IL12RB2

Summary

IL12RB2 (interleukin 12 receptor subunit beta 2, HGNC:5972) is a protein-coding gene on chromosome 1p31.3, encoding Interleukin-12 receptor subunit beta-2 (Q99665). Receptor for interleukin-12.

The protein encoded by this gene is a type I transmembrane protein identified as a subunit of the interleukin 12 receptor complex. The coexpression of this and IL12RB1 proteins was shown to lead to the formation of high-affinity IL12 binding sites and reconstitution of IL12 dependent signaling. The expression of this gene is up-regulated by interferon gamma in Th1 cells, and plays a role in Th1 cell differentiation. The up-regulation of this gene is found to be associated with a number of infectious diseases, such as Crohn’s disease and leprosy, which is thought to contribute to the inflammatory response and host defense. Several transcript variants encoding different isoforms and non-protein coding transcripts have been found for this gene.

Source: NCBI Gene 3595 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency disease (Limited, GenCC)
• GWAS associations: 28
• Clinical variants (ClinVar): 682 total
• MANE Select transcript: NM_001374259

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5972
Approved symbol	IL12RB2
Name	interleukin 12 receptor subunit beta 2
Location	1p31.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000081985
Ensembl biotype	protein_coding
OMIM	601642
Entrez	3595

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 13 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 non_stop_decay

ENST00000262345, ENST00000371000, ENST00000441640, ENST00000465396, ENST00000541374, ENST00000544434, ENST00000648487, ENST00000674203, ENST00000696754, ENST00000696755, ENST00000696756, ENST00000696757, ENST00000696758, ENST00000696759, ENST00000696760, ENST00000696761, ENST00000696762, ENST00000696763, ENST00000946360, ENST00000946361, ENST00000946362

RefSeq mRNA: 6 — MANE Select: NM_001374259 NM_001258214, NM_001258215, NM_001258216, NM_001319233, NM_001374259, NM_001559

CCDS: CCDS58006, CCDS58007, CCDS638, CCDS72805

Canonical transcript exons

ENST00000674203 — 17 exons

Exon	Start	End
ENSE00000903840	67320333	67320444
ENSE00003591754	67390029	67390128
ENSE00003776645	67338624	67338703
ENSE00003778639	67350870	67351089
ENSE00003778869	67330660	67330810
ENSE00003779988	67372625	67372783
ENSE00003780178	67379986	67380123
ENSE00003780343	67329587	67329729
ENSE00003780739	67372436	67372534
ENSE00003781545	67367825	67368025
ENSE00003782588	67328200	67328384
ENSE00003782631	67326735	67326849
ENSE00003783155	67321602	67321889
ENSE00003783434	67313913	67314000
ENSE00003783447	67386579	67386669
ENSE00003898215	67395547	67398724
ENSE00003968269	67307873	67307967

Expression profiles

Bgee: expression breadth ubiquitous, 170 present calls, max score 76.57.

FANTOM5 (CAGE): breadth broad, TPM avg 1.0561 / max 68.7528, expressed in 312 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
3407	0.8857	285
201542	0.0748	37
3406	0.0564	26
3405	0.0392	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	76.57	gold quality
gastrocnemius	UBERON:0001388	75.98	gold quality
muscle of leg	UBERON:0001383	75.66	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	72.76	gold quality
body of pancreas	UBERON:0001150	72.00	gold quality
calcaneal tendon	UBERON:0003701	71.36	gold quality
prefrontal cortex	UBERON:0000451	70.43	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	69.67	gold quality
muscle organ	UBERON:0001630	69.53	gold quality
granulocyte	CL:0000094	69.11	gold quality
lower esophagus mucosa	UBERON:0035834	68.17	gold quality
lymph node	UBERON:0000029	66.09	gold quality
pancreas	UBERON:0001264	65.09	gold quality
cingulate cortex	UBERON:0003027	64.91	gold quality
anterior cingulate cortex	UBERON:0009835	64.69	gold quality
frontal cortex	UBERON:0001870	64.15	gold quality
right lobe of liver	UBERON:0001114	63.80	gold quality
vermiform appendix	UBERON:0001154	63.70	gold quality
Brodmann (1909) area 9	UBERON:0013540	63.70	gold quality
neocortex	UBERON:0001950	63.68	gold quality
bone marrow cell	CL:0002092	63.63	silver quality
omental fat pad	UBERON:0010414	63.48	gold quality
peritoneum	UBERON:0002358	63.42	gold quality
esophagus mucosa	UBERON:0002469	63.17	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	62.86	gold quality
right frontal lobe	UBERON:0002810	62.60	gold quality
colonic epithelium	UBERON:0000397	62.48	silver quality
placenta	UBERON:0001987	62.31	gold quality
adipose tissue of abdominal region	UBERON:0007808	62.23	gold quality
tonsil	UBERON:0002372	62.12	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.87

