IL12B

Summary

IL12B (interleukin 12B, HGNC:5970) is a protein-coding gene on chromosome 5q33.3, encoding Interleukin-12 subunit beta (P29460). Cytokine that can act as a growth factor for activated T and NK cells, enhance the lytic activity of NK/lymphokine-activated killer cells, and stimulate the production of IFN-gamma by resting PBMC.

This gene encodes a subunit of interleukin 12, a cytokine that acts on T and natural killer cells, and has a broad array of biological activities. Interleukin 12 is a disulfide-linked heterodimer composed of the 40 kD cytokine receptor like subunit encoded by this gene, and a 35 kD subunit encoded by IL12A. This cytokine is expressed by activated macrophages that serve as an essential inducer of Th1 cells development. This cytokine has been found to be important for sustaining a sufficient number of memory/effector Th1 cells to mediate long-term protection to an intracellular pathogen. Overexpression of this gene was observed in the central nervous system of patients with multiple sclerosis (MS), suggesting a role of this cytokine in the pathogenesis of the disease. The promoter polymorphism of this gene has been reported to be associated with the severity of atopic and non-atopic asthma in children.

Source: NCBI Gene 3593 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency (Definitive, GenCC)
• GWAS associations: 50
• Clinical variants (ClinVar): 249 total — 12 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 58
• Druggable target: yes
• MANE Select transcript: NM_002187

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5970
Approved symbol	IL12B
Name	interleukin 12B
Location	5q33.3
Locus type	gene with protein product
Status	Approved
Aliases	CLMF, IL-12B, NKSF, CLMF2
Ensembl gene	ENSG00000113302
Ensembl biotype	protein_coding
OMIM	161561
Entrez	3593

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000231228, ENST00000696750, ENST00000696751, ENST00000696752

RefSeq mRNA: 1 — MANE Select: NM_002187 NM_002187

CCDS: CCDS4346

Canonical transcript exons

ENST00000231228 — 8 exons

Exon	Start	End
ENSE00000768660	159318736	159318893
ENSE00000768662	159320306	159320520
ENSE00000768664	159322394	159322511
ENSE00000768666	159323054	159323329
ENSE00000797274	159314780	159316100
ENSE00000797276	159326695	159326782
ENSE00001230769	159330432	159330487
ENSE00001371782	159316685	159316816

Expression profiles

Bgee: expression breadth broad, 33 present calls, max score 89.19.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5553 / max 85.5032, expressed in 67 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
64609	0.5553	67

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.19	gold quality
decidua	UBERON:0002450	56.55	gold quality
hair follicle	UBERON:0002073	52.43	gold quality
lymph node	UBERON:0000029	50.90	gold quality
ileal mucosa	UBERON:0000331	50.56	silver quality
pituitary gland	UBERON:0000007	49.73	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
quadriceps femoris	UBERON:0001377	48.80	gold quality
deltoid	UBERON:0001476	48.62	gold quality
epithelial cell of pancreas	CL:0000083	48.57	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
vastus lateralis	UBERON:0001379	48.25	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
upper arm skin	UBERON:0004263	48.06	gold quality
cervix epithelium	UBERON:0004801	48.04	gold quality
oviduct epithelium	UBERON:0004804	48.00	gold quality
vermiform appendix	UBERON:0001154	47.92	gold quality
tongue squamous epithelium	UBERON:0006919	47.92	gold quality
mucosa of urinary bladder	UBERON:0001259	47.80	gold quality
metanephric glomerulus	UBERON:0004736	47.45	gold quality
kidney epithelium	UBERON:0004819	47.39	gold quality
nephron tubule	UBERON:0001231	47.30	gold quality
tibialis anterior	UBERON:0001385	47.17	silver quality
diaphragm	UBERON:0001103	47.05	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.94

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, AP1, ATF3, CEBPA, CEBPB, CEBPG, ELF1, EP300, ETS1, ETS2, ETV6, FOS, GLI2, IRF1, IRF3, IRF4, IRF5, IRF6, IRF7, IRF8, JUN, JUNB, KAT7, KLF10, KLF1, MAF, MAFK, MAPK11, MAPK14, NCOR2, NFATC1, NFATC2, NFATC4, NFIL3, NFKB1, NFKB2, NFKB, NR0B2, PARP1, REL

miRNA regulators (miRDB)

70 targeting IL12B, 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-5692A	100.00	74.40	6850
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111

Literature-anchored findings (GeneRIF, showing 40)

• inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds (PMID:11753820)
• Heparins (unfractionated heparin, UFH and low molecular weight heparin certoparin) had no effect on the release of IL-1ra, IL-10, and IL-12p40 from neutrophils or peripheral blood mononuclear cells. (PMID:11820460)
• STATE OF ART REVIEW. Malignant B-cells from follicular and marginal zone lymphomas expressed IL-12 p35 and p40 transcripts, whereas only p35 mRNA was detected in mantle cell lymphoma. (PMID:11940489)
• The IL12B gene does not confer susceptibility to coeliac disease (PMID:11972887)
• results suggest that LPS stimulates the pituitary gland directly in vivo to increase IL-12 p40 gene expression (PMID:12065887)
• DISCUSSION FORUM: it is the p40 protein, either alone or paired with other polypeptides, rather than p75, that acts as an interface between the innate and adaptive immune responses (PMID:12100467)
• Leishmania priming of human dendritic cells for CD40 ligand-induced interleukin-12p40 secretion is strain and species dependent (PMID:12117904)
• The purified lipoprotein, Lpk, from Mycobacterium leprae, was found to induce production of interleukin-12 in human peripheral blood monocytes (PMID:12117918)
• results suggest that impaired IL-12 production in HIV-infected myeloid cells occurs, in part, via disruption of IL-12 p40 gene expression in a manner that requires cellular infection (PMID:12202149)
• ATPgammaS potentiated the IL-12p40 release induced by TNF-alpha. This potentiation was observed as long as the IL-12p40 concentration under agonist stimulation remained below a threshold value close to 10 ng/ml; inhibition was observed above this value. (PMID:12207325)
• IL12B promoter heterozygosity contributes to asthma severity rather than susceptibility per se. (PMID:12241719)
• possible role of IL-12 and tissue antioxidants in development and progression of chronic sinusitis (PMID:12270766)
• role of CD28 and IL-12/IL-15 signaling impairment in T cell proliferative deficiency during senescence (PMID:12297341)
• IL12B SNP is associated with susceptibility to atopic dermatitis and psoriasis vulgaris, presumably by affecting the Th1/Th2 balance. (PMID:12413772)
• IL-12 expression in PMN of SLE patients was less prominent than that of the normal controls. (PMID:12472178)
• A key mechanism in the pathogenesis of MS is the increased expression of CD86 and CD40L and the increased production of IL12 during disease progression. (PMID:12672403)
• Interleukin-10 induction of endothelial nitric-oxide synthase expression attenuates CD40-mediated interleukin-12 synthesis in human endothelial cells. (PMID:12857749)
• Diesel exhaust particles seem to inhibit the production of IL-12 p40 in lipopolysaccharide activated monocytes as a model for lung macrophages (PMID:12876411)
• These two potentially important candidate gene single nucleotide polymorphisms are not associated with susceptibility to idiopathic pulmonary fibrosis. (PMID:12914676)
• IL-12B 3’untranslated region has no effect or has a negligible effect on human susceptibility to tuberculosis. (PMID:14551880)
• The IL12B TaqI gene polymorphisms do not appear to be involved in susceptibility to celiac disease (PMID:14675396)
• interleukin-12 p40 transcription and NF-kappaB activation are inhibited by nitric oxide in macrophages and dendritic cells (PMID:14679201)
• Data show that reverse signaling via 4-1BB-ligand enhanced interleukin-12beta mRNA and the secretion of IL-12 p70 in various antigen-presenting cells, including monocytes. (PMID:14746806)
• identify erythroid Kruppel-like factor as a transcription factor in macrophages able to regulate IL-12 p40 transcription depending on the cellular activation status (PMID:14976188)
• no evidence to support the presence of a heterozygote effect of the IL12B promoter polymorphism on the level of asthma in early childhood or adulthood (PMID:15007350)
• Frequencies of the various genotypes for the promoter region of the gene encoding IL-12p40 (IL12B) did not differ between psoriasis patients and controls. (PMID:15102082)
• The polymorphism of IL12B (1188A/C) appears to have some influence on the outcome of hepatitis c virus infection. (PMID:15285014)
• association between IL12B intron 2 polymorphism and tuberculosis and between specific IL12B haplotypes and TB found in Hong Kong Chinese population (PMID:15295696)
• We found a strong association between the IL12B_4237 and IL12B_6402 polymorphisms and an asthma-severity phenotype in whites. (PMID:15322986)
• Decreased LPS-induced IL-12(p70) and IL-10 responses were associated with the TLR4 (Asp299Gly) polymorphism and independently with asthma, especially atopic asthma in school-age children (PMID:15356557)
• interleukin 12 and interferon gamma are involved in inhibition of cytotrophoblastic cell invasion (PMID:15448160)
• No association of IL12B polymorphisms and self-limited HCV infection could be demonstrated. (PMID:15464247)
• p300 is involved in the transcriptional regulation of IL-12 p40, and IL-12 p40 is one of the target genes of p300 (PMID:15482860)
• A direct role for IL12B in susceptibility to inflammatory bowel disease is unlikely. (PMID:15483662)
• study shows that PBMCs of patients with advanced gastric cancer show poor production of TNF and IL-12p40 in response to stimulation with tumor cells in vitro & this unresponsiveness is associated in some patients with diminished IRAK-1 expression in vivo (PMID:15523691)
• Heterozygosity of a polymorphism in the 3’untranslated region of the IL12B gene was associated with a delayed disease in late-onset diabetics. (PMID:15603869)
• The IL12B 1188 (A–>C) gene polymorphism is not involved in defining the genetic basis of the susceptibility to and final outcome of peptic ulcer disease. (PMID:15620465)
• synthesis in RAW264.7 cells is induced by IRF-8 (PMID:15837792)
• reversible histone acetylation/deacetylation modification plays an important role in the transcriptional regulation of IL-12 (PMID:15869883)
• chronically infected patients were significantly more likely than those with resolved HCV infection to be homozygous for the IL-12B 3’-UTR A allele (PMID:15871664)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	il12ba	ENSDARG00000033727
danio_rerio	il12bb	ENSDARG00000054542
		ENSDARG00000101415
mus_musculus	Il12b	ENSMUSG00000004296
rattus_norvegicus	Il12b	ENSRNOG00000004380

