IL12A

Summary

IL12A (interleukin 12A, HGNC:5969) is a protein-coding gene on chromosome 3q25.33, encoding Interleukin-12 subunit alpha (P29459). Heterodimerizes with IL12B to form the IL-12 cytokine or with EBI3/IL27B to form the IL-35 cytokine.

This gene encodes a subunit of a cytokine that acts on T and natural killer cells, and has a broad array of biological activities. The cytokine is a disulfide-linked heterodimer composed of the 35-kD subunit encoded by this gene, and a 40-kD subunit that is a member of the cytokine receptor family. This cytokine is required for the T-cell-independent induction of interferon (IFN)-gamma, and is important for the differentiation of both Th1 and Th2 cells. The responses of lymphocytes to this cytokine are mediated by the activator of transcription protein STAT4. Nitric oxide synthase 2A (NOS2A/NOS2) is found to be required for the signaling process of this cytokine in innate immunity.

Source: NCBI Gene 3592 — RefSeq curated summary.

At a glance

• GWAS associations: 41
• Clinical variants (ClinVar): 29 total
• Phenotypes (HPO): 124
• Druggable target: yes
• MANE Select transcript: NM_001397992

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5969
Approved symbol	IL12A
Name	interleukin 12A
Location	3q25.33
Locus type	gene with protein product
Status	Approved
Aliases	CLMF, IL-12A, p35, NFSK
Ensembl gene	ENSG00000168811
Ensembl biotype	protein_coding
OMIM	161560
Entrez	3592

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 3 retained_intron

ENST00000305579, ENST00000466512, ENST00000468862, ENST00000480088, ENST00000480787, ENST00000496308, ENST00000699704

RefSeq mRNA: 4 — MANE Select: NM_001397992 NM_000882, NM_001354582, NM_001354583, NM_001397992

CCDS: CCDS3187, CCDS93420

Canonical transcript exons

ENST00000699704 — 7 exons

Exon	Start	End
ENSE00001176433	159993568	159993609
ENSE00001176445	159993451	159993492
ENSE00001940566	159988835	159989174
ENSE00003494892	159993012	159993125
ENSE00003500360	159990167	159990312
ENSE00003555343	159995404	159996019
ENSE00003687587	159993701	159993844

Expression profiles

Bgee: expression breadth ubiquitous, 169 present calls, max score 90.93.

FANTOM5 (CAGE): breadth broad, TPM avg 0.6467 / max 35.9337, expressed in 316 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
39564	0.6467	316

Top tissues by expression

283 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	90.93	gold quality
lower esophagus mucosa	UBERON:0035834	89.24	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.13	gold quality
right uterine tube	UBERON:0001302	77.16	gold quality
esophagus mucosa	UBERON:0002469	73.46	gold quality
ventricular zone	UBERON:0003053	70.43	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	67.75	gold quality
esophagus	UBERON:0001043	66.33	gold quality
upper lobe of left lung	UBERON:0008952	66.02	gold quality
spleen	UBERON:0002106	65.14	gold quality
granulocyte	CL:0000094	64.82	gold quality
stromal cell of endometrium	CL:0002255	64.52	gold quality
upper lobe of lung	UBERON:0008948	64.40	gold quality
amygdala	UBERON:0001876	63.82	gold quality
bronchial epithelial cell	CL:0002328	63.74	silver quality
esophagus squamous epithelium	UBERON:0006920	63.17	silver quality
cingulate cortex	UBERON:0003027	62.37	gold quality
lymph node	UBERON:0000029	62.28	gold quality
anterior cingulate cortex	UBERON:0009835	62.19	gold quality
epithelium of esophagus	UBERON:0001976	62.11	silver quality
epithelium of bronchus	UBERON:0002031	61.74	silver quality
monocyte	CL:0000576	61.70	gold quality
bone marrow cell	CL:0002092	61.60	silver quality
leukocyte	CL:0000738	61.58	gold quality
mononuclear cell	CL:0000842	61.54	gold quality
vermiform appendix	UBERON:0001154	61.41	gold quality
muscle layer of sigmoid colon	UBERON:0035805	61.31	gold quality
putamen	UBERON:0001874	61.20	gold quality
prefrontal cortex	UBERON:0000451	61.01	gold quality
bronchus	UBERON:0002185	60.98	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.03

