IL36G

Summary

IL36G (interleukin 36 gamma, HGNC:15741) is a protein-coding gene on chromosome 2q14.1, encoding Interleukin-36 gamma (Q9NZH8). Cytokine that binds to and signals through the IL1RL2/IL-36R receptor which in turn activates NF-kappa-B and MAPK signaling pathways in target cells.

The protein encoded by this gene is a member of the interleukin 1 cytokine family. The activity of this cytokine is mediated by interleukin 1 receptor-like 2 (IL1RL2/IL1R-rp2), and is specifically inhibited by interleukin 1 family, member 5 (IL1F5/IL-1 delta). Interferon-gamma, tumor necrosis factor-alpha and interleukin 1, beta (IL1B) are reported to stimulate the expression of this cytokine in keratinocytes. The expression of this cytokine in keratinocytes can also be induced by a contact hypersensitivity reaction or herpes simplex virus infection. This gene and eight other interleukin 1 family genes form a cytokine gene cluster on chromosome 2.

Source: NCBI Gene 56300 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 33 total
• Druggable target: yes
• MANE Select transcript: NM_019618

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15741
Approved symbol	IL36G
Name	interleukin 36 gamma
Location	2q14.1
Locus type	gene with protein product
Status	Approved
Aliases	IL-1H1, IL-1RP2, IL-1F9, IL1H1, IL1E
Ensembl gene	ENSG00000136688
Ensembl biotype	protein_coding
OMIM	605542
Entrez	56300

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000259205, ENST00000376489, ENST00000447128

RefSeq mRNA: 2 — MANE Select: NM_019618 NM_001278568, NM_019618

CCDS: CCDS2108, CCDS62992

Canonical transcript exons

ENST00000259205 — 5 exons

Exon	Start	End
ENSE00000856859	112978620	112978693
ENSE00000856860	112979221	112979325
ENSE00000856861	112980009	112980148
ENSE00000856862	112984840	112985658
ENSE00001000626	112978006	112978078

Expression profiles

Bgee: expression breadth ubiquitous, 124 present calls, max score 96.68.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.0101 / max 181.8755, expressed in 89 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
22073	1.0101	89

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
periodontal ligament	UBERON:0008266	96.68	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	94.66	gold quality
gingiva	UBERON:0001828	89.84	gold quality
gingival epithelium	UBERON:0001949	89.51	gold quality
skin of leg	UBERON:0001511	86.42	gold quality
cartilage tissue	UBERON:0002418	85.68	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.72	gold quality
skin of abdomen	UBERON:0001416	82.01	gold quality
zone of skin	UBERON:0000014	81.95	gold quality
squamous epithelium	UBERON:0006914	77.14	gold quality
esophagus squamous epithelium	UBERON:0006920	76.36	gold quality
penis	UBERON:0000989	75.53	gold quality
tongue squamous epithelium	UBERON:0006919	74.20	gold quality
body of tongue	UBERON:0011876	73.80	gold quality
epithelium of esophagus	UBERON:0001976	72.29	gold quality
upper leg skin	UBERON:0004262	71.55	gold quality
esophagus mucosa	UBERON:0002469	70.34	gold quality
amniotic fluid	UBERON:0000173	70.10	gold quality
buccal mucosa cell	CL:0002336	69.26	gold quality
tongue	UBERON:0001723	66.81	gold quality
tonsil	UBERON:0002372	66.17	gold quality
mammalian vulva	UBERON:0000997	65.16	gold quality
ventricular zone	UBERON:0003053	63.15	gold quality
oral cavity	UBERON:0000167	63.14	gold quality
pancreatic ductal cell	CL:0002079	62.99	silver quality
superior surface of tongue	UBERON:0007371	61.90	gold quality
skin of hip	UBERON:0001554	59.63	gold quality
nasal cavity epithelium	UBERON:0005384	59.00	silver quality
cervix epithelium	UBERON:0004801	58.77	silver quality
decidua	UBERON:0002450	56.55	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.93