Protein

Protein identifiers

Interleukin-12 subunit beta — P29460 (reviewed: P29460)

Alternative names: Cytotoxic lymphocyte maturation factor 40 kDa subunit, IL-12 subunit p40, NK cell stimulatory factor chain 2

All UniProt accessions (3): P29460, A0A8Q3SJ12, A0A8Q3WML5

UniProt curated annotations — full annotation on UniProt →

Function. Cytokine that can act as a growth factor for activated T and NK cells, enhance the lytic activity of NK/lymphokine-activated killer cells, and stimulate the production of IFN-gamma by resting PBMC. Associates with IL23A to form the IL-23 interleukin, a heterodimeric cytokine which functions in innate and adaptive immunity. IL-23 may constitute with IL-17 an acute response to infection in peripheral tissues. IL-23 binds to a heterodimeric receptor complex composed of IL12RB1 and IL23R, activates the Jak-Stat signaling cascade, stimulates memory rather than naive T-cells and promotes production of pro-inflammatory cytokines. IL-23 induces autoimmune inflammation and thus may be responsible for autoimmune inflammatory diseases and may be important for tumorigenesis.

Subunit / interactions. Heterodimer with IL12A; disulfide-linked. The heterodimer is known as interleukin IL-12. Heterodimer with IL23A; disulfide-linked. The heterodimer is known as interleukin IL-23. Also secreted as a monomer. Interacts with NBR1; this interaction promotes IL-12 secretion.

Subcellular location. Secreted.

Post-translational modifications. Known to be C-mannosylated in the recombinant protein; it is not yet known for sure if the wild-type protein is also modified.

Disease relevance. Immunodeficiency 29 (IMD29) [MIM:614890] A form of Mendelian susceptibility to mycobacterial disease, a rare condition caused by impairment of interferon-gamma mediated immunity. It is characterized by predisposition to illness caused by moderately virulent mycobacterial species, such as Bacillus Calmette-Guerin (BCG) vaccine, environmental non-tuberculous mycobacteria, and by the more virulent Mycobacterium tuberculosis. Other microorganisms rarely cause severe clinical disease in individuals with susceptibility to mycobacterial infections, with the exception of Salmonella which infects less than 50% of these individuals. Clinical outcome severity depends on the degree of impairment of interferon-gamma mediated immunity. Some patients die of overwhelming mycobacterial disease with lepromatous-like lesions in early childhood, whereas others develop, later in life, disseminated but curable infections with tuberculoid granulomas. IMD29 is characterized by undetectable IL12B secretion from leukocytes. Affected individuals generally present with BCG disease after vaccination in childhood, and at least half also have Salmonella infection. Disease phenotype is relatively mild, and patients have a good prognosis. The disease is caused by variants affecting the gene represented in this entry. Psoriasis 11 (PSORS11) [MIM:612599] A common, chronic inflammatory disease of the skin with multifactorial etiology. It is characterized by red, scaly plaques usually found on the scalp, elbows and knees. These lesions are caused by abnormal keratinocyte proliferation and infiltration of inflammatory cells into the dermis and epidermis. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the IL-12B family.