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
IFNG	Unknown

Upstream regulators (CollecTRI, top): AR, EGR1, ELF1, FOS, FOXC1, HAND2, HES5, HSF2, IRF1, IRF3, IRF4, IRF5, IRF6, IRF7, IRF8, IRF9, JUN, MAF, NFKB1, NFKB2, NFKB, REL, RELA, RNF112, SP1, STAT1, STAT2, STAT3, TP63, TXK, ZHX2

miRNA regulators (miRDB)

34 targeting IL12A, 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-9-5P	100.00	72.28	2361
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-21-5P	99.46	70.54	1035
HSA-MIR-150-3P	99.43	70.51	920
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-410-3P	99.27	69.98	2457
HSA-MIR-590-5P	99.25	70.76	930
HSA-MIR-3973	99.20	69.19	1990
HSA-MIR-670-3P	99.03	68.88	2404
HSA-MIR-520G-3P	98.91	67.38	1914
HSA-MIR-520H	98.91	67.38	1914
HSA-MIR-513B-3P	98.76	68.12	1577
HSA-MIR-3691-5P	98.62	65.88	552
HSA-MIR-4766-3P	98.48	67.94	1347
HSA-MIR-5088-3P	98.29	66.63	1310
HSA-MIR-10226	98.25	66.50	811
HSA-MIR-4257	97.86	68.05	1190
HSA-MIR-96-3P	97.47	68.03	839
HSA-MIR-5579-3P	97.00	68.81	1111
HSA-MIR-6886-3P	96.96	66.36	844

Literature-anchored findings (GeneRIF, showing 40)

