue	7.7
Gallbladder	tissue	7.7	medium
Skin 1	tissue	7.5	high
Liver	tissue	6.7	not detected
Lung	tissue	6.3	medium
Parathyroid gland	tissue	5.8	not detected
Esophagus	tissue	5.5	medium
Stomach 1	tissue	5.4	medium
Endometrium 1	tissue	5.2	medium
Breast	tissue	5.1	medium
Placenta	tissue	5.1	medium
Pancreas	tissue	4.8	medium
Small intestine	tissue	4.8	medium
Rectum	tissue	4.5	medium
Duodenum	tissue	4.5	medium
Adipose tissue	tissue	4.4	not detected
Cervix	tissue	4.3	medium
Salivary gland	tissue	4.2	medium
Colon	tissue	4.2	medium
Adrenal gland	tissue	4.1	not detected

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Flocculonodular lobe (35.2), Vermis (33.3), Cerebellar cortex (31.2), Nucleus raphe obscurus (25.6), Parietal operculum (25.4).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

showing 30 of 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)

Targeting REL by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 219 miRNAs:

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

Functional genomics

gnomAD constraint: pLI 0.999, LOEUF 0.416, missense Z 1.76 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000394479 splits into 4 regions with different missense tolerance; 1 is missense-constrained (≈2% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
2:60,881,841–60,891,710	24 / 18.2	1.32	no
2:60,891,711–60,891,746	2 / 16.9	0.12	yes (p 2.9e-04)
2:60,891,747–60,920,586	241 / 347.0	0.69	no
2:60,920,587–60,922,532	334 / 333.1	1.00	no

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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:97897) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 67 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal cytokine secretion	4
decreased IgM level	3
abnormal macrophage physiology	3
decreased T cell proliferation	3
decreased IgG level	2
decreased IgE level	2
decreased B-1 B cell number	2
decreased B cell proliferation	2
abnormal CD4-positive, alpha-beta T cell physiology	2
decreased CD4-positive, alpha-beta T cell number	2
decreased IgG1 level	2
decreased IgG2b level	2
decreased IgG3 level	2
decreased monocyte cell number	1
extramedullary hematopoiesis	1
decreased bone marrow cell number	1
abnormal stomach morphology	1
abnormal liver morphology	1
abnormal spleen morphology	1
enlarged spleen	1
enlarged lymph nodes	1
tremors	1
abnormal lung morphology	1
dermatitis	1
absent vibrissae	1

+42 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Meleagris gallopavo	P01125	96.0%	Diamond
Gallus gallus	P16236	93.3%	Diamond
Canis lupus familiaris	Q6F3J0	90.1%	Diamond
Xenopus laevis	Q04865	66.7%	Diamond
Reticuloendotheliosis virus	P01126	96.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
REL-DT	ncRNA	400957
PAPOLG	protein-coding	64895
PUS10	protein-coding	150962
PEX13	protein-coding	5194

Protein

Protein identifiers

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

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

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 (3): NP_001278675, NP_001424954, 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

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Predicted intracellular proteins, Transcription factors, Immunoglobulin fold, RAS pathway related proteins, Cancer-related genes, Candidate cancer biomarkers, Disease related genes, Human disease related genes

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH uncertain

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)

Type	Positions
Phosphoserine	503, 267
N-acetylalanine	2

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 5; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

5 pathways:

ID	Pathway	Evidence
R-HSA-1169091	Activation of NF-kappaB in B cells	curated
R-HSA-1280218	Adaptive Immune System	—
R-HSA-1168372	Downstream signaling events of B Cell Receptor (BCR)	—
R-HSA-168256	Immune System	—
R-HSA-983705	Signaling by the B Cell Receptor (BCR)	—

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 (12): DNA-templated transcription (GO:0006351), 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 (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

4 top-level categories:

Category	Pathways
Downstream signaling events of B Cell Receptor (BCR)	1
Signaling by the B Cell Receptor (BCR)	1
Immune System	1
Adaptive Immune System	1

GO top-level categories

43 GO namespaces:

Category	Terms
cellular anatomical structure	4
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
gene expression	2
intracellular signaling cassette	2
regulation of gene expression	2
regulation of transcription by RNA polymerase II	2
RNA biosynthetic process	1
defense response	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
intracellular anatomical structure	1
cytoplasm	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 7 of 24 annotations. The rest are phylogenetic / computational / electronic (IEA).

