IL18R1

Summary

IL18R1 (interleukin 18 receptor 1, HGNC:5988) is a protein-coding gene on chromosome 2q12.1, encoding Interleukin-18 receptor 1 (Q13478). Within the IL18 receptor complex, responsible for the binding of the pro-inflammatory cytokine IL18, but not IL1A nor IL1B.

The protein encoded by this gene is a cytokine receptor that belongs to the interleukin 1 receptor family. This receptor specifically binds interleukin 18 (IL18), and is essential for IL18 mediated signal transduction. IFN-alpha and IL12 are reported to induce the expression of this receptor in NK and T cells. This gene along with four other members of the interleukin 1 receptor family, including IL1R2, IL1R1, ILRL2 (IL-1Rrp2), and IL1RL1 (T1/ST2), form a gene cluster on chromosome 2q. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8809 — RefSeq curated summary.

At a glance

• GWAS associations: 70
• Clinical variants (ClinVar): 63 total
• Druggable target: yes
• MANE Select transcript: NM_003855

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5988
Approved symbol	IL18R1
Name	interleukin 18 receptor 1
Location	2q12.1
Locus type	gene with protein product
Status	Approved
Aliases	IL-18R, IL1RRP, IL-1Rrp, CD218a
Ensembl gene	ENSG00000115604
Ensembl biotype	protein_coding
OMIM	604494
Entrez	8809

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 13 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000233957, ENST00000409599, ENST00000410040, ENST00000466357, ENST00000677287, ENST00000866212, ENST00000866213, ENST00000866214, ENST00000866215, ENST00000866216, ENST00000866217, ENST00000866218, ENST00000951164, ENST00000951165, ENST00000951166

RefSeq mRNA: 9 — MANE Select: NM_003855 NM_001282399, NM_001371418, NM_001371419, NM_001371420, NM_001371421, NM_001371422, NM_001371423, NM_001371424, NM_003855

CCDS: CCDS2060

Canonical transcript exons

ENST00000233957 — 11 exons

Exon	Start	End
ENSE00000772456	102371953	102372118
ENSE00000772457	102375907	102376063
ENSE00000772458	102381620	102381682
ENSE00000772459	102384878	102384998
ENSE00000772460	102386861	102387000
ENSE00000772461	102390056	102390217
ENSE00000772462	102394469	102394627
ENSE00000804366	102367825	102368068
ENSE00001578352	102362633	102362718
ENSE00003723430	102396531	102398776
ENSE00003907906	102355796	102356400

Expression profiles

Bgee: expression breadth ubiquitous, 191 present calls, max score 92.23.

FANTOM5 (CAGE): breadth broad, TPM avg 3.6786 / max 155.8302, expressed in 734 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21713	2.4001	72
21726	1.6697	568
21729	0.7931	326
21731	0.7491	149
21728	0.2203	87
21730	0.1748	51
21727	0.0715	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lung	UBERON:0002167	92.23	gold quality
upper lobe of left lung	UBERON:0008952	88.26	gold quality
upper lobe of lung	UBERON:0008948	87.18	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.13	gold quality
blood	UBERON:0000178	83.59	gold quality
granulocyte	CL:0000094	82.74	gold quality
spleen	UBERON:0002106	82.45	gold quality
lung	UBERON:0002048	81.24	gold quality
omental fat pad	UBERON:0010414	79.56	gold quality
peritoneum	UBERON:0002358	79.45	gold quality
small intestine Peyer’s patch	UBERON:0003454	79.10	gold quality
adipose tissue of abdominal region	UBERON:0007808	78.32	gold quality
vermiform appendix	UBERON:0001154	76.84	gold quality
gall bladder	UBERON:0002110	76.71	gold quality
right lobe of liver	UBERON:0001114	76.33	gold quality
small intestine	UBERON:0002108	76.33	gold quality
left uterine tube	UBERON:0001303	76.27	gold quality
calcaneal tendon	UBERON:0003701	76.18	gold quality
lymph node	UBERON:0000029	75.41	gold quality
subcutaneous adipose tissue	UBERON:0002190	74.31	gold quality
body of stomach	UBERON:0001161	74.09	gold quality
seminal vesicle	UBERON:0000998	73.50	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	73.38	gold quality
lower esophagus mucosa	UBERON:0035834	73.31	gold quality
right atrium auricular region	UBERON:0006631	73.12	gold quality
lower esophagus muscularis layer	UBERON:0035833	73.10	gold quality
lower esophagus	UBERON:0013473	73.05	gold quality
transverse colon	UBERON:0001157	72.83	gold quality
lower lobe of lung	UBERON:0008949	72.19	silver quality
adipose tissue	UBERON:0001013	71.96	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-6075	yes	93.32
E-ANND-3	yes	18.64
E-CURD-122	yes	12.01
E-CURD-10	no	359.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, EPAS1, GATA3, HAND1, HAND2, SPI1, STAT5A, STAT6

miRNA regulators (miRDB)