• 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)
• Leishmania priming of human dendritic cells for CD40 ligand-induced interleukin-12p35 secretion is strain and species dependent (PMID:12117904)
• possible role of IL-12 and tissue antioxidants in development and progression of chronic sinusitis (PMID:12270766)
• an alternate mRNA isoform of the human interleukin-12 p35 gene differing from normal p35 transcripts by the deletion of exon 3 is identified (PMID:12358856)
• IL-12 induces expression of the perforin gene in NK cells which is directly regulated by STAT4 (PMID:12372421)
• that p35 gene was intact in SLE patients. IL-12 expression in PMN of SLE patients was less prominent than that of the normal controls. (PMID:12472178)
• results demonstrate that interleukin-12(p35) gene activation in the course of dendritic cell maturation involves selective remodeling of a single positioned nucleosome within the promoter containing critical Sp1-binding sites (PMID:12576336)
• 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)
• Renal immune complex deposition can occur in absence of IL-12p35, but structural renal damage requires presence of IL-12p35 or mediators induced by this molecule, such as IFN-gamma. (PMID:12911539)
• IL-12 can enhance the expression of ICAM-1 in the presence of IFN-gamma and, with IL-18, enhances natural killer anti-tumor activity (PMID:14660053)
• IL-12(p35) transcriptional repression in neonatal dendritic cells takes place at the chromatin level. (PMID:15051764)
• IL12 does not activate STAT4 signaling in human vascular endothelial cells (PMID:15087447)
• 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)
• interleukin-12 p35 gene transcription is activated by interferon regulatory factor-1 and interferon consensus sequence-binding protein (PMID:15489234)
• TSLP is a major regulatory cytokine for CD40 ligand-induced IL-12 production by DCs, and TSLP-activated DCs could promote the persistence of Th2 inflammation even in the presence of IL-12-inducing signals (PMID:15741223)
• iC3b interferes with monocyte-derived dendritic cell differentiation and IL-12 and IL-10 production is mediated via an ERK MAPK-dependent mechanism (PMID:15810889)
• IL12A gene polymorphisms may affect the final steps of gastric carcinogenesis in H pylori infected subjects. (PMID:15937086)
• novel anti-inflammatory property of recombinant HBsAg which involves inhibition of interleukin 12. (PMID:15963597)
• This review summarizes information on the expression and role of IL-12 both in patients with Crohn’s diease and experimental models of colitis, thus emphasizing differences between IL-12 and IL-23 activity on the development of intestinal inflammation. (PMID:17007011)
• Our results suggest that IL-12 and IL-18 contribute to the establishment of Th1 polarization seen in FMF and play a part in its pathogenesis. (PMID:17225924)
• Interferon-gamma and bacterial lipopolysaccharide act synergistically on human neutrophils enhancing interleukin-8, interleukin-1beta, tumor necrosis factor-alpha, and interleukin-12 p70 secretion and phagocytosis via upregulation of toll-like receptor 4 (PMID:17304101)
• The positive expressions of IL-12 and IL-18 can play an important role in progression and metastasis of gastric cancer, and IL-12 might be an independent factor of poor prognosis in gastric carcinoma. (PMID:17461482)
• The levels of IFN-gamma, IL-12 and TRAIL in synovium fluid from the patients with RA are higher than those in healthy donors. This result indicates that the pattern of cytokine on course of RA is main of Th1, more typical in synovium fluid than in serum. (PMID:17553352)
• mRNA levels of IL12 subunit p35 in active SLE patients was significantly higher compared with those in the inactive SLE patients (PMID:17564777)
• Engagement of gC1qR on dendritic cells by hepatitis C virus core protein limits the induction of Th1 responses by inhibiting TLR-induced IL-12 production and may contribute to viral persistence. (PMID:17881511)
• Our data suggest that the intestinal microvasculature is responsive to ligands of TLR3 expressed on intestinal endothelial cells, thereby adding to the regulation of adaptive immunity and leukocyte recruitment. (PMID:17947455)
• In primary Sjogren’s syndrome, infiltration of the salivary gland by macrophages and dendritic cells and expression of IL-18 and IL-12 play active roles in infiltrative injuries and have a correlation with predictors of lymphoma development. (PMID:18050195)
• Single nucleotide polymorphisms and haplotype of interleukin-12A are not associated with hepatitis B virus persistence and development of hepatocellular carcinoma. (PMID:18159163)
• an increased expression of IL-12 p40, IL-12 p35 and IL-23 p19 mRNA was observed in bone marrow mononuclear cells and peripheral blood mononuclear cells of patients with aplastic anemia compared with the corresponding one in normal controls. (PMID:18190588)
• The expression of GATA-3 was negatively correlated to the expression of IL-12 in patients with allergic rhinitis. (PMID:18260379)
• probiotic S. thermophilus and Leuconostoc strains are more potent inducers of Th1 type cytokines IL-12 and IFN-gamma than the probiotic Lactobacillus strains (PMID:18300344)
• TAP1 and TAP2 expression restores both antigen presentation and immunogenicity in A375 melanoma cells and concomitantly increases IL-12 and IFN-gamma production in tumor antigen-specific cytotoxic T lymphocytes. (PMID:18385764)
• These observations suggest that lower measles-specific T-cell immune responses elicited by measles vaccine in infants may be due to diminished levels of IL-12 and IL-15. (PMID:18419254)
• anti-CD3/CD28 enhances vaccine efficacy by limiting the regulatory T cell response and promoting expansion of activated effector cells (PMID:18566447)
• The gene expression of IL-12 p35 was significantly higher in periodontitis compared with gingivitis. (PMID:18588867)
• study demonstrates that oxidative stress induced by soluble cigarette smoke components potently inhibits the production of IL-12 and IL-23 by maturing dendritic cells (PMID:18606709)
• IL-12 promotes disease development in acute inflammatory demyelinating polyradiculoneuropathy. (PMID:18717726)
• The elevation of IL-10 and the significant correlation between IL-10 and IL-12, a proinflammatory cytokine, may suggest that immunological disturbances and neuroprotective mechanisms are involved in patients with PD. (PMID:18976327)
• These findings suggest that IL12A rs568408 and IL12B rs3212227 may individually and jointly contribute to the risk of cervical cancer and may modify cervical cancer risk associated with parity. (PMID:19118071)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	il12a	ENSDARG00000038878
danio_rerio	zmp:0000001127	ENSDARG00000067814
mus_musculus	Il12a	ENSMUSG00000027776
rattus_norvegicus	Il12a	ENSRNOG00000009468