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA3, SIRPA, STAT1, STAT4

miRNA regulators (miRDB)

28 targeting IL12RB2, 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-5193	100.00	67.26	1744
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-6126	99.62	68.09	996
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-31-5P	98.58	68.35	1239
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-1265	98.36	66.46	598
HSA-MIR-1267	98.24	69.05	837
HSA-MIR-4294	97.86	65.72	1110
HSA-MIR-3664-3P	97.85	67.62	1452
HSA-MIR-3909	97.55	66.78	887
HSA-MIR-550B-2-5P	96.56	64.61	646
HSA-MIR-3654	96.43	66.55	646
HSA-MIR-644A	96.02	66.52	786
HSA-MIR-8053	92.82	66.12	79

Literature-anchored findings (GeneRIF, showing 40)

• In the generation of cell-mediated immunity against intracellular infection, the expression and function of the IL-12 receptor beta 2 chain correlate with the response of Th1-type cells to Mycobacterium leprae antigen. (PMID:11441083)
• STATE OF ART REVIEW. IL-12Rb2 gene is not expressed in EBV-transformed normal B-lymphocytes and in Burkitt’s lymphoma B-cell lines. (PMID:11940489)
• upregulated in Il-12 augmented T cell activation of mononclear leukocytes from HIV seropositive individuals (PMID:12804004)
• promoter activity is increased in case of the -465G allele, disrupting the intact GATA site (PMID:15140029)
• Study showed recombinant human interleukin-12 (rhIL-12) safe/well tolerated in healthy subjects given single doses (1 up to 8 ug) subcutaneously. Interferon-gamma and, signal transducer and activator of transcription may be useful biomarkers of rhIL-12. (PMID:15901746)
• Epigenetic silencing of IL-12Rbeta2 is a frequent event in lung cancers. Aberrant methylation of this gene seems to be a useful predictor of long-term outcome for adenocarcinoma of the lung. (PMID:17602269)
• frequencies of variant alleles were significantly higher in aggressive periodontitis patients as compared with healthy controls or chronic periodontitis patients (PMID:18353079)
• IL-12R beta 2 directly restrains multiple myeloma cell growth (PMID:18474725)
• These results suggest that these SNPs in IL12RB2 have differential effects on cellular activation of T cells and NK cells. (PMID:18771340)
• Single Nucleotide Polymorphism in interleukin 12 receptor beta 2 is associated with susceptibility to radiation dermatitis in breast cancer. (PMID:18927311)
• Our data show significant associations between primary biliary cirrhosis and common genetic variants at the HLA class II, IL12A, and IL12RB2 loci (PMID:19458352)
• Studies established the concept that the IL-12Rbeta2 gene is a gatekeeper from cancer. (PMID:19720917)
• significant interaction between the IL-12RB1 and IL-12RB2 genes contributes to a 4-fold increased risk for developing extrinsic atopic dermatitis (PMID:20060272)
• Our results support a potential influence of the rs3790567 IL12RB2 polymorphism in the pathogenesis of giant cell arteritis. (PMID:21285166)
• data clearly support the IL12RB2 genetic association with systemic sclerosis (SSc), and suggest a relevant role of the interleukin 12 signaling pathway in SSc pathogenesis. (PMID:22076442)
• Variants in IL10 and IL23R-IL12RB2 are associated with Behcet’s disease in Iranian patients. (PMID:22378604)
• the -237 polymorphic site in the 5’ promoter region of the IL-12Rbeta2 (SNP ID: rs11810249) gene associated with the AP-4 transcription motif GAGCTG (PMID:22509293)
• a differential regulation pattern for genes solely expressed in Th17 cells (IL17A and CCL20) compared to genes expressed in both Th17 and Th1 cells (IL23R and IL12RB2), where high levels of promoter methylation are correlated to near zero (PMID:22715389)
• Data indicate that SNP (rs452204) in the IL1RN gene was significantly associated with higher levels of IL-2 secretion, and IL12RB2 SNP rs3790567 was associated with a decrease in IL-1beta secretion. (PMID:23009887)