65 targeting IL18R1, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4465	99.71	72.56	2096

Literature-anchored findings (GeneRIF, showing 40)

• Expression of the IL-18 receptor is demonstrated on dendritic cells (DC) in peripheral blood and epidermis; on monocyte-derived DC its expression is up-regulated by interferon-gamma. (PMID:14662834)
• The biologically active IL-8R complex requires the membrane-proximal third immunoglobulin-like domain in IL-18Ralpha for formation of IL-18R ternary complex as well as for signaling involved in IL-18-induced interferon-gamma in natural killer cells. (PMID:14662859)
• IL-1F6, IL-1F8, and IL-1F9 signal through IL-1Rrp2 and IL-1RAcP in Jurkat cells. (PMID:14734551)
• the promoter region of IL-18 receptor has two novel single nucleotide polymorphisms (PMID:15009178)
• Thus, our results identified a functional region in the IL-1R AcP required for the recruitment and activation of PI 3-kinase. (PMID:15044087)
• Transfection of C33A cervical cancer cells with the IL-18 receptor induced IL-18 expression, and enhanced intracellular reactive oxygen species and Fas expression. (PMID:15202785)
• review of structure, function and tissue distribution of IL-18R [review] (PMID:15323361)
• IL-18, IL-18 receptor alpha, and CD48 complex formation via glycosylphosphatidylinositol anchor glycan triggers binding to IL-18 receptor beta, and thereby induces intracellular signal transduction and IFN-gamma production. (PMID:15760905)
• The overexpression of IL-18Ralpha predominantly by CD4+ T cells in sarcoidosis emphasizes crucial roles played by T-helper type 1 cells in the IL-18/IL-18Ralpha system in sarcoidosis (PMID:16236915)
• Two IFN-gammaR2 chains interact through species-specific determinants in their extracellular domains. Finally, these determinants also participate in the interaction of IFN-gammaR2 with IFN-gammaR1. (PMID:16467876)
• our data show that variola virus IL-18BP prevents IL-18 from binding to IL-18R by interacting with three residues that are part of the binding site for hIL-18Ralpha. (PMID:16979683)
• A twofold increase in the percentage of CD4-resting T cells expressing IL-12Rbeta1 and IL-18Ralpha from HIV-1-infected patients; deregulation of the IL-12 and IL-18 pathways may play a role in the immunopathogenesis of HIV-1 infection. (PMID:17403771)
• There is a significant association between polymorphisms of interleukin 18 receptor 1 and asthma. (PMID:18382474)
• study provides suggestive evidence for associations of SNPs in the IL1RL1 gene and adjacently located family members IL18R1 and IL18RAP with asthma and atopy in 2 independent Dutch asthma populations (PMID:18774397)
• Interleukin-18 receptor expression may possibly be responsible for the pathologic process of adenomyosis. (PMID:19394601)
• Our analysis suggests that the variability of IL18R1 genes is unlikely to contribute to modulate the risk of cardiovascular disease (PMID:19473509)
• a role for SOCS1 and -3 in the seemingly paradoxical hyperresponsive state in cells deficient in IL-18Ralpha, supporting the concept that IL-18Ralpha participates in both pro- and anti-inflammatory responses (PMID:19592492)
• These results demonstrate how IL-18 activity is regulated by TNFalpha and TGF-beta1, and how IFNgamma production through regulation of IL-18 receptor and T-bet expression. (PMID:19879772)
• The levels of plasma IL-18 and IL-18R on CD3(+) lymphocytes were significantly increased in active phase immune thrombocytopenia than in remission phase and controls. (PMID:19954659)
• Report increased expression of IL18R1 in multiple sclerosis but did not find evidence of a genetic association with SNPs. (PMID:20354066)
• IL-18 and IL-18Ralpha might upregulate the expression of Th1-cytokines in immune thrombocytopenia patients. (PMID:20627039)
• These data suggest a role for IL-1F family members in psoriasis. (PMID:20833839)
• The soluble IL-18Ralpha complex could be a potentially useful biomarker for the diagnosis of rheumatoid arthritis (PMID:21435242)
• IL18 and IL18R1 genes as plausible genes regulating the humoral immune response to smallpox vaccine in both Caucasians and African Americans. (PMID:21742843)
• IL18 and its receptor may play an important role in the pathogenesis of allergic asthma. (PMID:21965503)
• Genetic variation in the promoter region of IL18, but not IL18R1, may be associated with knee osteoarthritis. (PMID:22136483)
• Data suggest that IL-18RAP and IL-18R1 single-nucleotide polymorphisms identify African-American infants at risk for bronchopulmonary dysplasia. (PMID:22289858)
• Our study reveals the important role of IL12/IL18-mediated transcriptional regulation of IFN-gamma production in leprosy. (PMID:23103228)
• Association between single nucleotide polymorphisms in the IL18R1, IL18 and interferon-gamma genes and smallpox vaccine induced adaptive immunity. (PMID:23901078)
• increased levels of soluble IL-18Ralpha complex in serum may also exert an antagonistic effect in vivo and play an important role in the inflammatory process in allergic asthma. (PMID:23963474)
• results demonstrate clear functional consequences of the rs917997 risk polymorphism; this polymorphism leads to a loss-of-function through decreased IL-18RAP, IL-18R1, and IL-1R1 protein expression, which impairs autocrine IL-18 and IL-1 signaling (PMID:24842757)
• There was no association between the rs917997 in IL18R gene and rs187238 in IL18 gene polymorphisms and risk for non-Hodgkin’s malignant lymphomas in Novosibirsk population. (PMID:24909718)
• IL-18, IL-18BP, and IL-18R may have roles in the pathogenesis of epithelial ovarian carcinoma (PMID:24963217)
• IL-18R downregulates IFN-alpha production by activation-induced splicing of IL-18Ralpha into 2 isoforms: the full-length receptor (IL-18Ralpha1) and a novel, truncated variant (IL-18Ralpha2), a competitive molecular decoy inhibiting canonical IL-18Ralpha1/IL-18Rbeta signaling. (PMID:25170117)
• structural basis for the specific recognition of IL-18 by its alpha receptor (PMID:25261253)
• Human memory IL-18Ralpha and DR3 CD4+ T cells may contribute to antigen-independent innate responses at barrier surfaces. (PMID:25269704)
• PDGFB and IL18R1 represent plausible candidates for studying the pathophysiology of these disorders in the context of TLR4 activation (PMID:25327457)
• polymorphisms in the interleukin 18 receptor 1 gene and tuberculosis susceptibility among Chinese (PMID:25360588)
• The architecture of the IL-18 receptor second domain (D2) is unique among the other IL-1R family members, which presumably distinguishes them from the IL-1 receptors that exhibit a more promiscuous ligand recognition mode. (PMID:25500532)
• IL-37 requires the receptors IL-18Ralpha and IL-1R8 to carry out its multifaceted anti-inflammatory program upon innate signal transduction. (PMID:25729923)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Il18r1	ENSMUSG00000026070
rattus_norvegicus	Il18r1	ENSRNOG00000015027