RefSeq proteins (1): NP_002178* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003530	Hematopoietin_rcpt_L_F3_CS	Conserved_site
IPR003598	Ig_sub2	Domain
IPR003961	FN3_dom	Domain
IPR007110	Ig-like_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015528	IL-12_beta	Family
IPR019482	IL-12_beta_cen-dom	Domain
IPR036116	FN3_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050676	IL-12	Family

Pfam: PF10420

UniProt features (45 total): strand 27, disulfide bond 5, glycosylation site 3, sequence variant 2, domain 2, helix 2, signal peptide 1, chain 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
5MJ3	X-RAY DIFFRACTION	1.74
3D85	X-RAY DIFFRACTION	1.9
8CR8	X-RAY DIFFRACTION	2
3DUH	X-RAY DIFFRACTION	2.3
8UUI	X-RAY DIFFRACTION	2.43
1F42	X-RAY DIFFRACTION	2.5
5MXA	X-RAY DIFFRACTION	2.5
4GRW	X-RAY DIFFRACTION	2.55
6UIB	X-RAY DIFFRACTION	2.74
1F45	X-RAY DIFFRACTION	2.8
5MZV	X-RAY DIFFRACTION	2.8
3D87	X-RAY DIFFRACTION	2.9
3HMX	X-RAY DIFFRACTION	3
3QWR	X-RAY DIFFRACTION	3.25
5MJ4	X-RAY DIFFRACTION	3.4
6WDQ	X-RAY DIFFRACTION	3.4
8YI7	ELECTRON MICROSCOPY	3.57
8OE4	ELECTRON MICROSCOPY	3.6
8XRP	ELECTRON MICROSCOPY	3.75
5NJD	X-RAY DIFFRACTION	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P29460-F1	91.12	0.81

Antibody-complex structures (SAbDab): 5 — 3D85, 3HMX, 4GRW, 5MZV, 5NJD

Functional residue map

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

Disulfide bonds (5): 199, 300–327, 50–90, 131–142, 170–193

Glycosylation sites (3): 135, 222, 319

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-6783783	Interleukin-10 signaling
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-9020591	Interleukin-12 signaling
R-HSA-9020933	Interleukin-23 signaling

MSigDB gene sets: 612 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE_TO_ANTIGENIC_STIMULUS, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_NEGATIVE_REGULATION_OF_SMOOTH_MUSCLE_CELL_PROLIFERATION, GOBP_POSITIVE_REGULATION_OF_CELL_FATE_COMMITMENT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE

GO Biological Process (59): regulation of cytokine production (GO:0001817), positive regulation of T cell mediated cytotoxicity (GO:0001916), positive regulation of defense response to virus by host (GO:0002230), natural killer cell activation involved in immune response (GO:0002323), positive regulation of T-helper 1 type immune response (GO:0002827), positive regulation of natural killer cell mediated cytotoxicity directed against tumor cell target (GO:0002860), negative regulation of inflammatory response to antigenic stimulus (GO:0002862), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), response to UV-B (GO:0010224), cell migration (GO:0016477), natural killer cell activation (GO:0030101), negative regulation of interleukin-10 production (GO:0032693), negative regulation of interleukin-17 production (GO:0032700), positive regulation of granulocyte macrophage colony-stimulating factor production (GO:0032725), positive regulation of type II interferon production (GO:0032729), positive regulation of interleukin-10 production (GO:0032733), positive regulation of interleukin-12 production (GO:0032735), positive regulation of interleukin-17 production (GO:0032740), positive regulation of tumor necrosis factor production (GO:0032760), positive regulation of natural killer cell activation (GO:0032816), positive regulation of natural killer cell proliferation (GO:0032819), positive regulation of mononuclear cell proliferation (GO:0032946), positive regulation of tissue remodeling (GO:0034105), positive regulation of smooth muscle cell apoptotic process (GO:0034393), interleukin-12-mediated signaling pathway (GO:0035722), T-helper 1 type immune response (GO:0042088), T-helper cell differentiation (GO:0042093), T cell proliferation (GO:0042098), positive regulation of T cell proliferation (GO:0042102), positive regulation of activated T cell proliferation (GO:0042104), defense response to protozoan (GO:0042832), positive regulation of memory T cell differentiation (GO:0043382), positive regulation of osteoclast differentiation (GO:0045672), positive regulation of cell adhesion (GO:0045785), oocyte development (GO:0048599), negative regulation of smooth muscle cell proliferation (GO:0048662), positive regulation of lymphocyte proliferation (GO:0050671), negative regulation of protein secretion (GO:0050709), positive regulation of inflammatory response (GO:0050729), defense response to Gram-negative bacterium (GO:0050829)