7 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of gene expression	BP	direct assay
negative regulation of interferon-beta production	BP	direct assay
positive regulation of canonical NF-kappaB signal transduction	BP	expression pattern
positive regulation of transcription by RNA polymerase II	BP	direct assay
nucleus	CC	mutant phenotype
DNA-binding transcription activator activity, RNA polymerase II-specific	MF	direct assay
RNA polymerase II cis-regulatory region sequence-specific DNA binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 3,436 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
REL	NFKBIA	P25963	916
REL	NFKBIB	Q15653	913
REL	RELB	Q01201	890
REL	RELA	Q04206	890
REL	CHUK	O15111	887
REL	NFKB1	P19838	856
REL	NFKBIE	O00221	845
REL	IKBKB	O14920	845
REL	NFKB2	Q00653	833
REL	TNF	P01375	820
REL	IKBKG	Q9Y6K9	807
REL	BCL3	P20749	784
REL	IL1B	P01584	759
REL	NFATC1	O95644	715
REL	IL1A	P01583	707

IntAct

Human interaction partners of REL in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 203 partners by confidence:

Partner	Interaction type	MIscore	Records
EFHC1	physical association	0.670	7
NFKBIE	association	0.670	5
CDKN2C	physical association	0.670	4
CGGBP1	physical association	0.670	4
DYNC1LI1	physical association	0.670	4
EXOSC1	physical association	0.670	4
GADD45G	physical association	0.670	4
LGALS14	physical association	0.670	4
PIH1D2	physical association	0.670	4
PLEKHN1	physical association	0.670	4
VPS25	physical association	0.670	4
EGLN3	physical association	0.670	3
RELA	physical association	0.660	7
NFE2L2	physical association	0.630	5
BID	physical association	0.560	6
A1CF	physical association	0.560	3
ACOT8	physical association	0.560	3
AGPAT4	physical association	0.560	3
AIRIM	physical association	0.560	3
ALOX5	physical association	0.560	3
ARIH2	physical association	0.560	3
ASAP3	physical association	0.560	3
ATG9A	physical association	0.560	3
ATPAF2	physical association	0.560	3
ATXN1	physical association	0.560	3
BARHL2	physical association	0.560	3
BMF	physical association	0.560	3
C11orf68	physical association	0.560	3
C9orf72	physical association	0.560	3
CABP5	physical association	0.560	3

BioGRID (538 interactions; top human partners by supporting records): RELA (Two-hybrid; 16 records), NFKB1 (Affinity Capture-MS; 11 records), NFKB2 (Affinity Capture-MS; 9 records), NFKBIA (Affinity Capture-MS; 9 records), NFKBIB (Affinity Capture-MS; 8 records), NFKBIE (Affinity Capture-MS; 8 records), EP300 (Affinity Capture-Western; 6 records), TNIP2 (Affinity Capture-MS; 5 records), RELB (Affinity Capture-MS; 4 records), AURKA (Affinity Capture-MS; 3 records), EFHC1 (Two-hybrid; 3 records), HIF1AN (Affinity Capture-MS; 3 records), NFE2L2 (Two-hybrid; 3 records), PPP4C (Two-hybrid; 3 records), TSR3 (Affinity Capture-MS; 3 records)

SIGNOR signaling

6 signaling 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

Protein complexes (CORUM) (11)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

11 complexes by size:

Complex	Subunits	Members
★ TNFalpha-NFkappa B signaling complex 5	25	IQGAP2, MTIF2, POLR1A, POLR1E, RASAL2, RELA, SKP1, CHUK, KPNA2, NFKB2, NFKBIB, POLR2H, REL, IKBKB, MCC, POLR1D, CUL1, FBXW11, LRPPRC, NFKB1, PDCD2, POLR1B, POLR1G, POLR2L, IKBKG
★ TNFalpha-NFkappa B signaling complex	17	MAP3K8, TNIP2, NFKB2, NFKBIA, REL, RELB, RPS13, GLG1, GTF2I, NFKB1, NFKBIB, RELA, RPL30, CHUK, DDX3X, IKBKG, RPL6
★ TNFalpha-NFkappa B signaling complex	12	NFKB1, NFKB2, NFKBIA, RELA, KPNA3, NFKBIB, NFKBIE, REL, RELB, TNIP2, CHUK, IKBKG
TNF-alpha/NF-kappa B signaling complex (CHUK, BTRC, NFKB2, PPP6C, REL, CUL1, IKBKE, SAPS2, SAPS1, ANKRD28, RELA, SKP1)	12	CUL1, PPP6R2, ANKRD28, IKBKE, NFKB2, PPP6C, PPP6R1, REL, RELA, SKP1, BTRC, CHUK
★ NFKB1 signalling complex	12	SPAG9, TNIP1, TNIP2, COPB2, IKBKG, NFKB2, NFKBIE, REL, RELA, CHUK, NFKB1, NFKBIA
TNF-alpha/NF-kappa B signaling complex (SEC16A, CHUK, IKBKB, NFKB2, REL, IKBKG, MAP3K14, RELA, FBXW7, USP2)	10	REL, SEC16A, IKBKB, MAP3K14, NFKB2, RELA, USP2, CHUK, FBXW7, IKBKG
★ NFKB1-NFKB2-REL-RELA-RELB complex	5	RELB, NFKB1, NFKB2, REL, RELA
REL-MAP3K8-RELA-TNIP2-PAPOLA complex	5	MAP3K8, PAPOLA, REL, RELA, TNIP2
IKB(epsilon)-RELA-cREL complex	3	NFKBIE, REL, RELA
IKB(beta)-RELA-cREL complex	3	NFKBIB, REL, RELA
IKB(alpha)-RELA-cREL complex	3	NFKBIA, REL, RELA