Paralogs (10): LAG3 (ENSG00000089692), IL1R2 (ENSG00000115590), IL1R1 (ENSG00000115594), IL1RL2 (ENSG00000115598), IL1RL1 (ENSG00000115602), IL18RAP (ENSG00000115607), IL1RAPL1 (ENSG00000169306), SIGIRR (ENSG00000185187), IL1RAPL2 (ENSG00000189108), IL1RAP (ENSG00000196083)

Protein

Protein identifiers

Interleukin-18 receptor 1 — Q13478 (reviewed: Q13478)

Alternative names: CD218 antigen-like family member A, CDw218a, IL1 receptor-related protein, Interleukin-18 receptor alpha

All UniProt accessions (3): Q13478, B7ZKV7, Q86YL8

UniProt curated annotations — full annotation on UniProt →

Function. Within the IL18 receptor complex, responsible for the binding of the pro-inflammatory cytokine IL18, but not IL1A nor IL1B. Involved in IL18-mediated IFNG synthesis from T-helper 1 (Th1) cells. Contributes to IL18-induced cytokine production, either independently of SLC12A3, or as a complex with SLC12A3.

Subunit / interactions. Forms a ternary complex with IL18 and IL18RAP. Within this complex, IL18R1 is involved in ligand-binding and IL18RAP in signaling leading to NF-kappa-B and JNK activation. Interacts with SLC12A3 in peritoneal macrophages; this interaction is increased by IL18 treatment.