Protein

Protein identifiers

Interleukin-12 subunit alpha — P29459 (reviewed: P29459)

Alternative names: Cytotoxic lymphocyte maturation factor 35 kDa subunit, IL-12 subunit p35, NK cell stimulatory factor chain 1

All UniProt accessions (4): P29459, E7ENE1, E9PGR3, O60595

UniProt curated annotations — full annotation on UniProt →

Function. Heterodimerizes with IL12B to form the IL-12 cytokine or with EBI3/IL27B to form the IL-35 cytokine. IL-12 is primarily produced by professional antigen-presenting cells (APCs) such as B-cells and dendritic cells (DCs) as well as macrophages and granulocytes and regulates T-cell and natural killer-cell responses, induces the production of interferon-gamma (IFN-gamma), favors the differentiation of T-helper 1 (Th1) cells and is an important link between innate resistance and adaptive immunity. Mechanistically, exerts its biological effects through a receptor composed of IL12R1 and IL12R2 subunits. Binding to the receptor results in the rapid tyrosine phosphorylation of a number of cellular substrates including the JAK family kinases TYK2 and JAK2. In turn, recruited STAT4 gets phosphorylated and translocates to the nucleus where it regulates cytokine/growth factor responsive genes. As part of IL-35, plays essential roles in maintaining the immune homeostasis of the liver microenvironment and also functions as an immune-suppressive cytokine. Mediates biological events through unconventional receptors composed of IL12RB2 and gp130/IL6ST heterodimers or homodimers. Signaling requires the transcription factors STAT1 and STAT4, which form a unique heterodimer that binds to distinct DNA sites.

Subunit / interactions. Heterodimer with IL12B; disulfide-linked. This heterodimer is known as interleukin IL-12. Heterodimer with EBI3/IL27B; not disulfide-linked. This heterodimer is known as interleukin IL-35. Interacts with NBR1; this interaction promotes IL-12 secretion.

Subcellular location. Secreted.

Induction. (Microbial infection) By pathogenic organisms, including Gram- positive and Gram-negative bacteria, parasites, viruses, and fungi. Down-regulated in response to enterovirus 71 (EV71) infection.

Similarity. Belongs to the IL-6 superfamily.

RefSeq proteins (4): NP_000873, NP_001341511, NP_001341512, NP_001384921* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004281	IL-12_alpha	Family
IPR009079	4_helix_cytokine-like_core	Homologous_superfamily
IPR050676	IL-12	Family

Pfam: PF03039

UniProt features (19 total): helix 7, disulfide bond 4, turn 2, glycosylation site 2, signal peptide 1, chain 1, strand 1, sequence conflict 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
1F45	X-RAY DIFFRACTION	2.8
3HMX	X-RAY DIFFRACTION	3
8YI7	ELECTRON MICROSCOPY	3.57
8XRP	ELECTRON MICROSCOPY	3.75

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P29459-F1	79.65	0.48

Antibody-complex structures (SAbDab): 1 — 3HMX

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 (4): 37–110, 64–196, 85–123, 96

Glycosylation sites (2): 93, 107

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-8984722	Interleukin-35 Signalling
R-HSA-9020591	Interleukin-12 signaling

