IL1RL1

Summary

IL1RL1 (interleukin 1 receptor like 1, HGNC:5998) is a protein-coding gene on chromosome 2q12.1, encoding Interleukin-1 receptor-like 1 (Q01638). Receptor for interleukin-33 (IL-33) which plays crucial roles in innate and adaptive immunity, contributing to tissue homeostasis and responses to environmental stresses together with coreceptor IL1RAP.

The protein encoded by this gene is a member of the interleukin 1 receptor family. Studies of the similar gene in mouse suggested that this receptor can be induced by proinflammatory stimuli, and may be involved in the function of helper T cells. This gene, interleukin 1 receptor, type I (IL1R1), interleukin 1 receptor, type II (IL1R2) and interleukin 1 receptor-like 2 (IL1RL2) form a cytokine receptor gene cluster in a region mapped to chromosome 2q12. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 9173 — RefSeq curated summary.

At a glance

• GWAS associations: 65
• Clinical variants (ClinVar): 118 total
• Druggable target: yes
• MANE Select transcript: NM_016232

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5998
Approved symbol	IL1RL1
Name	interleukin 1 receptor like 1
Location	2q12.1
Locus type	gene with protein product
Status	Approved
Aliases	ST2, FIT-1, ST2L, ST2V, DER4, T1, IL33R
Ensembl gene	ENSG00000115602
Ensembl biotype	protein_coding
OMIM	601203
Entrez	9173

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 7 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000233954, ENST00000311734, ENST00000404917, ENST00000409584, ENST00000427077, ENST00000447231, ENST00000463990, ENST00000473175, ENST00000482701, ENST00000908526, ENST00000908527

RefSeq mRNA: 3 — MANE Select: NM_016232 NM_001282408, NM_003856, NM_016232

CCDS: CCDS2057, CCDS2058, CCDS74548

Canonical transcript exons

ENST00000233954 — 11 exons

Exon	Start	End
ENSE00000487403	102340666	102340828
ENSE00000772452	102347945	102348091
ENSE00000772453	102349079	102349246
ENSE00000804364	102351536	102352037
ENSE00001359423	102343270	102343415
ENSE00003520286	102338837	102339047
ENSE00003620706	102340098	102340272
ENSE00003646387	102343036	102343177
ENSE00003655459	102338116	102338325
ENSE00003684499	102342223	102342294
ENSE00003889741	102311563	102311623

Expression profiles

Bgee: expression breadth ubiquitous, 197 present calls, max score 96.86.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.4001 / max 1942.9657, expressed in 72 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21714	5.0110	108
21721	3.2914	292
21713	2.4001	72
21723	0.2588	98
21722	0.1847	74
21720	0.0623	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper lobe of left lung	UBERON:0008952	96.86	gold quality
upper lobe of lung	UBERON:0008948	96.80	gold quality
decidua	UBERON:0002450	96.64	gold quality
right lung	UBERON:0002167	95.70	gold quality
cartilage tissue	UBERON:0002418	90.66	gold quality
lower lobe of lung	UBERON:0008949	90.32	gold quality
left adrenal gland	UBERON:0001234	90.21	gold quality
left adrenal gland cortex	UBERON:0035825	89.94	gold quality
lung	UBERON:0002048	87.82	gold quality
adrenal cortex	UBERON:0001235	87.73	gold quality
right adrenal gland	UBERON:0001233	87.41	gold quality
adrenal gland	UBERON:0002369	86.76	gold quality
adult mammalian kidney	UBERON:0000082	86.59	gold quality
placenta	UBERON:0001987	85.92	gold quality
body of stomach	UBERON:0001161	85.68	gold quality
metanephros cortex	UBERON:0010533	84.85	gold quality
omental fat pad	UBERON:0010414	84.14	gold quality
peritoneum	UBERON:0002358	84.10	gold quality
metanephric glomerulus	UBERON:0004736	84.09	gold quality
gall bladder	UBERON:0002110	83.86	gold quality
right adrenal gland cortex	UBERON:0035827	83.64	gold quality
adipose tissue of abdominal region	UBERON:0007808	82.70	gold quality
right atrium auricular region	UBERON:0006631	82.63	gold quality
renal glomerulus	UBERON:0000074	82.31	gold quality
choroid plexus epithelium	UBERON:0003911	82.21	gold quality
cortex of kidney	UBERON:0001225	81.92	gold quality
stomach	UBERON:0000945	80.99	gold quality
cardiac atrium	UBERON:0002081	80.69	gold quality
kidney	UBERON:0002113	80.36	gold quality
sperm	CL:0000019	80.28	gold quality