Subcellular location. Membrane.

Tissue specificity. Highly expressed in leukocytes, spleen, lung. Also expressed, but at lower levels, in liver, small intestine, colon, prostate, thymus, placenta, and heart. Specifically coexpressed with IL18R1 in Th1 cells.

Post-translational modifications. N-glycosylated. N-linked glycosyl chains contribute to ligand recognition and intra-receptor interactions required for formation of an active ternary receptor complex.

Domain organisation. The TIR domain mediates NAD(+) hydrolase (NADase) activity. Self-association of TIR domains is required for NADase activity.

Induction. Induced by IL12/interleukin-12 in T-cells. Proposed to be a phenotypic marker for T-helper 1 (Th1) cells.

Similarity. Belongs to the interleukin-1 receptor family.

RefSeq proteins (9): NP_001269328, NP_001358347, NP_001358348, NP_001358349, NP_001358350, NP_001358351, NP_001358352, NP_001358353, NP_003846* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000157	TIR_dom	Domain
IPR003599	Ig_sub	Domain
IPR004074	IL-1_rcpt_I/II-typ	Family
IPR007110	Ig-like_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015621	IL-1_rcpt_fam	Family
IPR035897	Toll_tir_struct_dom_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily

Pfam: PF01582

Catalyzed reactions (Rhea), 1 shown:

• NAD(+) + H2O = ADP-D-ribose + nicotinamide + H(+) (RHEA:16301)

UniProt features (61 total): strand 24, glycosylation site 8, disulfide bond 5, sequence variant 5, turn 4, helix 4, domain 4, topological domain 2, signal peptide 1, chain 1, mutagenesis site 1, transmembrane region 1, active site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
4R6U	X-RAY DIFFRACTION	2.8
3WO3	X-RAY DIFFRACTION	3.1
3WO4	X-RAY DIFFRACTION	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13478-F1	79.60	0.40

Functional residue map

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

Catalytic / active sites (1): 455

Disulfide bonds (5): 22–41, 43–81, 119–158, 140–185, 237–298

Glycosylation sites (8): 91, 102, 150, 197, 203, 236, 255, 297

Mutagenesis-validated functional residues (1):

Position	Phenotype
297	decreases the affinity for il18 suggesting that the n-linked glycosylation contributes to ligand recognition.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9008059	Interleukin-37 signaling
R-HSA-9012546	Interleukin-18 signaling

MSigDB gene sets: 412 (showing top): GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, MODULE_255, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, MODULE_545, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION_INVOLVED_IN_IMMUNE_RESPONSE, MODULE_64, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, chr2q12, MODULE_317

GO Biological Process (13): adaptive immune response (GO:0002250), inflammatory response (GO:0006954), immune response (GO:0006955), signal transduction (GO:0007165), natural killer cell activation (GO:0030101), positive regulation of type II interferon production (GO:0032729), interleukin-18-mediated signaling pathway (GO:0035655), T-helper 1 cell differentiation (GO:0045063), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), negative regulation of cold-induced thermogenesis (GO:0120163), positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224), positive regulation of T-helper 1 cell cytokine production (GO:2000556), cytokine-mediated signaling pathway (GO:0019221)

GO Molecular Function (7): interleukin-1 receptor activity (GO:0004908), signaling receptor activity (GO:0038023), interleukin-18 binding (GO:0042007), interleukin-18 receptor activity (GO:0042008), NAD+ nucleosidase activity, cyclic ADP-ribose generating (GO:0061809), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (4): plasma membrane (GO:0005886), cell surface (GO:0009986), interleukin-18 receptor complex (GO:0045092), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Interleukin-1 family signaling	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytokine receptor activity	2
cellular anatomical structure	2
immune response	1
defense response	1
immune system process	1
response to stimulus	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
lymphocyte activation	1
positive regulation of cytokine production	1
type II interferon production	1
regulation of type II interferon production	1
cytokine-mediated signaling pathway	1
cellular response to interleukin-18	1
alpha-beta T cell activation involved in immune response	1
T cell differentiation involved in immune response	1
T-helper 1 type immune response	1
T-helper cell differentiation	1
negative regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
non-canonical NF-kappaB signal transduction	1
regulation of non-canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
positive regulation of T cell cytokine production	1
positive regulation of T-helper 1 type immune response	1
T-helper 1 cell cytokine production	1
regulation of T-helper 1 cell cytokine production	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
interleukin-1 binding	1
molecular transducer activity	1
cytokine binding	1
interleukin-18-mediated signaling pathway	1
interleukin-18 binding	1
hydrolase activity, hydrolyzing N-glycosyl compounds	1
binding	1