GO Molecular Function (11): cytokine receptor activity (GO:0004896), cytokine activity (GO:0005125), interleukin-12 receptor binding (GO:0005143), interleukin-12 alpha subunit binding (GO:0042164), identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), protein heterodimerization activity (GO:0046982), cytokine receptor binding (GO:0005126), protein binding (GO:0005515), growth factor activity (GO:0008083), interleukin-23 receptor binding (GO:0045519)

GO Cellular Component (11): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), cytosol (GO:0005829), cell surface (GO:0009986), membrane (GO:0016020), late endosome lumen (GO:0031906), interleukin-12 complex (GO:0043514), interleukin-23 complex (GO:0070743), cytoplasm (GO:0005737), endosome lumen (GO:0031904)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by Interleukins	2
Interleukin-12 family signaling	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of cytokine production	5
cellular anatomical structure	5
natural killer cell activation	2
negative regulation of cytokine production	2
interleukin-10 production	2
regulation of interleukin-10 production	2
interleukin-17 production	2
regulation of interleukin-17 production	2
receptor ligand activity	2
cytokine receptor binding	2
binding	2
intracellular organelle lumen	2
extracellular protein-containing complex	2
cytokine production	1
regulation of gene expression	1
regulation of multicellular organismal process	1
positive regulation of leukocyte mediated cytotoxicity	1
T cell mediated cytotoxicity	1
regulation of T cell mediated cytotoxicity	1
positive regulation of T cell mediated immunity	1
regulation of defense response to virus by host	1
lymphocyte activation involved in immune response	1
innate immune response	1
positive regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
regulation of T-helper 1 type immune response	1
T-helper 1 type immune response	1
natural killer cell mediated cytotoxicity directed against tumor cell target	1
positive regulation of natural killer cell mediated immune response to tumor cell	1
regulation of natural killer cell mediated cytotoxicity directed against tumor cell target	1
positive regulation of natural killer cell mediated cytotoxicity	1
inflammatory response to antigenic stimulus	1
regulation of inflammatory response to antigenic stimulus	1
negative regulation of inflammatory response	1
negative regulation of immune response	1
cell surface receptor signaling pathway via STAT	1
response to UV	1
cell motility	1
lymphocyte activation	1
granulocyte macrophage colony-stimulating factor production	1
regulation of granulocyte macrophage colony-stimulating factor production	1

Protein interactions and networks

STRING

782 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL12B	IL12A	P29459	879
IL12B	IL12RB1	P42701	798
IL12B	IL23A	Q9NPF7	650
IL12B	IFNGR2	P38484	632
IL12B	IL12RB2	Q99665	575
IL12B	IFNG	P01579	524
IL12B	IFNGR1	P15260	517
IL12B	TYK2	P29597	513
IL12B	IL10	P22301	507
IL12B	SLC11A1	P49279	506
IL12B	SP110	Q9HB58	497
IL12B	GLRA1	P23415	491
IL12B	IL6	P05231	475
IL12B	TNF	P01375	472
IL12B	IL23R	Q5VWK5	464

IntAct

15 interactions, top by confidence:

A	B	Type	Score
IL23A	IL12B	psi-mi:“MI:0914”(association)	0.810
IL12B	IL23A	psi-mi:“MI:2364”(proximity)	0.810
IL12B	IL23A	psi-mi:“MI:0915”(physical association)	0.810
IL23A	IL12B	psi-mi:“MI:0915”(physical association)	0.810
IL12B	IL23A	psi-mi:“MI:0914”(association)	0.810
IL12B	IL23A	psi-mi:“MI:0407”(direct interaction)	0.810
IL12B	IL12A	psi-mi:“MI:0407”(direct interaction)	0.610
IL12A	IL12B	psi-mi:“MI:0915”(physical association)	0.610
IL12B	IL12B	psi-mi:“MI:0915”(physical association)	0.520
IL12B	Il23a	psi-mi:“MI:0915”(physical association)	0.520
Il23a	IL12B	psi-mi:“MI:0915”(physical association)	0.520
IL12RB1	IL12A	psi-mi:“MI:0915”(physical association)	0.400
BOC	IL12B	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (7): ERP44 (Affinity Capture-Western), IL23A (FRET), IL12B (Affinity Capture-Luminescence), IL12B (Co-crystal Structure), IL12B (Affinity Capture-Western), IL23A (Affinity Capture-Western), IL12B (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0MSX9, A5HJM1, C8AW46, C8AW47, O02671, O02744, O35664, O46561, O70458, O88775, P05710, P14787, P15260, P15261, P16871, P16872, P21995, P29460, P33896, P43432, P46282, P46658, P48095, P48356, P48357, P48551, P68220, P68221, Q08501, Q28234, Q28235, Q28268, Q28938, Q2PE76, Q4W815, Q61727, Q61729, Q62959, Q80XZ4, Q865W9