MSigDB gene sets: 671 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, 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_CELLULAR_RESPONSE_TO_VIRUS, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_DENDRITIC_CELL_MIGRATION, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_NEGATIVE_REGULATION_OF_SMOOTH_MUSCLE_CELL_PROLIFERATION, GOBP_CELL_CHEMOTAXIS, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM

GO Biological Process (28): positive regulation of T cell mediated cytotoxicity (GO:0001916), positive regulation of natural killer cell mediated cytotoxicity directed against tumor cell target (GO:0002860), immune response (GO:0006955), response to virus (GO:0009615), response to UV-B (GO:0010224), cell migration (GO:0016477), response to lipopolysaccharide (GO:0032496), negative regulation of interleukin-17 production (GO:0032700), positive regulation of type II interferon production (GO:0032729), positive regulation of natural killer cell activation (GO:0032816), positive regulation of mononuclear cell proliferation (GO:0032946), positive regulation of smooth muscle cell apoptotic process (GO:0034393), interleukin-12-mediated signaling pathway (GO:0035722), positive regulation of tyrosine phosphorylation of STAT protein (GO:0042531), positive regulation of cell adhesion (GO:0045785), positive regulation of natural killer cell mediated cytotoxicity (GO:0045954), negative regulation of smooth muscle cell proliferation (GO:0048662), positive regulation of lymphocyte proliferation (GO:0050671), negative regulation of protein secretion (GO:0050709), defense response to Gram-positive bacterium (GO:0050830), positive regulation of NK T cell activation (GO:0051135), extrinsic apoptotic signaling pathway (GO:0097191), cellular response to virus (GO:0098586), negative regulation of vascular endothelial growth factor signaling pathway (GO:1900747), negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis (GO:1903588), positive regulation of dendritic cell chemotaxis (GO:2000510), signal transduction (GO:0007165), T-helper 1 cell differentiation (GO:0045063)

GO Molecular Function (7): cytokine activity (GO:0005125), interleukin-12 receptor binding (GO:0005143), growth factor activity (GO:0008083), interleukin-12 beta subunit binding (GO:0042163), interleukin-27 binding (GO:0045513), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), late endosome lumen (GO:0031906), interleukin-12 complex (GO:0043514)

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 leukocyte mediated cytotoxicity	2
positive regulation of lymphocyte activation	2
receptor ligand activity	2
T cell mediated cytotoxicity	1
regulation of T cell mediated cytotoxicity	1
positive regulation of T cell mediated immunity	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
immune system process	1
response to stimulus	1
response to other organism	1
response to UV	1
cell motility	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
negative regulation of cytokine production	1
interleukin-17 production	1
regulation of interleukin-17 production	1
positive regulation of cytokine production	1
type II interferon production	1
regulation of type II interferon production	1
natural killer cell activation	1
regulation of natural killer cell activation	1
mononuclear cell proliferation	1
regulation of mononuclear cell proliferation	1
positive regulation of leukocyte proliferation	1
positive regulation of muscle cell apoptotic process	1
smooth muscle cell apoptotic process	1
regulation of smooth muscle cell apoptotic process	1
cytokine-mediated signaling pathway	1
cellular response to interleukin-12	1
tyrosine phosphorylation of STAT protein	1
regulation of tyrosine phosphorylation of STAT protein	1
positive regulation of peptidyl-tyrosine phosphorylation	1
cell adhesion	1
regulation of cell adhesion	1
positive regulation of cellular process	1

Protein interactions and networks

STRING

408 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL12A	IL12B	P29460	879
IL12A	EBI3	Q14213	785
IL12A	GLRA1	P23415	637
IL12A	IL12RB2	Q99665	590
IL12A	CRLF1	O75462	461
IL12A	EGR1	P18146	422
IL12A	FGF1	P05230	412
IL12A	IL12RB1	P42701	406
IL12A	IL23A	Q9NPF7	396
IL12A	IFNG	P01579	386
IL12A	EEF1D	P29692	377
IL12A	LEPR	P48357	376
IL12A	IL27	Q8NEV9	365
IL12A	IL10	P22301	363
IL12A	SERPINF1	P36955	362