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 203 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
RIP-mediated NFkB activation via ZBP1	5	25.1×	4e-04
TRAF6 mediated NF-kB activation	5	17.0×	1e-03
RHO GTPases activate IQGAPs	5	12.9×	5e-03
TAK1-dependent IKK and NF-kappa-B activation	5	11.2×	6e-03
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	7	10.1×	1e-03
Activation of NF-kappaB in B cells	6	8.8×	5e-03
Translocation of SLC2A4 (GLUT4) to the plasma membrane	7	8.1×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein refolding	6	20.5×	5e-04

Disease & clinical

Genetic variants

Variant evidence for REL: 272 ClinVar records (7 pathogenic / likely pathogenic); 1 CIViC cancer variant; 28 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	1
Uncertain significance	87
Likely benign	147
Benign	7

Top pathogenic / likely-pathogenic (7)

Showing all 7 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
2709063	NM_001291746.2(REL):c.910_911del (p.Cys304fs)	Pathogenic	criteria provided, single submitter	1
2744659	NM_001291746.2(REL):c.923-140C>G	Pathogenic	criteria provided, single submitter	1
2781196	NM_001291746.2(REL):c.923-184_923-183del	Pathogenic	criteria provided, single submitter	1
4736334	NM_001291746.2(REL):c.88C>T (p.Arg30Ter)	Pathogenic	criteria provided, single submitter	1
2824163	NM_001291746.2(REL):c.922+1G>A	Likely pathogenic	criteria provided, single submitter	1
1327625	NM_001291746.2(REL):c.535+1G>A	Pathogenic	no assertion criteria provided	1
1327626	NM_001291746.2(REL):c.395-1G>A	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore REL’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 39 predictions of 762):

Position(s)	Effect	Δscore	Sites
2:60881851–60881852	donor_loss	1.0000	4
2:60891826–60891827	donor_loss	1.0000	5
2:60894395–60894396	acceptor_loss	1.0000	5
2:60894546–60894547	donor_loss	1.0000	4
2:60894581	donor_gain	1.0000
2:60901084–60901085	donor_loss	1.0000	5
2:60916872	acceptor_gain	1.0000
2:60916875–60916876	acceptor_loss	1.0000	5
2:60917018–60917019	donor_loss	1.0000	4
2:60918296–60918297	donor_loss	1.0000	5

AlphaMissense

1,339 missense substitutions predicted likely pathogenic (of 3,887 scored), across 267 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M21	9	0.961	0.999
M261	9	0.890	0.999
H77	8	0.999	1.000
D177	8	0.999	1.000
D235	8	0.998	1.000
H237	8	0.998	1.000
D215	8	0.997	1.000
F231	8	0.997	1.000
F23	8	0.996	1.000
H75	8	0.996	1.000
D209	8	0.995	1.000
D268	8	0.995	0.999
F220	8	0.994	1.000
F244	8	0.992	1.000
F277	8	0.992	1.000
F102	8	0.991	1.000
F205	8	0.983	1.000
N104	8	0.980	0.999
S34	8	0.974	1.000
F152	8	0.969	0.999

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Rectum Adenocarcinoma (validation)	favorable	6.61e-05
Kidney Chromophobe (TCGA)	unfavorable	0.000211
Ovary Serous Cystadenocarcinoma (validation)	unfavorable	0.000373

Disease associations

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

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
immunodeficiency 92	Strong	Autosomal recessive	2