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFE2L2

miRNA regulators (miRDB)

51 targeting IL36G, 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-4795-3P	100.00	74.62	4024
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-425-5P	99.59	67.67	900
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-6083	99.47	68.73	2393
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-155-5P	99.35	70.16	1509
HSA-MIR-6088	99.29	68.45	1284
HSA-MIR-196A-3P	99.19	67.34	1204
HSA-MIR-4528	99.18	69.77	1936

Literature-anchored findings (GeneRIF, showing 40)

• IL-1F6 and IL-1F8, in addition to IL-1F9, activate the pathway leading to NF-kappaB in an IL-1Rrp2-dependent manner in Jurkat cells (PMID:14734551)
• This is the first report of IL-1 genotype association with the inflammation of skeletal muscle following acute resistance exercise that may potentially affect the adaptations to chronic resistance exercise. (PMID:15331687)
• This report demonstrates expression of IL1F9 by bronchial epithelial cells induced by pro-inflammatory stimuli, suggesting a function of this molecule in airway inflammation. (PMID:15701729)
• Regulation and function of the IL-1 family cytokine IL-1F9 in human bronchial epithelial cells. (PMID:20870894)
• Expression of IL-1F9 is increased in human plaque psoriasis skin and is overexpressed in a transgenic mouse psoriasis model. (PMID:21242515)
• Interleukin-36 (IL-36) ligands require processing for full agonist (IL-36alpha, IL-36beta, and IL-36gamma) or antagonist (IL-36Ra) activity (PMID:21965679)
• This is the first report of extracellular release of endogenous IL-36gamma through pyroptosis suggesting a function of IL-36gamma as an alarmin. (PMID:22318382)
• Data presented herein shed further light on involvement of T-bet in innate immunity and suggest that IL-36gamma, besides IFNgamma, may contribute to functions of this transcription factor in immunopathology. (PMID:23095752)
• IL-36 promotes myeloid cell infiltration, activation, and inflammatory activity in skin (PMID:24829417)
• Decreased Langerhans cell responses to IL36G: altered innate immunity in patients with recurrent respiratory papillomatosis (PMID:24950037)
• CAMP induces IL-36gamma expression leading to initiation of skin inflammation and occasional exacerbations of psoriasis. (PMID:25305315)
• IL-36gamma is a valuable biomarker in psoriasis patients, both for diagnostic purposes and measurement of disease activity during the clinical course (PMID:25525775)
• IL36G was identified as strong regulators of skin pathology in both lesional and non-lesional skin samples. (PMID:25897967)
• IL-36gamma expression inversely correlated with the progression of human melanoma and lung cancer. (PMID:26321222)
• Study shows that plasma concentrations of IL-36alpha and IL-36gamma are overexpressed in active systemic lupus erythematosus patients and that IL-36alpha has a substantial pro-inflammatory effect through regulation of IL-6 and CXCL8 production. (PMID:26516833)
• IL-36gamma is significantly more strongly expressed in the epidermis of patients with psoriasis-based erythroderma than in other inflammatory skin diseases. (PMID:26524325)
• Findings indicate that Interleukin (IL)-1beta-induced interleukin 36 gamma (IL-36gamma) expression is mediated by the activation of transcriptional factors, NF-kappaB p65 and AP-1 (c-jun). (PMID:26562662)
• IRF6 is likely to promote inflammation to P. gingivalis through its regulation of IL-36gamma. (PMID:26819203)
• Autocrine and Paracrine Regulation of Keratinocyte Proliferation through a Novel Nrf2-IL-36gamma Pathway (PMID:27183581)
• Here the authors show that Mycobacterium tuberculosis infection of macrophages induces IL-36gamma production in a 2-stage-regulated fashion. (PMID:27389350)
• IL-36gamma-stimulated endothelial cells secrete the proinflammatory chemokines IL-8, CCL2 and CCL20. (PMID:27673278)