IntAct

9 interactions, top by confidence:

A	B	Type	Score
ETFB	ETFA	psi-mi:“MI:0914”(association)	0.810
IL12B	IL12A	psi-mi:“MI:0407”(direct interaction)	0.610
IL12A	IL12B	psi-mi:“MI:0915”(physical association)	0.610
IL12A	EBI3	psi-mi:“MI:0915”(physical association)	0.400
IL12RB1	IL12A	psi-mi:“MI:0915”(physical association)	0.400
IL12A	RAB3B	psi-mi:“MI:0914”(association)	0.350
IL12A	ACTA2	psi-mi:“MI:0914”(association)	0.350
IL12A	PTX3	psi-mi:“MI:0914”(association)	0.350

BioGRID (15): SPDL1 (Affinity Capture-MS), F11R (Affinity Capture-MS), FSTL1 (Affinity Capture-MS), COL14A1 (Affinity Capture-MS), RAB3B (Affinity Capture-MS), IL12A (Negative Genetic), PIK3CG (Negative Genetic), IL12B (Co-crystal Structure), ACTA2 (Affinity Capture-MS), SPDL1 (Affinity Capture-MS), F11R (Affinity Capture-MS), COL14A1 (Affinity Capture-MS), FSTL1 (Affinity Capture-MS), S100P (Reconstituted Complex), S100A6 (Reconstituted Complex)

ESM2 similar proteins: A0S0B0, A3FBE9, O02743, O02814, O73847, P01241, P05231, P08505, P0DML2, P20607, P26893, P29455, P29459, P33093, P41323, P41683, P43431, P46650, P46661, P48091, P51494, P54349, P58756, P79341, Q07370, Q14406, Q25BC2, Q28233, Q28267, Q28319, Q28819, Q29053, Q2PE77, Q2XNF5, Q5I6E3, Q61728, Q6JV22, Q865W7, Q865X0, Q865X6

Diamond homologs: O02743, O02814, P29459, P43431, P46661, P48091, P54349, Q28233, Q28267, Q29053, Q2PE77, Q61728, Q865X0, Q865Y2, Q91ZK6, Q9R103, Q9TU27, Q9XSQ6

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
STAT1	“up-regulates quantity by expression”	IL12A	“transcriptional regulation”
IL12A	“up-regulates quantity by expression”	IFNG	“transcriptional regulation”
IL12A	up-regulates	T_cell_activation
IL12A	up-regulates	IL12B	binding
IL12A	“up-regulates activity”	STAT4	binding
IL12A	up-regulates	IL12RB2	binding
IL12A	up-regulates	IL12RB1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	23
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

703 predictions. Top by Δscore:

Variant	Effect	Δscore
3:159989024:A:T	donor_gain	1.0000
3:159989170:GCGCA:G	donor_gain	1.0000
3:159989175:G:GG	donor_gain	1.0000
3:159990164:CAGG:C	acceptor_loss	1.0000
3:159990165:A:AG	acceptor_gain	1.0000
3:159990165:AGGC:A	acceptor_loss	1.0000
3:159990166:G:GG	acceptor_gain	1.0000
3:159990309:GAAG:G	donor_gain	1.0000
3:159990313:G:GC	donor_loss	1.0000
3:159990314:T:G	donor_loss	1.0000
3:159993007:TATA:T	acceptor_loss	1.0000
3:159993009:TA:T	acceptor_loss	1.0000
3:159993010:A:AG	acceptor_gain	1.0000
3:159993010:AGGCC:A	acceptor_loss	1.0000
3:159993011:G:GA	acceptor_loss	1.0000
3:159993011:G:GG	acceptor_gain	1.0000
3:159993011:GGCC:G	acceptor_gain	1.0000
3:159993011:GGCCA:G	acceptor_gain	1.0000
3:159993121:CCAAG:C	donor_loss	1.0000
3:159993122:CAAG:C	donor_loss	1.0000
3:159993123:AAGGT:A	donor_loss	1.0000
3:159993124:AGGTA:A	donor_loss	1.0000
3:159993125:GGTAT:G	donor_loss	1.0000
3:159993126:GTATA:G	donor_loss	1.0000
3:159993127:T:A	donor_loss	1.0000
3:159993564:CTAGA:C	acceptor_loss	1.0000
3:159993566:A:AG	acceptor_gain	1.0000
3:159993566:AG:A	acceptor_loss	1.0000
3:159993566:AGAAT:A	acceptor_gain	1.0000
3:159993567:G:GC	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000958892 (3:159990720 C>A,G), RS1001624071 (3:159993827 A>G), RS1001822079 (3:159987432 A>G), RS1001878676 (3:159993209 C>T), RS1002010084 (3:159987842 C>T), RS1002169681 (3:159987601 G>C), RS1003245783 (3:159991584 G>A), RS1003263596 (3:159996030 T>G), RS1003421753 (3:159989088 C>A,T), RS1003904665 (3:159988870 G>A,C), RS1004049571 (3:159991483 A>G,T), RS1004110317 (3:159992110 A>G), RS1004479128 (3:159988779 A>G), RS1004518070 (3:159989688 C>A,T), RS1005225612 (3:159989369 G>T)

Disease associations

OMIM: gene MIM:161560 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

124 total (30 of 124 shown, HPO-id order):

HPO	Term
HP:0000031	Epididymitis
HP:0000083	Renal insufficiency
HP:0000099	Glomerulonephritis
HP:0000155	Oral ulcer
HP:0000488	Retinopathy
HP:0000518	Cataract
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000708	Atypical behavior
HP:0000737	Irritability
HP:0000820	Abnormality of the thyroid gland
HP:0000939	Osteoporosis
HP:0000952	Jaundice
HP:0000953	Hyperpigmentation of the skin
HP:0000989	Pruritus
HP:0001061	Acne
HP:0001097	Keratoconjunctivitis sicca
HP:0001114	Xanthelasma
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001262	Excessive daytime somnolence
HP:0001269	Hemiparesis
HP:0001278	Orthostatic hypotension
HP:0001287	Meningitis
HP:0001288	Gait disturbance
HP:0001289	Confusion
HP:0001347	Hyperreflexia
HP:0001369	Arthritis
HP:0001394	Cirrhosis
HP:0001395	Hepatic fibrosis

GWAS associations

41 associations (top):

Study	Trait	p-value
GCST000157_2	Celiac disease	1.000000e-09
GCST000408_1	Primary biliary cholangitis	2.000000e-14
GCST000424_4	Multiple sclerosis	6.000000e-06
GCST000612_33	Celiac disease	4.000000e-28
GCST000733_5	Primary biliary cholangitis	8.000000e-12
GCST001010_9	Primary biliary cholangitis	2.000000e-16
GCST001198_46	Multiple sclerosis	7.000000e-06
GCST001804_4	Behcet’s disease	6.000000e-07
GCST001850_13	Major depressive disorder	1.000000e-06
GCST002824_1	Behcet’s disease	1.000000e-10
GCST003129_8	Primary biliary cholangitis	1.000000e-23
GCST003155_46	Systemic lupus erythematosus	2.000000e-09
GCST003156_24	Systemic lupus erythematosus	6.000000e-11
GCST003622_73	Systemic lupus erythematosus	1.000000e-06
GCST004145_2	Primary biliary cholangitis	1.000000e-06
GCST004302_8	Primary biliary cholangitis	2.000000e-11
GCST004878_8	Sjögren’s syndrome	1.000000e-10
GCST005523_17	Celiac disease	1.000000e-08
GCST005523_18	Celiac disease	8.000000e-08
GCST005523_41	Celiac disease	3.000000e-27
GCST005531_113	Multiple sclerosis	1.000000e-18
GCST005531_91	Multiple sclerosis	5.000000e-07
GCST005533_2	Limited cutaneous systemic scleroderma	2.000000e-11
GCST005534_12	Systemic sclerosis	9.000000e-06
GCST005534_2	Systemic sclerosis	1.000000e-11
GCST005534_9	Systemic sclerosis	2.000000e-08
GCST005581_1	Primary biliary cirrhosis	3.000000e-11
GCST005581_26	Primary biliary cirrhosis	3.000000e-35
GCST005581_27	Primary biliary cirrhosis	5.000000e-06
GCST005581_28	Primary biliary cirrhosis	5.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004267	biliary liver cirrhosis
EFO:1001017	limited scleroderma