• Association of IL12RB2 rs6679356 polymorphism with the age of type 1 diabetes mellitus onset suggests that this gene plays a role in defining the time of disease onset. (PMID:23152861)
• ERbeta2 and IL-12Rbeta5 had longer OS. (PMID:23677568)
• Data indicate that four of the IL-12Rbeta2 variants, N271Y, R313G, A604V and L808R showed reduced IL-12 responses compared to the wild type variant. (PMID:23911393)
• results suggest the rs924080 risk A allele does not affect baseline expression of IL-12RB2, IL-23R, IFN-gamma and TNF-alpha but enhances IL-23R and TNF-alpha expression capacity in response to LPS stimulation; the A allele appears to enhance baseline IL-6 production (PMID:24434271)
• Polymorphisms present in the promoter region of IL12RB2 may not be associated with susceptibility to leprosy or its clinical forms. (PMID:24486579)
• Genetic variations of IL-12B, IL-12Rbeta1, IL-12Rbeta2 in Behcet’s disease and VKH syndrome. (PMID:24859272)
• Estrogen receptor beta 2 regulates IL12RB2 expression via p38 MAPK signaling and inhibits non-small-cell lung cancer proliferation and invasion. (PMID:25695486)
• IL12RB2 polymorphism is associated with systemic lupus erythematosus in the Chinese population. (PMID:25720506)
• IL12RB2 polymorphisms correlate with risk of lung adenocarcinoma. (PMID:26547104)
• The effects of rs3762315 and rs3762316 single nucleotide polymorphisms in 5’ flanking region on IL12RB2 transcription (PMID:26552659)
• In ankylosing spondylitis, conditional analysis identified rs11209032 as the probable causal single-nucleotide polymorphism within a 1.14 kb putative enhancer between IL23R and IL12RB2. The rs11209032 single-nucleotide polymorphism downstream of IL23R forms part of an enhancer, allelic variation of which may influence Th1-cell numbers. (PMID:26916345)
• The results of this case-control study suggest that IL-12A, IL-12B, IL12RB1, IL12RB2 and IL23R make no genetic contribution to the susceptibility of Takayasu arteritis in Chinese populations (PMID:26987707)
• this study identified susceptibility single nucleotide polymorphisms in IL12RB2 with Behcet’s disease in Han Chinese (PMID:27464962)
• this study shows that single nucleotide polymorphisms of the IL23R-IL12RB2 region are associated with Behcet’s disease in a Northern Chinese Han population (PMID:27660093)
• study confirmed the relationship of IL12RB2 polymorphisms with primary biliary cholangitis (PBC) susceptibility; provided evidence that IL12RB2 polymorphisms are associated with liver cirrhosis and an increased concentration of disease-specific anti-mitochondrial antibodies in sera of PBC patients (PMID:28299343)
• inhibition of the H3K27 demethylase JMJD3 in naive CD4 T cells demonstrates how critically important molecules required for T cell differentiation, such as JAK2 and IL12RB2, are regulated by H3K27me3. (PMID:28947543)
• Tumor cell differentiation is associated with TILs’ expression of IL-12Rbeta2, and an IL-12Rbeta2(+) TIL ratio >/=35%) indicates favorable prognosis in LC (PMID:29103744)
• we analyzed common variants located in genes of the IL12/STAT4 and IL10/STAT3 signaling pathways in patients with myasthenia gravis. (PMID:29576322)
• The Cox proportional hazard models revealed that IL12Rb2 and p38MAPK predicted a long OS. To the best of our knowledge, the present study is the first to reveal a close association between IL12Rb2 and p38MAPK, and their possible function in nonsmall cell lung cancer progression (PMID:29956791)
• Mutation analysis showed three previously reported mutations, two novel mutations in IL-12 R (beta1/beta2), and one previously reported mutation in IL-12 Mendelian Susceptibility to Mycobacterial Disease patients. (PMID:31158284)
• Expressions of IL-12 and its receptors in patients with lumbar disc herniation and their relationship with clinical efficacy. (PMID:33287915)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	il23r	ENSDARG00000052158
mus_musculus	Il12rb2	ENSMUSG00000018341
rattus_norvegicus	Il12rb2	ENSRNOG00000007270