Diamond homologs: O02744, P29460, P43432, P46282, P46658, P48095, P68220, P68221, Q14213, Q28234, Q28268, Q28938, Q2PE76, Q61729, Q865W9, Q865Y3, Q866G3, Q8CJE6, Q91ZK7, Q924V5, Q9XSQ5, O35228, O88507, P26992, P51641, P70225, Q08406, Q14626, Q5RF19, Q62959, Q64385, Q71DR4, Q99MF4, Q9MYL0

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
STAT1	“up-regulates quantity by expression”	IL12B	“transcriptional regulation”
IL12A	up-regulates	IL12B	binding
IL12B	up-regulates	IL12RB1	binding
IL12B	“form complex”	“Interleukin-23 receptor-ligand complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	6
Uncertain significance	120
Likely benign	88
Benign	13

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
1323111	NM_002187.3(IL12B):c.510C>A (p.Cys170Ter)	Pathogenic
14053	NC_000005.10:g.(159317671_159317673)_(159322312_159322314)del	Pathogenic
14054	NM_002187.3(IL12B):c.320dup (p.Glu108fs)	Pathogenic
183390	NM_002187.3(IL12B):c.298_305del (p.Ser100fs)	Pathogenic
2424368	NC_000005.9:g.(?158753683)(158753790_?)del	Pathogenic
2859768	NM_002187.3(IL12B):c.383_386del (p.Thr127_Phe128insTer)	Pathogenic
2893379	NM_002187.3(IL12B):c.507dup (p.Cys170fs)	Pathogenic
3663107	NM_002187.3(IL12B):c.862dup (p.Arg288fs)	Pathogenic
4734468	NM_002187.3(IL12B):c.130G>T (p.Glu44Ter)	Pathogenic
571326	NM_002187.3(IL12B):c.259C>T (p.Gln87Ter)	Pathogenic
847134	NM_002187.3(IL12B):c.30G>A (p.Trp10Ter)	Pathogenic
970534	NM_002187.3(IL12B):c.900C>A (p.Cys300Ter)	Pathogenic
1366710	NM_002187.3(IL12B):c.697+5G>A	Likely pathogenic
2701815	NM_002187.3(IL12B):c.364+1G>T	Likely pathogenic
3383385	NM_002187.3(IL12B):c.527_528del (p.Ser176fs)	Likely pathogenic
3779762	NM_002187.3(IL12B):c.855+1G>A	Likely pathogenic
4071541	NM_002187.3(IL12B):c.282dup (p.Glu95fs)	Likely pathogenic
4278399	NM_002187.3(IL12B):c.179G>A (p.Trp60Ter)	Likely pathogenic

SpliceAI

797 predictions. Top by Δscore:

Variant	Effect	Δscore
5:159316680:CTCA:C	donor_loss	1.0000
5:159316681:TCAC:T	donor_loss	1.0000
5:159316682:CACC:C	donor_loss	1.0000
5:159316683:A:T	donor_loss	1.0000
5:159316684:CCTAA:C	donor_gain	1.0000
5:159316688:A:C	donor_gain	1.0000
5:159316812:TCTTT:T	acceptor_loss	1.0000
5:159316813:CTTT:C	acceptor_gain	1.0000
5:159316814:TTT:T	acceptor_gain	1.0000
5:159316814:TTTCT:T	acceptor_loss	1.0000
5:159316815:TT:T	acceptor_gain	1.0000
5:159316815:TTCTG:T	acceptor_loss	1.0000
5:159316816:TCTGC:T	acceptor_loss	1.0000
5:159316817:C:CC	acceptor_gain	1.0000
5:159316817:C:G	acceptor_loss	1.0000
5:159316820:C:CT	acceptor_gain	1.0000
5:159318732:TTAC:T	donor_loss	1.0000
5:159318734:ACCT:A	donor_loss	1.0000
5:159318735:C:CG	donor_loss	1.0000
5:159318889:TTTGA:T	acceptor_gain	1.0000
5:159318890:TTGA:T	acceptor_gain	1.0000
5:159318891:TGA:T	acceptor_gain	1.0000
5:159318892:GA:G	acceptor_gain	1.0000
5:159318894:C:CC	acceptor_gain	1.0000
5:159320300:ACTCA:A	donor_loss	1.0000
5:159320302:TCACT:T	donor_loss	1.0000
5:159320303:CA:C	donor_loss	1.0000
5:159320304:A:AC	donor_gain	1.0000
5:159320305:C:CA	donor_gain	1.0000
5:159320305:CTG:C	donor_gain	1.0000