Single-cell (SCXA)

Detected in 18 experiment(s), a significant marker in 18.

Experiment	Marker?	Max mean expression
E-HCAD-23	yes	4855.12
E-MTAB-6308	yes	3018.54
E-HCAD-29	yes	2536.08
E-MTAB-9801	yes	1321.30
E-MTAB-6678	yes	1308.84
E-GEOD-130473	yes	1025.15
E-CURD-88	yes	45.57
E-HCAD-1	yes	31.19
E-MTAB-8142	yes	18.10
E-CURD-112	yes	17.82
E-MTAB-9067	yes	17.57
E-MTAB-8410	yes	14.22
E-CURD-122	yes	13.65
E-CURD-46	yes	13.45
E-HCAD-10	yes	11.99

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, AR, GATA1, GATA2, GATA3, HAND2, HES1, SPI1

miRNA regulators (miRDB)

10 targeting IL1RL1, 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-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-6858-3P	96.37	64.41	771
HSA-MIR-4268	94.45	64.09	819

Literature-anchored findings (GeneRIF, showing 40)

• T1/ST2 is the first member of the IL-1 receptor superfamily so far studied that is apparently unable to activate NF-kappaB (PMID:12368275)
• the results suggest that the expression of ST2 suppressed the anchorage-independent growth and malignancy (PMID:12492487)
• Soluble ST2, a marker for Th2 cytokine producing cells, is increased in sepsis and trauma patients. (PMID:14991091)
• Interleukin-1 receptor-1 gene is associated with increased risk of helicobacter pylori infection but not with gastic cancer. (PMID:15481335)
• The -26999A allele of ST2 is correlated with an increased risk for atopic dermatitis. (PMID:16118232)
• IL-33, which mediates its biological effects via IL-1 receptor ST 2, activates NF-kappaB and MAP kinases, and drives production of T(H)2-associated cytokines from in vitro polarized T(H)2 cells (PMID:16286016)
• ST2 negatively regulates LPS-induced IL-6 production via the inhibition of IkappaB degradation in THP-1 cells (PMID:16426569)
• ST2 reduced production of IL-4, IL-5, and IL-13 from IL-33-stimulated splenocytes. These results indicate that soluble ST2 acts as a negative regulator of Th2 cytokine production by the IL-33 signaling. (PMID:17623648)
• We suggest that sST2 could be a potential marker of dengue infection, could be associated with severity or could play a role in the immune response in secondary dengue virus infection. (PMID:18226917)
• Increased sST2 plasma concentrations are independently and strongly associated with one-year all-cause mortality in these patients. (PMID:18375488)
• 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)
• ST2 concentrations are frequently elevated in acute pulmonary diseases and are markedly prognostic for death by 1 year. (PMID:18794051)
• Human cord blood CD4-positive T cells, which are mainly comprised of naive cells, produce enhanced levels of interleukin (IL)-5 and IL-13 but not interferon-gamma or IL-4 when cultured with anti-CD3 antibody and IL-33, compared with anti-CD3 alone. (PMID:18802081)
• As discussed in this Review, the interleukin(IL)-33/IL-1 receptor family member ST2 pathway may play a part in the progression of atherosclerotic vascular disease. (PMID:18827826)
• Human basophils express ST2, a receptor for interleukin (IL)-33 which plays a key role in many of IL-33’s effects on basophils. (PMID:18941187)
• Percent change in ST2 biomarker concentrations during acute heart failure treatment is predictive of 90-day mortality and is independent of B-type natriuretic peptide (BNP) or amino-terminal brain natriuretic peptide precursor (NT-proBNP) levels. (PMID:18995177)
• Consistent with proposed role in myocardial-specific response to stretch, ST2 has strong clinical and biochemical correlates in patients with acute HF. Prognostically, ST2 is powerful in acute HF and is synergistic with natriuretic peptides for this use. (PMID:19017513)
• Secretion of soluble ST2 - possible explanation for systemic immunosuppression after heart surgery. (PMID:19169993)