Protein interactions and networks

STRING

1752 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL18R1	IL18	Q14116	998
IL18R1	IL37	Q9NZH6	994
IL18R1	IL18RAP	O95256	987
IL18R1	IL1RAP	Q9NPH3	936
IL18R1	IL33	O95760	893
IL18R1	IL18BP	O95998	850
IL18R1	IL1A	P01583	847
IL18R1	SIGIRR	Q6IA17	838
IL18R1	IL1B	P01584	833
IL18R1	IL12RB1	P42701	830
IL18R1	IL1R1	P14778	791
IL18R1	IL12RB2	Q99665	777
IL18R1	CCR6	P51684	740
IL18R1	CCRL2	O00421	739
IL18R1	IL1F10	Q8WWZ1	721

IntAct

7 interactions, top by confidence:

A	B	Type	Score
IL18	IL18R1	psi-mi:“MI:0407”(direct interaction)	0.560
IL18R1	IL18	psi-mi:“MI:0407”(direct interaction)	0.560
IL18R1	VAPB	psi-mi:“MI:0915”(physical association)	0.400
IL18R1	SPTBN1	psi-mi:“MI:0915”(physical association)	0.400
M		psi-mi:“MI:0914”(association)	0.350
	FAM171A2	psi-mi:“MI:0914”(association)	0.350

BioGRID (8): IL18R1 (Proximity Label-MS), IL18R1 (Proximity Label-MS), TNFRSF1A (Positive Genetic), IL1RAP (Reconstituted Complex), IL18R1 (Affinity Capture-MS), IL37 (Reconstituted Complex), IL18R1 (Co-fractionation), SMCHD1 (Co-fractionation)

ESM2 similar proteins: A5D7R1, D3ZF92, F1LW30, O00300, O08712, O08727, O14763, O62802, O70458, O70535, O75509, O77736, O95256, P01590, P20334, P20352, P22934, P25118, P25445, P25446, P26897, P30836, P41690, P42703, P51867, P83626, Q07011, Q13478, Q5M9I1, Q61098, Q63199, Q65Z14, Q6UXZ4, Q6X782, Q6X784, Q6X786, Q764M8, Q8K1S2, Q8K5B1, Q90VY2

Diamond homologs: A2TF48, A5HNF6, A8QMS7, B3SRQ2, B3Y678, B3Y679, B3Y680, B3Y681, B3Y682, B3Y683, B6CJX2, C8BKC7, P22366, Q13478, Q28DJ2, Q4LBC6, Q599T9, Q5FWM2, Q5XJ85, Q61098, Q6Y1S1, Q99836, Q9DF60, Q9R1F8, V5NAL9, B2LT61, B2LT62, B2LT64, B2LT65, B3Y613, B3Y614, B3Y615, B3Y618, B5T267, O00206, O60603, P0DUE1, P10810, P34595, P58727

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
IL18R1	“form complex”	“Interleukin-37 receptor-ligand complex”	binding
IL18	up-regulates	IL18R1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	50
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

3554 predictions. Top by Δscore:

Variant	Effect	Δscore
2:102338321:GTTTA:G	donor_gain	1.0000
2:102338322:TTTA:T	donor_gain	1.0000
2:102340096:A:AG	acceptor_gain	1.0000
2:102340097:G:GG	acceptor_gain	1.0000
2:102342220:A:AG	acceptor_gain	1.0000
2:102342220:AAGAT:A	acceptor_gain	1.0000
2:102342221:A:AG	acceptor_gain	1.0000
2:102342222:G:GG	acceptor_gain	1.0000
2:102342222:GAT:G	acceptor_gain	1.0000
2:102343070:T:TA	acceptor_gain	1.0000
2:102347943:A:AG	acceptor_gain	1.0000
2:102347944:G:GG	acceptor_gain	1.0000
2:102356399:AGGTA:A	donor_loss	1.0000
2:102356401:G:GC	donor_loss	1.0000
2:102362631:A:AG	acceptor_gain	1.0000
2:102362632:G:GG	acceptor_gain	1.0000
2:102337958:GAA:G	donor_gain	0.9900
2:102338114:A:AG	acceptor_gain	0.9900
2:102338115:G:GG	acceptor_gain	0.9900
2:102338322:T:G	donor_gain	0.9900
2:102338326:G:GG	donor_gain	0.9900
2:102338957:A:T	donor_gain	0.9900
2:102340097:GTCCC:G	acceptor_gain	0.9900
2:102340268:TTAAG:T	donor_loss	0.9900
2:102340269:TAAG:T	donor_loss	0.9900
2:102340270:AAG:A	donor_loss	0.9900
2:102340271:AGGTA:A	donor_loss	0.9900
2:102340272:GGT:G	donor_loss	0.9900
2:102340273:G:GA	donor_loss	0.9900
2:102340274:T:G	donor_loss	0.9900