Paralogs (23): CRLF1 (ENSG00000006016), IL5RA (ENSG00000091181), IL12RB1 (ENSG00000096996), IL27RA (ENSG00000104998), EBI3 (ENSG00000105246), GHR (ENSG00000112964), PRLR (ENSG00000113494), LIFR (ENSG00000113594), LEPR (ENSG00000116678), CSF3R (ENSG00000119535), CNTFR (ENSG00000122756), IL13RA2 (ENSG00000123496), IL13RA1 (ENSG00000131724), IL6ST (ENSG00000134352), IL11RA (ENSG00000137070), OSMR (ENSG00000145623), IL2RG (ENSG00000147168), IL6R (ENSG00000160712), IL23R (ENSG00000162594), IL31RA (ENSG00000164509), IL3RA (ENSG00000185291), CSF2RA (ENSG00000198223), CRLF2 (ENSG00000205755)

Protein

Protein identifiers

Interleukin-12 receptor subunit beta-2 — Q99665 (reviewed: Q99665)

All UniProt accessions (7): Q99665, A0A0A0MTN7, A0A8Q3SIS8, A0A8Q3SIT5, A0A8Q3SIX0, A0A8Q3SJ07, H0Y5V0

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for interleukin-12. This subunit is the signaling component coupling to the JAK2/STAT4 pathway. Promotes the proliferation of T-cells as well as NK cells. Induces the promotion of T-cells towards the Th1 phenotype by strongly enhancing IFN-gamma production.

Subunit / interactions. Heterodimer/heterooligomer; disulfide-linked. The functional high affinity IL12 receptor is composed of I12RB1 and IL12RB2. Il12RB2 binds JAK2 (via its N-terminal) through a membrane-proximal region of the cytoplasmic domain. Interaction, in vitro and in vivo, with SOCS3 (via its SH2 domain) inhibits the STAT4-mediated activation. Binds STAT4 through a membrane-distal C-terminal region.

Subcellular location. Membrane.

Tissue specificity. Isoform 2 is expressed at similar levels in both naive and activated T-cells.

Post-translational modifications. On IL12 binding, phosphorylated on C-terminal tyrosine residues by JAK2. Phosphorylation on Tyr-800 is required for STAT4 binding and activation, and for SOCS3 binding.

Domain organisation. The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding. The box 1 motif is required for JAK interaction and/or activation.

Induction. In vitro, up-regulated by IFN-alpha.

Polymorphism. Heterozygotic variants Gly-313 and Arg-720 are associated with atopy, an immunological condition that can lead to clinical symptoms such as allergic rhinitis, sinusitis, asthma and eczema.

Similarity. Belongs to the type I cytokine receptor family. Type 2 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q99665-1	1	yes
Q99665-2	2
Q99665-3	3

RefSeq proteins (6): NP_001245143, NP_001245144, NP_001245145, NP_001306162, NP_001361188, NP_001550 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003529	Hematopoietin_rcpt_Gp130_CS	Conserved_site
IPR003961	FN3_dom	Domain
IPR010457	IgC2-like_lig-bd	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR052672	Type1_Cytokine_Rcpt_Type2	Family

Pfam: PF00041, PF06328

UniProt features (46 total): sequence variant 12, glycosylation site 8, mutagenesis site 7, domain 5, splice variant 3, region of interest 2, short sequence motif 2, topological domain 2, signal peptide 1, chain 1, compositionally biased region 1, modified residue 1, transmembrane region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8YI7	ELECTRON MICROSCOPY	3.57
8XRP	ELECTRON MICROSCOPY	3.75

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99665-F1	73.23	0.38

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 (1): 800

Glycosylation sites (8): 48, 129, 166, 195, 271, 347, 376, 480

Mutagenesis-validated functional residues (7):

Position	Phenotype
678	no loss of stat4 activation. no loss of socs3 binding.
767	no loss of stat4 activation. no loss of socs3 binding.
800	loss of stat4 activation. abolishes socs3 binding.
801	abolishes in vitro stat4 binding to a phosphorylated y-800 peptide.
802	no effect on in vitro stat4 binding to a phosphorylated y-800 peptide.
803	no effect on in vitro stat4 binding to a phosphorylated y-800 peptide.
804	no effect on in vitro stat4 binding to a phosphorylated y-800 peptide.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-8984722	Interleukin-35 Signalling
R-HSA-9020591	Interleukin-12 signaling
R-HSA-9942503	Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)