• IL-36gamma, a member of the IL-1 superfamily, is involved in host defense and contributes to proinflammatory responses and development of inflammatory diseases. (PMID:27853811)
• enhanced expression of IL-36gamma was observed in plasma and bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome because of bacterial pneumonia (PMID:28176791)
• Cathepsin S was identified as the major IL-36gamma-activating protease expressed in epithelial cells. (PMID:28289191)
• skin injury increases IL-36gamma via the activation of TLR3-SLUG-VDR axis and IL-36gamma induces REG3A to promote wound healing (PMID:28774595)
• With a focus on the skin as a target for microbial and viral invasion, the current knowledge of IL-36: IL-36alpha, IL-36beta and IL-36gamma, functions is reviewed. One physiological function of the IL-36smay be to counteract microbial immune evasion. [Review] (PMID:28811383)
• IL-36-mediated IL-6 and CXCL8 production in human lung fibroblasts and bronchial epithelial cells may be involved in pulmonary inflammation especially caused by bacterial or viral infections. (PMID:28869889)
• IL-36gamma inhibits differentiation and induces inflammation of keratinocyte via Wnt signaling pathway in psoriasis. (PMID:28924372)
• Increased production and activation of IL-36gamma may act on neutrophils and further exaggerate neutrophilic inflammation in CRS. (PMID:29274415)
• this study not only advances our understanding of how IL-36 cytokines may control mucosal inflammation, but also establishes EGFR signaling as a potentially important modulator of IL-36 cytokine function (PMID:29474749)
• serum IL-36gamma levels were higher in active systemic lupus erythematosus patients and correlated with disease activity and arthritis (PMID:29571080)
• The results presented here confirm that IL-36gamma is a robust, specific, and reliable biomarker for psoriatic inflammation that outperforms previously reported biomarkers and is likely to withstand all challenges in real-life primary and secondary dermatologic care. (PMID:29782895)
• The expression of IL-36gamma by oral epithelial cells in response to P. gingivalis might enable the subsequent autocrine stimulation of PGLYRP2 expression. Our data identify how IL-36gamma may promote oral mucosal homeostasis by regulating PGLYRP2 expression. (PMID:29914927)
• data indicate that IL-36gamma may participate as a key player in host defense mechanisms against invading pathogens in the female reproductive tract. (PMID:30118914)
• Interleukin 36 gamma (IL-36gamma) is detected in the immune and vascular compartments in the tumor microenvironment. (PMID:30315348)
• IL-36gamma secretion by monocytes/macrophages and keratinocytes in response to culprit drug exposure likely plays a key role in the pathogenesis of AGEP. (PMID:30395846)
• IL-17A synergistically enhances TLR3-mediated IL-36gamma production by keratinocytes (PMID:30614571)
• Polymorphisms in IL36G gene are associated with plaque psoriasis. IL36G has previously demonstrated markedly increased levels in plaque psoriasis patients and is linked to IL-23/IL-17 axis critical in psoriasis pathology. (PMID:30634937)
• High expression of IL-36gamma exaggerates eosinophilic inflammation in allergic rhinitis by promoting the survival, adhesion, and activation of eosinophils. (PMID:30831444)
• IL-36gamma regulates mediators of tissue homeostasis in epithelial cells. (PMID:30856602)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	il1fma	ENSDARG00000089383
danio_rerio	il1b	ENSDARG00000098700
mus_musculus	Il36g	ENSMUSG00000044103
rattus_norvegicus	Il36g	ENSRNOG00000005701

Paralogs (7): IL1B (ENSG00000125538), IL37 (ENSG00000125571), IL1RN (ENSG00000136689), IL36A (ENSG00000136694), IL36RN (ENSG00000136695), IL36B (ENSG00000136696), IL1F10 (ENSG00000136697)