AlphaMissense

2165 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:159318805:C:A	W262C	0.997
5:159318805:C:G	W262C	0.997
5:159318807:A:G	W262R	0.997
5:159318807:A:T	W262R	0.997
5:159318784:G:C	F269L	0.995
5:159318784:G:T	F269L	0.995
5:159318786:A:G	F269L	0.995
5:159318825:A:G	W256R	0.994
5:159318825:A:T	W256R	0.994
5:159322457:A:G	F140S	0.994
5:159322484:C:G	C131S	0.994
5:159322485:A:T	C131S	0.994
5:159318772:G:C	F273L	0.992
5:159318772:G:T	F273L	0.992
5:159318774:A:G	F273L	0.992
5:159322446:A:G	W144R	0.992
5:159322446:A:T	W144R	0.992
5:159316738:C:G	D312H	0.991
5:159322485:A:G	C131R	0.991
5:159322452:A:G	C142R	0.990
5:159322444:C:A	W144C	0.989
5:159322444:C:G	W144C	0.989
5:159320425:C:G	C193S	0.988
5:159320426:A:T	C193S	0.988
5:159322450:G:C	C142W	0.988
5:159322451:C:G	C142S	0.988
5:159322451:C:T	C142Y	0.988
5:159322452:A:T	C142S	0.988
5:159322456:G:C	F140L	0.988
5:159322456:G:T	F140L	0.988

dbSNP variants (sampled 300 via entrez): RS1000180399 (5:159314564 T>A), RS1000261829 (5:159314712 T>C), RS1000314839 (5:159314407 T>C), RS1000355956 (5:159321144 G>C), RS1000480881 (5:159316036 G>A), RS1000512893 (5:159316376 C>T), RS1000829561 (5:159321443 A>T), RS1000885309 (5:159320792 A>T), RS1001089831 (5:159322779 C>A), RS1001555035 (5:159329957 A>G), RS1001586133 (5:159330324 C>T), RS1001920341 (5:159331760 G>T), RS1002203350 (5:159317600 T>C), RS1002289458 (5:159331539 C>A,T), RS1002595031 (5:159330770 G>T)

Disease associations

OMIM: gene MIM:161561 | disease phenotypes: MIM:614890, MIM:600807

GenCC curated gene-disease

Disease	Classification	Inheritance
Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency	Definitive	Autosomal recessive

Mondo (3): Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency (MONDO:0013954), inherited susceptibility to asthma (MONDO:0010940), inherited susceptibility to mycobacterial diseases (MONDO:0019146)

Orphanet (3): Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency (Orphanet:319558), Autosomal recessive mendelian susceptibility to mycobacterial diseases due to a complete deficiency (Orphanet:319535), Mendelian susceptibility to mycobacterial diseases (Orphanet:748)

HPO phenotypes

58 total (30 of 58 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000488	Retinopathy
HP:0000505	Visual impairment
HP:0000822	Hypertension
HP:0001250	Seizure
HP:0001297	Stroke
HP:0001324	Muscle weakness
HP:0001369	Arthritis
HP:0001635	Congestive heart failure
HP:0001644	Dilated cardiomyopathy
HP:0001646	Abnormal aortic valve morphology
HP:0001654	Abnormal heart valve morphology
HP:0001658	Myocardial infarction
HP:0001659	Aortic regurgitation
HP:0001824	Weight loss
HP:0001903	Anemia
HP:0001920	Renal artery stenosis
HP:0001945	Fever
HP:0002039	Anorexia
HP:0002076	Migraine
HP:0002092	Pulmonary arterial hypertension
HP:0002094	Dyspnea
HP:0002105	Hemoptysis
HP:0002167	Abnormal speech pattern
HP:0002315	Headache
HP:0002321	Vertigo
HP:0002326	Transient ischemic attack
HP:0002617	Vascular dilatation
HP:0002633	Vasculitis
HP:0002637	Cerebral ischemia

GWAS associations

50 associations (top):