MSigDB gene sets: 271 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GOBP_B_CELL_ACTIVATION, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOCC_CELL_SURFACE, GOBP_B_CELL_PROLIFERATION, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_CELL_SURFACE_RECEPTOR_SIGNALING_PATHWAY_VIA_JAK_STAT, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_CELL_CELL_ADHESION

GO Biological Process (8): cell surface receptor signaling pathway (GO:0007166), positive regulation of cell population proliferation (GO:0008284), cytokine-mediated signaling pathway (GO:0019221), response to lipopolysaccharide (GO:0032496), positive regulation of type II interferon production (GO:0032729), interleukin-12-mediated signaling pathway (GO:0035722), response to cytokine (GO:0034097), T-helper 1 cell differentiation (GO:0045063)

GO Molecular Function (5): cytokine receptor activity (GO:0004896), coreceptor activity (GO:0015026), protein kinase binding (GO:0019901), cytokine binding (GO:0019955), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), signaling receptor complex (GO:0043235), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Interleukin-12 family signaling	2
Differentiation of T cells	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytokine-mediated signaling pathway	2
signal transduction	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
positive regulation of cytokine production	1
type II interferon production	1
regulation of type II interferon production	1
cellular response to interleukin-12	1
response to peptide	1
alpha-beta T cell activation involved in immune response	1
T cell differentiation involved in immune response	1
T-helper 1 type immune response	1
T-helper cell differentiation	1
transmembrane signaling receptor activity	1
cytokine binding	1
immune receptor activity	1
signaling receptor activity	1
kinase binding	1
protein binding	1
binding	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
protein-containing complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1175 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL12RB2	IL12RB1	P42701	999
IL12RB2	JAK2	O60674	983
IL12RB2	IL27RA	Q6UWB1	978
IL12RB2	TYK2	P29597	946
IL12RB2	STAT4	Q14765	923
IL12RB2	TBX21	Q9UL17	868
IL12RB2	IFNG	P01579	833
IL12RB2	IL6	P05231	805
IL12RB2	IL27	Q8NEV9	805
IL12RB2	IL10	P22301	803
IL12RB2	IL23A	Q9NPF7	802
IL12RB2	IL18R1	Q13478	777
IL12RB2	STAT1	P42224	759
IL12RB2	CD4	P01730	758
IL12RB2	IL17A	Q16552	758

IntAct

8 interactions, top by confidence:

A	B	Type	Score
STAT4	IL12RB2	psi-mi:“MI:0914”(association)	0.530
IL12RB2	RAB34	psi-mi:“MI:0915”(physical association)	0.400
IL12RB2	HLA-A	psi-mi:“MI:0915”(physical association)	0.400
M		psi-mi:“MI:0914”(association)	0.350
INSR	UBXN8	psi-mi:“MI:0914”(association)	0.350
SOCS3	IL12RB2	psi-mi:“MI:0914”(association)	0.350

BioGRID (14): JAK2 (Reconstituted Complex), IL12RB2 (Affinity Capture-Western), RAB34 (Proximity Label-MS), IL12RB2 (Affinity Capture-MS), IL12RB2 (Affinity Capture-RNA), IL12RB2 (Protein-peptide), IL12RB2 (Phenotypic Enhancement), IL12RB2 (Affinity Capture-MS), IL12RB2 (Co-fractionation), IL12RB2 (Co-fractionation), IL12RB2 (Co-fractionation), IL12RB2 (Affinity Capture-RNA), SOCS3 (Reconstituted Complex), SOCS3 (Affinity Capture-Western)

ESM2 similar proteins: K7NA32, K7NAJ3, O09030, O70458, O70535, P14753, P16310, P17181, P19235, P21183, P22272, P22273, P24055, P26955, P31785, P33896, P34902, P40190, P40223, P40321, P42701, P42702, P42703, P78552, Q00560, Q04790, Q07303, Q28589, Q5XNR9, Q60837, Q65Z14, Q6PHB0, Q6UXL0, Q764M8, Q7TNI4, Q80XF5, Q8K5B1, Q8MJS1, Q8NI17, Q95118

Diamond homologs: P97378, Q8MJS1, Q99665, Q9BEG2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
IL12A	up-regulates	IL12RB2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	413
Likely benign	210
Benign	27

Top pathogenic / likely-pathogenic (0)

SpliceAI

3013 predictions. Top by Δscore:

Variant	Effect	Δscore
1:67320330:A:AG	acceptor_gain	1.0000
1:67320331:A:G	acceptor_gain	1.0000
1:67326733:A:AG	acceptor_gain	1.0000
1:67326734:G:GG	acceptor_gain	1.0000
1:67326834:C:CG	donor_gain	1.0000
1:67326834:C:G	donor_gain	1.0000
1:67326850:GTGA:G	donor_gain	1.0000
1:67328340:G:GT	donor_gain	1.0000
1:67328378:GACA:G	donor_gain	1.0000
1:67367813:T:A	acceptor_gain	1.0000
1:67367821:AAAG:A	acceptor_gain	1.0000
1:67386670:G:GG	donor_gain	1.0000
1:67320330:AAG:A	acceptor_gain	0.9900
1:67321596:TTGCA:T	acceptor_loss	0.9900
1:67321597:TGCAG:T	acceptor_loss	0.9900
1:67321598:GCAG:G	acceptor_loss	0.9900
1:67321599:CAG:C	acceptor_loss	0.9900
1:67321600:A:AC	acceptor_loss	0.9900
1:67321600:A:AG	acceptor_gain	0.9900
1:67321601:G:GA	acceptor_gain	0.9900
1:67321601:GAT:G	acceptor_gain	0.9900
1:67321601:GATGC:G	acceptor_gain	0.9900
1:67326731:A:AG	acceptor_gain	0.9900
1:67326732:A:G	acceptor_gain	0.9900
1:67326734:GTT:G	acceptor_gain	0.9900
1:67326854:G:GG	donor_gain	0.9900
1:67328194:TTACA:T	acceptor_loss	0.9900
1:67328195:TACAG:T	acceptor_loss	0.9900
1:67328197:CAGGC:C	acceptor_loss	0.9900
1:67328198:A:AG	acceptor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000094339 (1:67376175 A>G), RS1000120405 (1:67341262 CA>C,CAA), RS1000153803 (1:67362868 G>A), RS1000166408 (1:67377885 G>A), RS1000229472 (1:67355151 C>T), RS1000247276 (1:67323282 G>T), RS1000260810 (1:67354975 G>T), RS1000305798 (1:67305487 C>T), RS1000312151 (1:67356091 A>G), RS1000341328 (1:67348120 G>A), RS1000344305 (1:67396014 C>G,T), RS1000356926 (1:67310517 TAAATC>T), RS1000379133 (1:67390220 T>C), RS1000410641 (1:67310226 A>C,G), RS1000419235 (1:67396454 G>T)

Disease associations

OMIM: gene MIM:601642 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency disease	Limited	Autosomal recessive

Mondo (1): immunodeficiency disease (MONDO:0021094)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

28 associations (top):

Study	Trait	p-value
GCST000408_2	Primary biliary cholangitis	3.000000e-11
GCST000726_1	Behcet’s disease	7.000000e-09
GCST000728_1	Behcet’s disease	2.000000e-11
GCST000733_4	Primary biliary cholangitis	8.000000e-12
GCST001010_17	Primary biliary cholangitis	9.000000e-20
GCST001438_1	Crohn’s disease	1.000000e-18
GCST001725_29	Inflammatory bowel disease	8.000000e-161
GCST003129_26	Primary biliary cholangitis	7.000000e-28
GCST003155_28	Systemic lupus erythematosus	3.000000e-07
GCST004125_9	Type 2 diabetes (age of onset)	5.000000e-06
GCST004131_16	Inflammatory bowel disease	5.000000e-111
GCST004132_7	Crohn’s disease	6.000000e-93
GCST004133_2	Ulcerative colitis	4.000000e-41
GCST004867_15	Systemic lupus erythematosus	3.000000e-07
GCST005356_15	Severe malaria	8.000000e-07
GCST005357_10	Severe malaria (adjusted for sickle cell variant rs334)	9.000000e-07
GCST005554_9	Systemic sclerosis	1.000000e-06
GCST005752_155	Systemic lupus erythematosus	2.000000e-09
GCST006585_1700	Blood protein levels	4.000000e-10
GCST007278_1	Systemic seropositive rheumatic diseases (Systemic sclerosis or systemic lupus erythematosus or rheumatoid arthritis or idiopathic inflammatory myopathies)	6.000000e-11
GCST007400_58	Systemic lupus erythematosus	1.000000e-06
GCST007932_83	Medication use (thyroid preparations)	8.000000e-10
GCST009131_1	Systemic sclerosis	4.000000e-10
GCST010124_1	Crohn’s disease or systemic sclerosis	1.000000e-11
GCST010730_1	Rheumatoid arthritis	8.000000e-10
GCST011096_28	Systemic lupus erythematosus	3.000000e-09
GCST011097_8	Systemic lupus erythematosus	2.000000e-08
GCST012322_3	Triglyceride levels x SSRI defined daily dose interaction in schizophrenia or bipolar disorder	1.000000e-07