Protein

Protein identifiers

Interleukin-36 gamma — Q9NZH8 (reviewed: Q9NZH8)

Alternative names: IL-1-related protein 2, Interleukin-1 epsilon, Interleukin-1 family member 9, Interleukin-1 homolog 1

All UniProt accessions (2): Q9NZH8, C9J681

UniProt curated annotations — full annotation on UniProt →

Function. Cytokine that binds to and signals through the IL1RL2/IL-36R receptor which in turn activates NF-kappa-B and MAPK signaling pathways in target cells. Part of the IL-36 signaling system that is thought to be present in epithelial barriers and to take part in local inflammatory response; similar to the IL-1 system with which it shares the coreceptor IL1RAP. Seems to be involved in skin inflammatory response by acting on keratinocytes, dendritic cells and indirectly on T-cells to drive tissue infiltration, cell maturation and cell proliferation. In cultured keratinocytes induces the expression of macrophage, T-cell, and neutrophil chemokines, such as CCL3, CCL4, CCL5, CCL2, CCL17, CCL22, CL20, CCL5, CCL2, CCL17, CCL22, CXCL8, CCL20 and CXCL1; also stimulates its own expression and that of the prototypic cutaneous pro-inflammatory parameters TNF, S100A7/psoriasin and inducible NOS. May play a role in pro-inflammatory responses during particular neutrophilic airway inflammation: activates mitogen-activated protein kinases and NF-kappa B in primary lung fibroblasts, and stimulates the expression of IL-8 and CXCL3 and Th17 chemokine CCL20 in lung fibroblasts. May be involved in the innate immune response to fungal pathogens, such as Aspergillus fumigatus.

Subunit / interactions. Interacts with cargo receptor TMED10; the interaction mediates the translocation from the cytoplasm into the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) and thereby secretion.

Subcellular location. Cytoplasm. Secreted.

Tissue specificity. Highly expressed in tissues containing epithelial cells: skin, lung, stomach and esophagus. Expressed in bronchial epithelial. In skin is expressed only in keratinocytes but not in fibroblasts, endothelial cells or melanocytes. Up-regulated in lesional psoriasis skin. Expressed in monocyte-derived dendritic cells and M1 macrophages.

Post-translational modifications. N-terminal truncation leads to a dramatic enhancement of its activity (>1000-fold). Proteolytically cleaved by cathepsin CTSG.

Induction. By TNF and by IFNG/IFN-gamma in keratinocytes. By Aspergillus fumigatus conidia in peripheral blood mnonocytes; involves CLEC7A and SYK.

Similarity. Belongs to the IL-1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NZH8-1	1	yes
Q9NZH8-2	2

RefSeq proteins (2): NP_001265497, NP_062564* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000975	IL-1_fam	Family
IPR003297	IL-1RA/IL-36	Family
IPR008996	IL1/FGF	Homologous_superfamily

Pfam: PF00340

UniProt features (25 total): strand 15, helix 5, propeptide 1, chain 1, turn 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
4P0L	X-RAY DIFFRACTION	1.55
4P0K	X-RAY DIFFRACTION	1.7
4IZE	X-RAY DIFFRACTION	2
6P9E	X-RAY DIFFRACTION	2
4P0J	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZH8-F1	91.25	0.84

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9014826	Interleukin-36 pathway

MSigDB gene sets: 174 (showing top): REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, ONDER_CDH1_TARGETS_3_DN, GOBP_CELL_CELL_SIGNALING, MARTINEZ_RB1_TARGETS_UP, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_PRODUCTION_OF_MOLECULAR_MEDIATOR_INVOLVED_IN_INFLAMMATORY_RESPONSE, GOBP_CYTOKINE_PRODUCTION, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_RESPONSE_TO_LIPID