AlphaMissense

3576 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:102386943:T:A	C298S	0.995
2:102386944:G:C	C298S	0.995
2:102384898:T:A	C237S	0.993
2:102384899:G:C	C237S	0.993
2:102384936:G:C	W249C	0.993
2:102384936:G:T	W249C	0.993
2:102386943:T:C	C298R	0.991
2:102386945:C:G	C298W	0.991
2:102384898:T:C	C237R	0.990
2:102368020:T:C	F85S	0.989
2:102384900:C:G	C237W	0.989
2:102375985:T:G	Y183D	0.988
2:102386944:G:A	C298Y	0.987
2:102396570:G:C	R437P	0.986
2:102396576:T:C	L439P	0.985
2:102384899:G:A	C237Y	0.984
2:102396566:A:C	S436R	0.984
2:102396568:C:A	S436R	0.984
2:102396568:C:G	S436R	0.984
2:102384904:G:C	A239P	0.983
2:102394489:T:C	F378L	0.983
2:102394491:T:A	F378L	0.983
2:102394491:T:G	F378L	0.983
2:102375979:G:T	G181W	0.982
2:102386989:T:C	L313S	0.982
2:102394486:G:C	A377P	0.982
2:102386937:T:G	Y296D	0.981
2:102384934:T:A	W249R	0.980
2:102384934:T:C	W249R	0.980
2:102396794:T:C	F512L	0.979

dbSNP variants (sampled 300 via entrez): RS1000117409 (2:102391703 A>AT), RS1000176930 (2:102373713 C>A), RS1000183822 (2:102380176 A>G), RS1000219085 (2:102389787 G>A,T), RS1000257222 (2:102380475 C>A,G,T), RS1000343822 (2:102361114 AT>A,ATT), RS1000344474 (2:102386424 C>A,T), RS1000374432 (2:102379326 C>T), RS1000396214 (2:102361484 G>A,T), RS1000639250 (2:102367148 A>G,T), RS1000721131 (2:102390313 G>C), RS1000773122 (2:102384023 T>C), RS1000825535 (2:102384321 G>T), RS1000862137 (2:102386733 T>C), RS1000986307 (2:102377975 T>A)

Disease associations

OMIM: gene MIM:604494 | disease phenotypes: MIM:109650

GenCC curated gene-disease

Mondo (1): Behcet disease (MONDO:0007191)

Orphanet (1): Behçet disease (Orphanet:117)

HPO phenotypes

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

GWAS associations

70 associations (top):

Study	Trait	p-value
GCST000157_6	Celiac disease	4.000000e-09
GCST000612_30	Celiac disease	1.000000e-15
GCST000804_2	Asthma	3.000000e-09
GCST000879_29	Crohn’s disease	2.000000e-12
GCST001508_6	Asthma	6.000000e-08
GCST001701_1	Asthma	1.000000e-09
GCST001709_2	Atopic dermatitis	8.000000e-18
GCST001725_46	Inflammatory bowel disease	3.000000e-20
GCST002084_2	Allergic sensitization	5.000000e-11
GCST002772_2	Leprosy	2.000000e-23
GCST003097_6	Pediatric autoimmune diseases	9.000000e-08
GCST003129_29	Primary biliary cholangitis	5.000000e-09
GCST003176_2	Asthma	2.000000e-06
GCST003184_33	Atopic dermatitis	2.000000e-13
GCST004131_93	Inflammatory bowel disease	5.000000e-11
GCST004132_63	Crohn’s disease	6.000000e-11
GCST004600_73	Eosinophil percentage of white cells	1.000000e-95
GCST004606_62	Eosinophil count	6.000000e-93
GCST004617_66	Eosinophil percentage of granulocytes	1.000000e-86
GCST004623_160	Neutrophil percentage of granulocytes	5.000000e-70
GCST004624_69	Sum eosinophil basophil counts	7.000000e-76
GCST005038_122	Allergic disease (asthma, hay fever or eczema)	4.000000e-26
GCST005038_44	Allergic disease (asthma, hay fever or eczema)	7.000000e-61
GCST005212_18	Asthma	4.000000e-21
GCST005213_1	Asthma (childhood onset)	5.000000e-13
GCST005537_161	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	3.000000e-17
GCST005851_3	Delirium	1.000000e-08
GCST006052_7	Polymyositis	6.000000e-06
GCST006585_134	Blood protein levels	6.000000e-134
GCST006585_1571	Blood protein levels	9.000000e-75