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004267	biliary liver cirrhosis
EFO:0009933	Thyroid preparation use measurement
EFO:0004530	triglyceride measurement
EFO:0005658	response to selective serotonin reuptake inhibitor

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2229546	IL12RB2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — IL-12 receptor family

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
glucuronoxylomannan	decreases expression	2
Nickel	increases expression	2
Tetradecanoylphorbol Acetate	increases expression, affects cotreatment, affects expression	2
aristolochic acid I	increases expression	1
bisphenol F	decreases methylation	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
arsenite	increases methylation	1
aflatoxin B2	decreases methylation	1
bisphenol S	decreases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	increases expression	1
Benzo(a)pyrene	affects methylation	1
Butyrates	decreases expression	1
Cadmium	increases abundance, decreases expression	1
Cholera Toxin	decreases expression	1
Copper	affects cotreatment, decreases expression	1
Dexamethasone	decreases expression	1
Ivermectin	decreases expression	1
Rifampin	decreases expression	1
Dronabinol	increases expression	1
Valproic Acid	affects expression	1
Zinc	affects cotreatment, affects expression	1
Dinoprostone	decreases expression	1
Cyclosporine	increases expression	1
Cadmium Chloride	decreases expression, increases abundance	1

Cellosaurus cell lines

2 cell lines: 1 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C8GA	Calu6/Beta2	Cancer cell line	Female
CVCL_UF31	HEK-Blue IL-12	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00001542	PHASE4	COMPLETED	Fluconazole Prophylaxis of Thrush in AIDS
NCT00144157	PHASE4	COMPLETED	Open Label Study of NVP+CBV Treatment in Women Who Have Received sdNVP for the pMTCT of HIV
NCT00162643	PHASE4	UNKNOWN	PI Vs. NNRTI Based Therapy for HIV Advanced Disease
NCT00273988	PHASE4	COMPLETED	Pharmacokinetic Study of Interaction Between Nevirapine and Methadone in HIV-1 Infected, Opioid-dependent Adults
NCT00981318	PHASE4	TERMINATED	Pilot Assessment of Lopinavir/Ritonavir and Maraviroc
NCT01086878	PHASE4	COMPLETED	Safety of Cotrimoxazole in HIV- and HAART-exposed Infants
NCT01090102	PHASE4	COMPLETED	Mesalamine to Reduce T Cell Activation in HIV Infection
NCT01147042	PHASE4	TERMINATED	Biochemical Response to Interferon-Gamma in Subjects With Specific Gene Mutation in Chronic Granulomatous Disease
NCT01230580	PHASE4	UNKNOWN	Protease Inhibitor Monotherapy Versus Ongoing Triple-therapy in the Long Term Management of HIV Infection (PIVOT)
NCT01465958	PHASE4	COMPLETED	Pharmacokinetics, Safety, and Tolerability of Subcutaneous GAMUNEX-C in Pediatric Subjects With Primary Immunodeficiency
NCT02274662	PHASE4	COMPLETED	Expanded Access Protocol Thymus Transplantation
NCT02348177	PHASE4	COMPLETED	Pharmacokinetics of Lopinavir/Ritonavir Superboosting in Infants and Young Children Co-infected With HIV and TB
NCT02396979	PHASE4	COMPLETED	Intervention of HIV, Drug Use and the Criminal Justice System in Malaysia
NCT02490956	PHASE4	UNKNOWN	Diagnostic Immunization With Rabies Vaccine in Patients With PID
NCT02503293	PHASE4	COMPLETED	A Study to Compare Quality of Life and Satisfaction in Primary Immunodeficient Patients Treated With Subcutaneous Injections of Gammanorm® 165 mg/mL Administered With Two Different Delivery Devices: Injections Using Pump or Rapid Push