Study	Trait	p-value
GCST000039_4	Crohn’s disease	9.000000e-06
GCST000207_8	Crohn’s disease	4.000000e-13
GCST000321_1	Psoriasis	3.000000e-26
GCST000322_5	Psoriasis	2.000000e-28
GCST000705_6	Crohn’s disease	7.000000e-08
GCST000833_7	Psoriasis	5.000000e-11
GCST000835_1	Psoriatic arthritis	7.000000e-17
GCST000836_3	Psoriasis	1.000000e-20
GCST000879_30	Crohn’s disease	5.000000e-14
GCST000964_42	Ulcerative colitis	1.000000e-21
GCST001149_3	Ankylosing spondylitis	2.000000e-08
GCST001198_23	Multiple sclerosis	1.000000e-11
GCST001341_14	Multiple sclerosis	7.000000e-07
GCST001341_7	Multiple sclerosis	8.000000e-08
GCST001694_2	Response to taxane treatment (paclitaxel)	9.000000e-06
GCST001725_85	Inflammatory bowel disease	1.000000e-42
GCST002772_3	Leprosy	2.000000e-21
GCST002874_1	Psoriasis	1.000000e-11
GCST002874_11	Psoriasis	5.000000e-10
GCST002874_40	Psoriasis	3.000000e-20
GCST002874_47	Psoriasis	2.000000e-08
GCST002874_5	Psoriasis	2.000000e-30
GCST002874_67	Psoriasis	7.000000e-13
GCST003097_15	Pediatric autoimmune diseases	2.000000e-10
GCST003129_3	Primary biliary cholangitis	1.000000e-10
GCST003268_36	Psoriasis vulgaris	2.000000e-42
GCST003269_7	Cutaneous psoriasis	1.000000e-13
GCST003270_7	Psoriatic arthritis	1.000000e-24
GCST003723_5	Serum sulfate level	3.000000e-06
GCST004131_19	Inflammatory bowel disease	3.000000e-38

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:1001494	psoriasis vulgaris
EFO:0007773	cutaneous psoriasis measurement
EFO:0007864	sulfate measurement
EFO:0801715	interleukin-12 receptor subunit beta-1 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2364153 (PROTEIN COMPLEX), CHEMBL2364154 (PROTEIN COMPLEX), CHEMBL3580484 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2546890	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Psoriasis
rs3213094	Efficacy	3	ustekinumab	Psoriasis

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs6894567	IL12B		0.00	0
rs3213094	IL12B	3	1.75	1	ustekinumab
rs3212217	IL12B		0.00	0
rs3212227	IL12B		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	affects cotreatment, increases expression, affects reaction, decreases reaction, increases secretion (+2 more)	35
nickel sulfate	increases expression, increases reaction, increases secretion, decreases reaction, affects expression	6
SB 203580	decreases reaction, increases expression, affects binding, increases secretion	5
Tretinoin	increases expression, decreases expression, affects binding, affects reaction, decreases secretion (+1 more)	5
lipopolysaccharide, E coli O55-B5	decreases reaction, increases expression, increases secretion, affects binding, affects cotreatment (+2 more)	4
Histamine	increases activity, increases reaction, affects binding, decreases reaction, increases expression (+2 more)	4
apilimod	affects binding, affects cotreatment, decreases reaction, increases secretion, decreases expression	3
Acetylmuramyl-Alanyl-Isoglutamine	increases expression, increases reaction, increases secretion, affects binding, affects cotreatment	3
Poly I-C	increases secretion, decreases reaction, increases expression, increases activity, increases reaction (+2 more)	3
Dinoprostone	affects binding, decreases reaction, increases secretion, increases expression, affects cotreatment	3
4-methylhistamine	affects binding, decreases reaction, increases expression	2
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	increases secretion, increases reaction, affects binding, decreases reaction	2
U 0126	affects binding, increases expression, decreases expression, decreases reaction, increases activity	2
resiquimod	increases reaction, increases secretion, affects binding, affects cotreatment, increases expression	2
BAY 11-7085	decreases reaction, increases secretion	2
Resveratrol	increases expression, increases reaction, increases secretion, affects cotreatment, decreases reaction	2
Alitretinoin	affects binding, decreases reaction, increases secretion, decreases expression	2
Vehicle Emissions	affects reaction, decreases reaction, increases expression, affects binding, affects cotreatment (+1 more)	2
Azathioprine	increases secretion, affects binding, increases expression, decreases reaction	2
Carbamates	increases expression	2
Dexamethasone	increases secretion, increases expression, decreases reaction	2
Estradiol	affects cotreatment, increases expression, affects binding, decreases reaction	2
Ranitidine	increases expression, decreases expression, affects binding, decreases reaction	2
Ribavirin	affects binding, affects cotreatment, increases reaction, increases secretion	2
Tetradecanoylphorbol Acetate	increases secretion, increases expression, decreases reaction	2
Zymosan	increases reaction, increases secretion, affects binding, affects cotreatment, increases expression	2
Famotidine	affects binding, decreases reaction, increases expression	2
Dimaprit	affects binding, decreases reaction, increases expression	2
Particulate Matter	affects reaction, decreases reaction, increases expression, increases secretion	2
ferric oxide	decreases reaction, increases secretion	1

Clinical trials (associated diseases)

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