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0005298	allergic sensitization measurement
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0007996	eosinophil percentage of granulocytes
EFO:0007994	neutrophil percentage of granulocytes
EFO:0005090	basophil count
EFO:0004847	age at onset
EFO:1002011	adult onset asthma
EFO:0009941	Inhalant adrenergic use measurement
EFO:0009942	Glucocorticoid use measurement
EFO:0009958	response to bisphosphonate
EFO:0009960	atypical femoral fracture
EFO:0007990	neutrophil percentage of leukocytes

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D001528	Behcet Syndrome	C07.465.075; C11.941.879.780.880.200; C14.907.940.100; C16.320.382.250; C17.800.827.368.250; C17.800.862.150

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4804253 (PROTEIN COMPLEX)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — Immunoglobulin-like family of IL-1 receptors

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, increases mutagenesis, decreases expression	3
Cyclosporine	increases expression, decreases expression	3
bisphenol A	decreases expression, increases expression, increases methylation	2
(+)-JQ1 compound	decreases expression	2
Lipopolysaccharides	affects cotreatment, increases expression, affects response to substance	2
Nickel	increases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Tretinoin	increases expression	2
pirinixic acid	affects binding, increases activity, increases expression	1
sulforaphane	increases expression	1
zinc chloride	decreases expression, decreases reaction	1
cobaltous chloride	decreases reaction, decreases expression	1
nickel chloride	increases expression	1
tobacco tar	decreases expression	1
benzo(e)pyrene	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
brequinar	increases expression	1
avobenzone	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	increases expression	1
entinostat	increases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
MT19c compound	increases expression	1
Calcimycin	affects cotreatment, increases expression	1
Bortezomib	increases expression	1
Zoledronic Acid	increases expression	1
Norethindrone Acetate	affects cotreatment, increases expression	1
Acetaminophen	decreases expression, affects cotreatment, increases expression	1