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
immunodeficiency 92	Moderate	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (2 panels, 2 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

2 panels:

Panel	Rating
COVID-19 research	green
Primary immunodeficiency or monogenic inflammatory bowel disease	green

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

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

HPO phenotypes

showing 60 of 99 phenotypes (HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000098	Tall stature
HP:0000126	Hydronephrosis
HP:0000135	Hypogonadism
HP:0000160	Narrow mouth
HP:0000218	High palate
HP:0000232	Everted lower lip vermilion
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000319	Smooth philtrum
HP:0000340	Sloping forehead
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000348	High forehead
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000411	Protruding ear
HP:0000426	Prominent nasal bridge
HP:0000431	Wide nasal bridge
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000505	Visual impairment
HP:0000506	Telecanthus
HP:0000508	Ptosis
HP:0000527	Long eyelashes
HP:0000581	Blepharophimosis
HP:0000609	Optic nerve hypoplasia
HP:0000648	Optic atrophy
HP:0000717	Autism
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000767	Pectus excavatum
HP:0000771	Gynecomastia
HP:0001182	Tapered finger
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001321	Cerebellar hypoplasia
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001511	Intrauterine growth retardation
HP:0001561	Polyhydramnios
HP:0001601	Laryngomalacia
HP:0001611	Hypernasal speech
HP:0001653	Mitral regurgitation
HP:0001659	Aortic regurgitation
HP:0001763	Pes planus
HP:0001840	Metatarsus adductus
HP:0001852	Sandal gap
HP:0001863	Toe clinodactyly
HP:0001894	Thrombocytosis
HP:0001954	Recurrent fever
HP:0001974	Increased total leukocyte count
HP:0002015	Dysphagia

GWAS associations

28 associations:

Study	Trait	p-value
GCST001725_44	Inflammatory bowel disease	9e-32
GCST005527_4	Psoriasis	2e-17
GCST002318_72	Rheumatoid arthritis	4e-16
GCST002318_73	Rheumatoid arthritis	2e-15
GCST006959_158	Rheumatoid arthritis	5e-14
GCST006959_47	Rheumatoid arthritis	2e-13
GCST000612_18	Celiac disease	4e-13
GCST006048_18	Rheumatoid arthritis (ACPA-positive)	4e-13
GCST000420_2	Rheumatoid arthritis	2e-12
GCST003268_31	Psoriasis vulgaris	4e-12
GCST005568_2	Rheumatoid arthritis (ACPA-positive)	1e-11
GCST002738_9	Psoriasis	3e-11
GCST002874_68	Psoriasis	2e-10
GCST005569_30	Rheumatoid arthritis	1e-9
GCST000833_2	Psoriasis	4e-9
GCST001438_15	Crohn’s disease	5e-9
GCST000624_10	Ulcerative colitis	7e-9
GCST000879_49	Crohn’s disease	7e-9
GCST001355_1	Psoriatic arthritis	1e-8
GCST002874_46	Psoriasis	1e-8
GCST000851_2	Hodgkin’s lymphoma	2e-8
GCST005568_39	Rheumatoid arthritis (ACPA-positive)	3e-8
GCST008644_7	Celiac disease and Rheumatoid arthritis	4e-8
GCST001355_2	Psoriatic arthritis	2e-7
GCST003270_6	Psoriatic arthritis	6e-7
GCST002480_2	Hodgkin’s lymphoma	3e-6
GCST005569_40	Rheumatoid arthritis	4e-6
GCST006956_8	Erectile dysfunction	8e-6

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:1001494	psoriasis vulgaris

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296310 (SINGLE PROTEIN)

CIViC curated variants (1)

Named clinical variants curated in CIViC for this gene (the catalogue beneath the predictive evidence above):

AMPLIFICATION (transcript amplification).

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

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

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

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

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

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	affects binding, decreases reaction, increases reaction, affects cotreatment, increases expression (+2 more)	5
Doxorubicin	affects localization, decreases expression, affects response to substance	4
Tetradecanoylphorbol Acetate	affects localization, affects cotreatment, decreases reaction, increases expression	3
Arsenic Trioxide	decreases expression	2
Curcumin	decreases reaction, increases expression, increases reaction	2
Oxygen	decreases reaction, increases expression, affects cotreatment, decreases expression	2
Ozone	increases abundance, increases expression, affects cotreatment, decreases expression	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	affects cotreatment, decreases reaction, increases expression	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

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)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for REL across ~30M SureChEMBL compounds — explore on Sugi Predict.