GO Biological Process (7): inflammatory response (GO:0006954), immune response (GO:0006955), cell-cell signaling (GO:0007267), cytokine-mediated signaling pathway (GO:0019221), innate immune response (GO:0045087), cellular response to lipopolysaccharide (GO:0071222), immune system process (GO:0002376)

GO Molecular Function (2): cytokine activity (GO:0005125), interleukin-1 receptor binding (GO:0005149)

GO Cellular Component (6): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleoplasm (GO:0005654), cytosol (GO:0005829), plasma membrane (GO:0005886), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Interleukin-1 family signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
defense response	1
immune system process	1
response to stimulus	1
cell communication	1
signaling	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
immune response	1
defense response to symbiont	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
biological_process	1
receptor ligand activity	1
cytokine receptor binding	1
growth factor receptor binding	1
nuclear lumen	1
cytoplasm	1
membrane	1
cell periphery	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

946 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL36G	IL1RL2	Q9HB29	805
IL36G	IL1B	P01584	794
IL36G	IL1A	P01583	717
IL36G	CCL27	Q9Y4X3	586
IL36G	IL6	P05231	567
IL36G	IL1R2	P27930	563
IL36G	IL33	O95760	562
IL36G	NFKBIZ	Q9BYH8	560
IL36G	S100A7	P31151	527
IL36G	IL1R1	P14778	506
IL36G	CCL20	P78556	505
IL36G	S100A7A	Q86SG5	495
IL36G	TNF	P01375	492
IL36G	IL1RL1	Q01638	489
IL36G	CSF3	P09919	482

IntAct

43 interactions, top by confidence:

A	B	Type	Score
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
KIR3DS1	PPL	psi-mi:“MI:0914”(association)	0.530
MYL2	MYL5	psi-mi:“MI:0914”(association)	0.530
SSBP2	CLEC18A	psi-mi:“MI:0914”(association)	0.530
VHL	IL36G	psi-mi:“MI:0915”(physical association)	0.400
ATG16L1		psi-mi:“MI:0914”(association)	0.350
KLHL11	PIPSL	psi-mi:“MI:0914”(association)	0.350
STX17	A2ML1	psi-mi:“MI:0914”(association)	0.350
OR2A4	A2ML1	psi-mi:“MI:0914”(association)	0.350
PPP2R2B	A2ML1	psi-mi:“MI:0914”(association)	0.350
CDK15	A2ML1	psi-mi:“MI:0914”(association)	0.350
GABPA	A2ML1	psi-mi:“MI:0914”(association)	0.350
ZNF154	A2ML1	psi-mi:“MI:0914”(association)	0.350
IL36G	GOT1	psi-mi:“MI:0914”(association)	0.350
CCR1	UBA6	psi-mi:“MI:0914”(association)	0.350
SSUH2	IGLC7	psi-mi:“MI:0914”(association)	0.350
RNF115	IGLC7	psi-mi:“MI:0914”(association)	0.350
CERS3	IGLC7	psi-mi:“MI:0914”(association)	0.350
PIGT	A2ML1	psi-mi:“MI:0914”(association)	0.350
C18orf21	A2ML1	psi-mi:“MI:0914”(association)	0.350
PINK1	A2ML1	psi-mi:“MI:0914”(association)	0.350
APTX	A2ML1	psi-mi:“MI:0914”(association)	0.350
NUDT3	A2ML1	psi-mi:“MI:0914”(association)	0.350
AGPAT1	A2ML1	psi-mi:“MI:0914”(association)	0.350
PHF11	A2ML1	psi-mi:“MI:0914”(association)	0.350
SARAF	A2ML1	psi-mi:“MI:0914”(association)	0.350
MOGAT3	A2ML1	psi-mi:“MI:0914”(association)	0.350
MBNL1	A2ML1	psi-mi:“MI:0914”(association)	0.350
SCGB1D1	IGLL5	psi-mi:“MI:0914”(association)	0.350
ZC3HC1	SULT2B1	psi-mi:“MI:0914”(association)	0.350