• A SNP at IL1RL1 associated with asthma in a collection of ten different populations. (PMID:19198610)
• ST2 may play a role in the pathophysiology of asthma. (PMID:19254249)
• ST2 protein is a marker of idiopathic nephrotic syndrome (INS) recurrence that does not seem to be involved in the development of INS. (PMID:19520469)
• Polymorphisms within the IL1RL1 gene may be associated with CRS, conferring a protective effect, particularly among those with severe disease. (PMID:19671251)
• IL-33 is supposed to involve in inflammatory reaction of vascular endothelial cells through its receptor, ST2L (PMID:19756962)
• Serum contents of caspase-cleaved cytokeratin-18 and histone-associated-DNA-fragments were increased in patients with Chronic obstructive pulmonary disease (COPD), whereas anti-inflammatory soluble ST2 showed a peak in patients with COPD I&II. (PMID:19927353)
• Lung- and heart-derived ST2 might serve as an ‘autologous rescue system’ in order to attenuate innate and adaptive immune responses in organs exposed to environmental and autologous antigenic triggers. (PMID:20363761)
• The IL-33/ST2 system plays an important role in inflammatory bowel disease and experimental colitis, is modulated by anti-TNF therapy, and may represent a specific biomarker for active ulcerative colitis. (PMID:20385815)
• KU812 represents the first human cell line-based in vitro model of the IL-33/ST2L axis and provides a valuable tool to aid in understanding the mechanism and significance of IL-33 and ST2L interaction and function. (PMID:20406635)
• ST2 levels are elevated early in NSTE-ACS (acute coronary syndrome) and predict 1-year mortality. Date indicates that ST2 represents an interesting novel pathophysiologic pathyway in the setting os ischemia-related myocardial dysfunction. (PMID:20435187)
• two new polymorphisms in the distal promoter region of the ST2 gene that possibly influence susceptibility to severe coronary artery disease (PMID:20602249)
• IL1RL1 gene were also differentially transcribed in atopic dermatitis. (PMID:20625511)
• genetic variation in IL1RL1 significantly influences asthma risk (PMID:21150878)
• ST2 is a potent marker of risk in chronic heart failure and when used in combination with NT-proBNP offers moderate improvement in assessing prognosis beyond clinical risk scores. (PMID:21178018)
• Data show that the IL-33 receptor ST2L is not constitutively expressed in human bone marrow stromal cells, osteoblasts or CD14-positive monocytes. (PMID:21190867)
• sST2 is a strong predictor of mortality in patients presenting with acute dyspnea, particularly those with preserved LVEF. (PMID:21515743)
• Soluble ST2 levels correlated with disease severity and inflammatory cytokines, are able to differentiate active from inactive ulcerative colitis and might have a role as a biomarker. (PMID:21633527)
• no independent association of sST2 with sex-hormones in healthy males and females (PMID:21663467)
• Variation in genes encoding IL-33 and thymic stromal lymphopoietin (TSLP), and the IL1RL1 gene encoding the IL-33 receptor, play the central roles for innate immune response pathways in the pathogenesis of both asthma and allergic diseases. (Review) (PMID:21682736)
• these results unravel a novel soluble ST2 mediated signaling pathway that has physiological relevance to airway inflammation and remodeling (PMID:21871564)
• IL-33 and ST2 can be detected in lysates from both normal and pre-eclampsia placentas (PMID:21949719)
• Soluble ST2 is a marker for acute cardiac allograft rejection. (PMID:22035779)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000101527
mus_musculus	Il1rl1	ENSMUSG00000026069
rattus_norvegicus	Il1rl1	ENSRNOG00000014835