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2364153 (PROTEIN COMPLEX)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs568408	Toxicity	3	mycophenolate mofetil	Kidney Transplantation

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs568408	IL12A	3	3.00	1	mycophenolate mofetil

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	affects binding, decreases reaction, increases secretion, increases expression, affects cotreatment (+2 more)	21
Histamine	increases expression, affects reaction, decreases expression, increases activity, increases reaction (+2 more)	4
(+)-JQ1 compound	decreases expression	3
Tretinoin	decreases secretion, decreases reaction, decreases expression, affects binding, affects reaction	3
manganese chloride	affects binding, increases expression, increases reaction	2
4-methylhistamine	affects binding, decreases reaction, increases expression	2
SB 203580	affects binding, decreases reaction, increases secretion, increases expression	2
U 0126	decreases expression, decreases reaction, increases activity, affects binding, increases expression	2
resiquimod	affects cotreatment, increases expression, affects binding, increases reaction, increases secretion	2
lipopolysaccharide, E coli O55-B5	affects binding, increases secretion, affects cotreatment, decreases reaction, increases expression	2
CL 075	decreases reaction, increases expression, affects binding, affects cotreatment, increases secretion	2
Resveratrol	increases secretion, decreases reaction, increases expression, affects cotreatment, increases reaction	2
Alitretinoin	decreases reaction, increases secretion, decreases expression, affects binding	2
Acetylmuramyl-Alanyl-Isoglutamine	affects binding, increases reaction, affects cotreatment, increases expression	2
Carbamates	increases expression	2
Cisplatin	increases expression	2
Estradiol	affects cotreatment, affects binding, decreases reaction, increases expression	2
Oxygen	decreases reaction, increases expression	2
Poly I-C	decreases reaction, increases expression, affects binding, affects cotreatment, increases secretion (+1 more)	2
Ranitidine	affects binding, decreases reaction, increases expression, decreases expression	2
Famotidine	increases expression, affects binding, decreases reaction	2
Cyclosporine	increases expression	2
Aflatoxin B1	affects expression, increases expression	2
Dimaprit	affects binding, decreases reaction, increases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
Esketamine	decreases expression	1
TL8-506	increases reaction, increases secretion, affects cotreatment, increases expression, affects binding	1
helenalin	increases secretion, affects binding, decreases reaction	1
triptolide	decreases reaction, increases expression, affects binding, affects cotreatment	1

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8I6	Abcam HCT 116 IL12A KO	Cancer cell line	Male
CVCL_B8X8	Abcam MCF-7 IL12A KO	Cancer cell line	Female
CVCL_B9KF	Abcam A-549 IL12A KO	Cancer cell line	Male
CVCL_D7S0	Ubigene A-549 IL12A KO	Cancer cell line	Male
CVCL_D8N1	Ubigene HCT 116 IL12A KO	Cancer cell line	Male
CVCL_D9GZ	Ubigene HEK293 IL12A KO	Transformed cell line	Female

Clinical trials (associated diseases)

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