BioGRID (46): IL36G (Affinity Capture-MS), IL36G (Affinity Capture-MS), IL36G (Affinity Capture-MS), IL36G (Affinity Capture-MS), IL36G (Affinity Capture-MS), IL36G (Affinity Capture-MS), IL36G (Affinity Capture-MS), IL36G (Affinity Capture-MS), IL36G (Affinity Capture-MS), GOT1 (Affinity Capture-MS), IL36G (Affinity Capture-MS), IL36G (Affinity Capture-MS), IL36G (Affinity Capture-MS), IL36G (Affinity Capture-MS), IL36G (Affinity Capture-MS)

ESM2 similar proteins: B0LPN4, E9PZQ0, E9Q401, F1LMY4, O14926, O18728, O95834, P10767, P11403, P11716, P16960, P21658, P21817, P30957, P47823, P55075, P85845, Q13144, Q16658, Q24498, Q24524, Q32M02, Q3U7R1, Q4R4H3, Q5CZL1, Q5E9M9, Q5XGM5, Q61553, Q64350, Q6P6T4, Q6P9Z4, Q6PFQ7, Q6SZW1, Q7TNG5, Q7TSA0, Q7Z6L1, Q8CHW4, Q8IXI1, Q8JZN7, Q8K2J0

Diamond homologs: A4UYK8, O18999, P01584, P09428, P10749, P14628, P18510, P21621, P25085, P25086, P26889, P26890, P41687, P46648, P48090, P51493, P51745, P79162, P79182, Q28292, Q28386, Q29056, Q2HZH0, Q2MH07, Q63264, Q6PUD2, Q6R2X3, Q865X8, Q866R8, Q8WNR2, Q9BEH0, Q9D6Z6, Q9NZH8, Q9WVG1, Q9XS77, Q9YGD3, Q9GMZ4, O77482, Q8R459, Q8WWZ1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	28
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

478 predictions. Top by Δscore:

Variant	Effect	Δscore
2:112978694:G:GG	donor_gain	1.0000
2:112978728:GCT:G	donor_gain	1.0000
2:112978762:G:GT	donor_gain	1.0000
2:112979219:A:AG	acceptor_gain	1.0000
2:112979220:G:GG	acceptor_gain	1.0000
2:112979220:GT:G	acceptor_gain	1.0000
2:112979220:GTGT:G	acceptor_gain	1.0000
2:112980007:A:AG	acceptor_gain	1.0000
2:112980008:G:GG	acceptor_gain	1.0000
2:112980008:GTC:G	acceptor_gain	1.0000
2:112980008:GTCA:G	acceptor_gain	1.0000
2:112980146:AAAG:A	donor_loss	1.0000
2:112980147:AAGTG:A	donor_loss	1.0000
2:112980148:AGTG:A	donor_loss	1.0000
2:112980149:G:GG	donor_gain	1.0000
2:112980149:GTG:G	donor_loss	1.0000
2:112980150:T:G	donor_loss	1.0000
2:112980151:G:GC	donor_loss	1.0000
2:112980152:A:AT	donor_loss	1.0000
2:112980157:C:G	donor_gain	1.0000
2:112984833:A:AG	acceptor_gain	1.0000
2:112984835:TTCAG:T	acceptor_loss	1.0000
2:112978673:G:GT	donor_gain	0.9900
2:112979208:A:AG	acceptor_gain	0.9900
2:112979209:T:G	acceptor_gain	0.9900
2:112979213:A:AG	acceptor_gain	0.9900
2:112979214:A:G	acceptor_gain	0.9900
2:112980004:TACA:T	acceptor_loss	0.9900
2:112980005:ACAG:A	acceptor_loss	0.9900
2:112980006:CAGT:C	acceptor_loss	0.9900