Paralogs (10): LAG3 (ENSG00000089692), IL1R2 (ENSG00000115590), IL1R1 (ENSG00000115594), IL1RL2 (ENSG00000115598), IL18R1 (ENSG00000115604), IL18RAP (ENSG00000115607), IL1RAPL1 (ENSG00000169306), SIGIRR (ENSG00000185187), IL1RAPL2 (ENSG00000189108), IL1RAP (ENSG00000196083)

Protein

Protein identifiers

Interleukin-1 receptor-like 1 — Q01638 (reviewed: Q01638)

Alternative names: Protein ST2

All UniProt accessions (3): C9JSY6, E9PC41, Q01638

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for interleukin-33 (IL-33) which plays crucial roles in innate and adaptive immunity, contributing to tissue homeostasis and responses to environmental stresses together with coreceptor IL1RAP. Its stimulation recruits MYD88, IRAK1, IRAK4, and TRAF6, followed by phosphorylation of MAPK3/ERK1 and/or MAPK1/ERK2, MAPK14, and MAPK8. Possibly involved in helper T-cell function. Upon tissue injury, induces UCP2-dependent mitochondrial rewiring that attenuates the generation of reactive oxygen species and preserves the integrity of Krebs cycle required for persistent production of itaconate and subsequent GATA3-dependent differentiation of inflammation-resolving alternatively activated macrophages. Inhibits IL-33 signaling.

Subunit / interactions. Interacts with MYD88, IRAK1, IRAK4, and TRAF6. Bound to its ligand IL-33, interacts with IL1RAP to form the minimal interleukin-33 signaling complex with a 1:1:1 stoichiometry. Interacts with KIT (bound to KITLG/SCF). A mast cell-specific KITLG/SCF-induced interleukin-33 signaling complex contains IL1RL1, IL1RAP, KIT and MYD88. Interacts with TMED1.

Subcellular location. Cell membrane Secreted Cell membrane.

Tissue specificity. Highly expressed in kidney, lung, placenta, stomach, skeletal muscle, colon and small intestine. Isoform A is prevalently expressed in the lung, testis, placenta, stomach and colon. Isoform B is more abundant in the brain, kidney and the liver. Isoform C is not detected in brain, heart, liver, kidney and skeletal muscle. Expressed on T-cells in fibrotic liver; at protein level. Overexpressed in fibrotic and cirrhotic liver.

Post-translational modifications. Ubiquitinated at Lys-321 in a FBXL19-mediated manner; leading to proteasomal degradation. Ubiquitination by TRAF6 via ‘Lys-27’-linked polyubiquitination and deubiquitination by USP38 serves as a critical regulatory mechanism for fine-tuning IL1RL1-mediated inflammatory response.

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

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the interleukin-1 receptor family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q01638-1	A, ST2L	yes
Q01638-2	B, ST2S
Q01638-3	C, ST2V
Q01638-4	4

RefSeq proteins (3): NP_001269337, NP_003847, NP_057316* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000157	TIR_dom	Domain
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR004074	IL-1_rcpt_I/II-typ	Family
IPR007110	Ig-like_dom	Domain
IPR013098	Ig_I-set	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, PF07679

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (65 total): strand 23, glycosylation site 8, sequence variant 6, disulfide bond 5, splice variant 5, helix 4, domain 4, topological domain 2, signal peptide 1, chain 1, active site 1, cross-link 1, transmembrane region 1, sequence conflict 1, turn 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4KC3	X-RAY DIFFRACTION	3.27