NCT02881437	PHASE4	COMPLETED	IgG Level in Primary Immunodeficiency Switching From Standard SCIG to Every Other Week HyQvia
NCT03033745	PHASE4	COMPLETED	Safety and Tolerability of Higher Infusion Parameters of IgPro20 (Hizentra) in Subjects With Primary Immunodeficiency (PID)
NCT03677557	PHASE4	UNKNOWN	Safety, Tolerability, Patient Satisfaction and Cost of 16.5% Subcutaneous Immunoglobulin (Cutaquig®) Treatment
NCT04192487	PHASE4	COMPLETED	Effects of Crofelemer on the Gut Microbiome in Healthy Volunteers and in HIV+ Patients With Non-Infectious Diarrhea
NCT04566692	PHASE4	COMPLETED	A Study to Evaluate IGSC 20% Biweekly Dosing in Treatment-Experienced Participants and Loading/Maintenance Dosing in Treatment-Naïve Participants With Primary Immunodeficiency
NCT05493969	PHASE4	NOT_YET_RECRUITING	Efficacy and Tolerability of DTG Plus 3TC in HIV Infected Adults With Virologically Suppression and TDF Toxicity
NCT06576024	PHASE4	COMPLETED	Immunogenicity and Safety of Inactivated Hepatitis A Vaccine in HIV-infected People
NCT06634641	PHASE4	RECRUITING	Clozapine-related Immunodeficiency in Parkinsons Disease
NCT07076446	PHASE4	ACTIVE_NOT_RECRUITING	An Open-label, Multicenter Study to Assess the Pharmacokinetics (PK), Safety, and Tolerability of Subcutaneous IgPro20 in Immunoglobulin (IG) Treatment-naïve Participants With Primary Immunodeficiency (PID)
NCT00000118	PHASE3	COMPLETED	Ganciclovir Implant Study for Cytomegalovirus Retinitis
NCT00000134	PHASE3	COMPLETED	Studies of the Ocular Complications of AIDS (SOCA)–Cytomegalovirus Retinitis Retreatment Trial (CRRT)
NCT00000590	PHASE3	COMPLETED	Anti-HIV Immunoglobulin (HIVIG) in Prevention of Maternal-Fetal HIV Transmission (Pediatric ACTG Protocol 185)
NCT00001267	PHASE3	COMPLETED	A Randomized Pilot Study for the Treatment of AIDS or AIDS Related Complex With an Alternating or Simultaneous Combination Regimen of AZT and 2’,3’-Dideoxyinosine
NCT00001646	PHASE3	COMPLETED	Voriconazole vs. Amphotericin B in the Treatment of Invasive Aspergillosis
NCT00144183	PHASE3	COMPLETED	A Study of Single Dose Nevirapine (NVP) Combined With Combivir® for the Prevention of Mother to Child Transmission (pMTCT) - Treatment Options Preservation Study (TOPS)
NCT00243568	PHASE3	WITHDRAWN	Vicriviroc, a CCR5 Inhibitor, Added to an Optimized Antiretroviral Therapy for Previously Treated HIV (VICTOR-E2) (Study P04285
NCT00278954	PHASE3	COMPLETED	Efficacy, Safety and Pharmacokinetics of Gammaplex in Primary Immunodeficiency Diseases.
NCT00474370	PHASE3	COMPLETED	Vicriviroc in HIV-Treatment Experienced Subjects (Study P04889AM8)(COMPLETED)
NCT00478231	PHASE3	COMPLETED	Multicenter, Safety Study Of Maraviroc
NCT00523211	PHASE3	COMPLETED	Vicriviroc in HIV-Treatment Experienced Subjects (Study P04405AM5)
NCT00698334	PHASE3	COMPLETED	Efficacy of Thrice Weekly Directly Observed Treatment, Short-course (DOTS) in HIV-associated Tuberculosis
NCT00966160	PHASE3	COMPLETED	CD4 Cell Recovery in HIV-1 Patients Comparing 2 Treatment Regimes
NCT01363011	PHASE3	COMPLETED	Cobicistat-containing Highly Active Antiretroviral Regimens in HIV-1 Infected Patients With Mild to Moderate Renal Impairment
NCT01440569	PHASE3	COMPLETED	Safety and Efficacy of Cobicistat-boosted Darunavir in HIV Infected Adults
NCT01475838	PHASE3	COMPLETED	Study to Evaluate Switching From Regimens Consisting of a Ritonavir-boosted Protease Inhibitor Plus Emtricitabine/Tenofovir Fixed-Dose Combination to the Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF Single-Tablet Regimen in Virologically Suppressed, HIV-1 Infected Patients