AlphaMissense

1095 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:112985026:T:C	F163L	0.987
2:112985028:T:A	F163L	0.987
2:112985028:T:G	F163L	0.987
2:112984954:T:C	F139L	0.986
2:112984956:C:A	F139L	0.986
2:112984956:C:G	F139L	0.986
2:112979268:T:A	W35R	0.985
2:112979268:T:C	W35R	0.985
2:112984921:T:C	S128P	0.980
2:112984888:T:C	F117L	0.979
2:112984890:C:A	F117L	0.979
2:112984890:C:G	F117L	0.979
2:112984894:T:C	F119L	0.979
2:112984896:C:A	F119L	0.979
2:112984896:C:G	F119L	0.979
2:112984895:T:C	F119S	0.976
2:112984942:T:C	F135L	0.972
2:112984944:C:A	F135L	0.972
2:112984944:C:G	F135L	0.972
2:112980138:T:C	L97S	0.966
2:112984932:G:C	E131D	0.965
2:112984932:G:T	E131D	0.965
2:112980074:T:G	Y76D	0.959
2:112979252:T:A	D29E	0.954
2:112979252:T:G	D29E	0.954
2:112980105:T:C	L86S	0.953
2:112984895:T:G	F119C	0.950
2:112985027:T:G	F163C	0.950
2:112980015:T:A	V56D	0.946
2:112980029:T:C	C61R	0.946

dbSNP variants (sampled 300 via entrez): RS1000261689 (2:112976410 C>T), RS1001042152 (2:112984070 C>T), RS1001075833 (2:112977800 C>T), RS1001094081 (2:112984411 T>C), RS1001375568 (2:112985617 T>C), RS1001423877 (2:112977361 AC>A), RS1001549044 (2:112978079 G>A,C), RS1001576548 (2:112982709 C>T), RS1001801875 (2:112976107 C>T), RS1001856171 (2:112980837 A>C,G), RS1001999674 (2:112978425 A>G), RS1002284513 (2:112979685 C>A), RS1003526316 (2:112979334 T>A,G), RS1003866513 (2:112981416 C>T), RS1003903329 (2:112981923 G>C)

Disease associations

OMIM: gene MIM:605542 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90011898_66	Alanine aminotransferase levels	6.000000e-09

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291561 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.17	Kd	67.6	nM	CHEMBL5288469

PubChem BioAssay actives

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

Compound	Assay	Type	Value	Unit
(2S)-2-[4-(3-amino-4-methylphenyl)-6-methylpyrimidin-2-yl]oxy-3-methoxy-3,3-diphenylpropanoic acid	1924941: Inhibition of IL-36 gamma (unknown origin) assessed as dissociation constant by ITC assay	kd	0.0676	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	decreases reaction, increases expression, affects expression, affects reaction, affects response to substance (+1 more)	4
Particulate Matter	decreases expression, increases expression, affects expression, increases abundance	4
sodium arsenite	increases expression	3
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Plant Extracts	affects expression, affects reaction, affects cotreatment, decreases expression	2
Silicon Dioxide	increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Glupearl 19S	increases expression	1
TL8-506	affects cotreatment, increases expression	1
alpha phellandrene	decreases expression	1
deoxynivalenol	increases expression	1
sodium arsenate	increases abundance, decreases expression	1
hydroquinone	increases expression	1
vanadyl sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
pentanal	decreases expression	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	increases expression	1
lipopolysaccharide, E. coli O26-B6	increases expression	1
abrine	increases expression	1
brevetoxin 2	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Zoledronic Acid	increases expression	1
Air Pollutants	increases abundance, decreases expression	1
Arsenic	decreases expression, increases abundance	1
Vehicle Emissions	affects expression, increases abundance	1
Demecolcine	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Malathion	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5228025	Binding	Inhibition of IL-36 gamma (unknown origin) assessed as dissociation constant by ITC assay	Small molecule approaches to treat autoimmune and inflammatory diseases (Part III): Targeting cytokines and cytokine receptor complexes. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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