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q01638-F1	82.08	0.39

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): 461

Post-translational modifications (1): 321

Disulfide bonds (5): 36–87, 111–151, 133–181, 235–303, 238–282

Glycosylation sites (8): 54, 95, 101, 140, 191, 232, 254, 273

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-9014843	Interleukin-33 signaling

MSigDB gene sets: 280 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_MACROPHAGE_ACTIVATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, MODULE_255, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, MODULE_545, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, chr2q12, GOBP_REGULATION_OF_MACROPHAGE_ACTIVATION, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, MODULE_317

GO Biological Process (13): negative regulation of T-helper 1 type immune response (GO:0002826), inflammatory response (GO:0006954), immune response (GO:0006955), signal transduction (GO:0007165), response to wounding (GO:0009611), macrophage differentiation (GO:0030225), negative regulation of type II interferon production (GO:0032689), positive regulation of chemokine production (GO:0032722), positive regulation of interleukin-5 production (GO:0032754), interleukin-33-mediated signaling pathway (GO:0038172), positive regulation of macrophage activation (GO:0043032), positive regulation of inflammatory response (GO:0050729), cytokine-mediated signaling pathway (GO:0019221)

GO Molecular Function (7): interleukin-33 binding (GO:0002113), interleukin-33 receptor activity (GO:0002114), cytokine receptor activity (GO:0004896), interleukin-1 receptor activity (GO:0004908), NAD+ nucleosidase activity, cyclic ADP-ribose generating (GO:0061809), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (7): extracellular region (GO:0005576), cytosol (GO:0005829), plasma membrane (GO:0005886), focal adhesion (GO:0005925), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Intracellular signaling by second messengers	1
Negative regulation of the PI3K/AKT network	1
Interleukin-1 family signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
positive regulation of cytokine production	2
cytokine-mediated signaling pathway	2
cytokine binding	2
cytokine receptor activity	2
negative regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
regulation of T-helper 1 type immune response	1
T-helper 1 type immune response	1
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
response to stress	1
myeloid leukocyte differentiation	1
mononuclear cell differentiation	1
negative regulation of cytokine production	1
type II interferon production	1
regulation of type II interferon production	1
chemokine production	1
regulation of chemokine production	1
interleukin-5 production	1
regulation of interleukin-5 production	1
positive regulation of leukocyte activation	1
macrophage activation	1
regulation of macrophage activation	1
inflammatory response	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
regulation of inflammatory response	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
interleukin-33 binding	1
interleukin-33-mediated signaling pathway	1
transmembrane signaling receptor activity	1
immune receptor activity	1
interleukin-1 binding	1

Protein interactions and networks

STRING

1552 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL1RL1	IL33	O95760	999
IL1RL1	IL1RAP	Q9NPH3	987
IL1RL1	IL1R1	P14778	928
IL1RL1	MYD88	P78397	926
IL1RL1	IL1B	P01584	883
IL1RL1	IL13	P35225	858
IL1RL1	IL1A	P01583	848
IL1RL1	TSLP	Q969D9	823
IL1RL1	IRAK1	P51617	818
IL1RL1	TMED1	Q13445	814
IL1RL1	KIT	P10721	805
IL1RL1	IL5	P05113	788
IL1RL1	IL18	Q14116	773
IL1RL1	IL7R	P16871	725
IL1RL1	IL17RB	Q9NRM6	723