Cellosaurus cell lines

3 cell lines: 3 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9H2	Ubigene HEK293 IL18R1 KO	Transformed cell line	Female
CVCL_E6U6	Genomeditech HEK-293 H_IL18 Reporter	Transformed cell line	Female
CVCL_UF33	HEK-Blue IL-18	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05879419	PHASE4	ACTIVE_NOT_RECRUITING	Recombinant Herpes Zoster Vaccine in Patients With Autoimmune Rheumatic Diseases
NCT00995709	PHASE3	COMPLETED	Phase III Study in Refractory Behcet’s Disease
NCT01532570	PHASE3	COMPLETED	Clinical Study of TA-650 in Patients With Behcet’s Disease (BD) With Special Lesions
NCT02307513	PHASE3	COMPLETED	A Phase 3 Randomized, Double-blind Study to Evaluate the Efficacy and Safety of Apremilast (CC-10004) in Subjects With Active Behçet’s Disease
NCT02505568	PHASE3	COMPLETED	A Study to Evaluate Efficacy and Safety of Infliximab in Participant With Moderate-to-Severe Refractory Intestinal Behcet’s Disease
NCT03209219	PHASE3	COMPLETED	Interferon α2a Versus Cyclosporine for Refractory Behçet’s Disease Uveitis
NCT04528082	PHASE3	RECRUITING	Apremilast Pediatric Study in Children With Active Oral Ulcers Associated With Behçet’s Disease
NCT05767047	PHASE3	RECRUITING	A Study of Apremilast in Children With Oral Ulcers Associated With Behçet’s Disease or Juvenile Psoriatic Arthritis
NCT06145893	PHASE3	RECRUITING	A Study of Efficacy and Safety of Hemay005 Tablets in Patients With Behçet’s Disease
NCT06780462	PHASE3	RECRUITING	Randomized Controlled Multicenter Study Comparing Steroid Therapy Plus Anticoagulants to Steroid Therapy Alone in Deep Venous Thrombosis of Behçet’s Syndrome
NCT06925698	PHASE3	NOT_YET_RECRUITING	Immunosuppressive Therapy Alone Versus Plus Oral Anticoagulation in the Treatment of VT Associated With Behcet’s Disease
NCT00001865	PHASE2	COMPLETED	HAT in Eye Complications of Behcet’s Disease
NCT00483184	PHASE2	COMPLETED	Low Dose Interferon Alpha Treatment for Oral Ulcers of Behcet’s Disease
NCT00664599	PHASE2	COMPLETED	Rituximab for the Treatment of Severe Ocular Manifestations of Behcet’s Disease
NCT00700297	PHASE2	COMPLETED	Colchicine Randomized Double-Blind Controlled Crossover Study in Behcet’s Disease
NCT00866359	PHASE2	COMPLETED	A Study to Evaluate the Efficacy and Safety of Apremilast (CC-10004) in the Treatment of Behçet Disease
NCT01693653	PHASE2	TERMINATED	Tocilizumab for the Treatment of Behcet’s Syndrome
NCT02648581	PHASE2	COMPLETED	Efficacy and Safety of Ustekinumab, a Human Monoclonal Anti-IL-12/IL-23 Antibody, in Patients With Behçet Disease
NCT02756650	PHASE2	COMPLETED	1 Year of Treatment With Canakinumab in Behçet’s Disease Patients With Neurologic or Vascular Involvement
NCT03554161	PHASE2	TERMINATED	Tocilizumab for the Treatment of Refractory Behcet’s Uveitis
NCT04186559	PHASE2	UNKNOWN	Topical Pentoxifylline Gel on Behcet’s Disease Genital Ulcers
NCT04218565	PHASE2	TERMINATED	Golimumab for the Treatment of Refractory Behcet’s Uveitis
NCT04609397	PHASE2	TERMINATED	A Study to Evaluate the Efficacy and Safety of Hemay005 in the Treatment of Behçet Disease
NCT06386744	PHASE2	COMPLETED	Dusquetide for the Treatment of Behcet’s Disease
NCT06794008	PHASE2	RECRUITING	BCMA-CD19 CAR-T Therapy for Refractory Autoimmune Diseases
NCT07080346	PHASE2	COMPLETED	Upadacitinib for Refractory Behcet’s Syndrome
NCT00550498	PHASE1	TERMINATED	Stem Cell Transplantation in Ocular Lesions of Behcet’s Disease
NCT06371417	PHASE1	RECRUITING	Phase 1b Trial of RAY121 in Immunological Diseases (RAINBOW Trial)
NCT06723106	PHASE1	ENROLLING_BY_INVITATION	Phase 1b Long-term Extension Trial of RAY121 in Immunological Diseases (RAINBOW-LTE Trial)
NCT02620618	PHASE1/PHASE2	COMPLETED	Intravitreal Infliximab in Refractory Uveitis in Behcet’s Disease: A Safety and Efficacy Clinical Study
NCT00699985	Not specified	COMPLETED	Psychological Symptoms in Patients With Behcet’s Disease by SCL90-R
NCT00931957	Not specified	UNKNOWN	Etanercept: Single Blind Control Study in Ocular Manifestations of Behcet’s Disease
NCT01584778	Not specified	COMPLETED	Behçet’s Disease and Eosinophil Cationic Protein
NCT01720628	Not specified	COMPLETED	The Relationship Between Serum Levels of Angiogenin, bFGF, VEGF and Ocular Involvement in Patients With Behçet’s Disease
NCT01780363	Not specified	COMPLETED	MEVALONATE KINASE GENE MUTATIONS AND THEIR CLINICAL CORRELATIONS IN BEHÇET’S DISEASE
NCT02020200	Not specified	UNKNOWN	The Effect of Methylphenidate on Cognitive Abilities of Adults With Bipolar Disorder
NCT03264391	Not specified	COMPLETED	Evaluation of Macular Vascular Changes in Behcet’s Disease Using Optical Coherence Tomography Angiography
NCT03274648	Not specified	COMPLETED	Dietary Interventions and Butyrate Production in Behçet’s Patients
NCT03514056	Not specified	COMPLETED	Frequency of Fibromyalgia in Behcet Disease
NCT03747354	Not specified	UNKNOWN	Assessment of Disease Activity in Behcet by Complete Blood Count