IntAct

16 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CLEC7A	IL1RL1	psi-mi:“MI:0915”(physical association)	0.560
IL1RL1	CLEC7A	psi-mi:“MI:0915”(physical association)	0.560
IL1RL1	IL33	psi-mi:“MI:0407”(direct interaction)	0.440
IL1RL1	MPIG6B	psi-mi:“MI:0915”(physical association)	0.400
IL1RL1	HAPLN1	psi-mi:“MI:0915”(physical association)	0.400
IL1RL1	AXL	psi-mi:“MI:0915”(physical association)	0.400
SIGLEC9	IL1RL1	psi-mi:“MI:0915”(physical association)	0.400
LTF	IL1RL1	psi-mi:“MI:0915”(physical association)	0.400
IL1RL1	MYD88	psi-mi:“MI:0915”(physical association)	0.400
TRAF6	IL1RL1	psi-mi:“MI:0915”(physical association)	0.400
IRAK4	IL1RL1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (22): CLEC7A (Two-hybrid), IL1RL1 (Reconstituted Complex), IL33 (Reconstituted Complex), IL1RL1 (Reconstituted Complex), IL1RL1 (Affinity Capture-Western), IL1RL1 (Two-hybrid), IL1RL1 (Two-hybrid), GPR42 (Two-hybrid), TSPAN18 (Two-hybrid), CREB3L1 (Two-hybrid), ASGR2 (Two-hybrid), GPR152 (Two-hybrid), MCFD2 (Two-hybrid), YIPF6 (Two-hybrid), SIGLEC12 (Two-hybrid)

ESM2 similar proteins: A0A8M2B818, A3KPA0, A5D7C3, B0JYH6, O35112, O46634, O46651, O88792, P17790, P18461, P18572, P21802, P21803, P26453, P35613, P42292, P57087, P78310, P97792, Q01638, Q13740, Q15198, Q1WIM2, Q2PFX1, Q2WGK2, Q3V3F6, Q5R764, Q5RJP7, Q61490, Q66KX2, Q68FQ2, Q6DJ83, Q6PE55, Q6UWV2, Q7ZXX1, Q8BLQ9, Q8N3J6, Q8WMV3, Q90Y50, Q99795

Diamond homologs: P14719, Q01638, Q62611, P13504, Q9ERS7

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
IL1RL1	“up-regulates activity”	MYD88	binding
IL1RL1	“up-regulates activity”	IRAK4	binding
IL1RL1	“up-regulates activity”	IRAK1	binding
IL1RL1	“up-regulates activity”	TRAF6	binding
IL33	“up-regulates activity”	IL1RL1	binding
IL1RL1	“up-regulates activity”	IL1RAP	binding
IL1RL1	“up-regulates activity”	MAP3K7	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 12 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of canonical NF-kappaB signal transduction	5	30.3×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	84
Likely benign	13
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

1788 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
2:102337958: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
2:102342221:AGA:A	acceptor_loss	0.9900
2:102342222:G:GT	acceptor_loss	0.9900
2:102342222:GATGA:G	acceptor_gain	0.9900
2:102342282:G:GT	donor_gain	0.9900

AlphaMissense

3684 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:102343106:G:C	W251C	0.996
2:102343106:G:T	W251C	0.996
2:102340222:T:A	C133S	0.994
2:102340223:G:C	C133S	0.994
2:102351578:G:C	R443P	0.994
2:102340266:G:C	W147C	0.993
2:102340266:G:T	W147C	0.993
2:102340759:T:A	C181S	0.993
2:102340760:G:C	C181S	0.993
2:102340264:T:A	W147R	0.992
2:102340264:T:C	W147R	0.992
2:102340222:T:C	C133R	0.991
2:102338919:G:C	W48C	0.989
2:102338919:G:T	W48C	0.989
2:102351832:T:A	W528R	0.989
2:102351832:T:C	W528R	0.989
2:102340760:G:A	C181Y	0.988
2:102343104:T:A	W251R	0.988
2:102343104:T:C	W251R	0.988
2:102351829:T:C	F527L	0.988
2:102351831:C:A	F527L	0.988
2:102351831:C:G	F527L	0.988
2:102340759:T:C	C181R	0.987
2:102351854:T:C	M535T	0.987
2:102340223:G:A	C133Y	0.986
2:102343352:T:A	C303S	0.986
2:102343353:G:C	C303S	0.986
2:102349103:T:A	V381D	0.986
2:102339028:T:G	Y85D	0.985
2:102340224:T:G	C133W	0.985

dbSNP variants (sampled 300 via entrez): RS1000045629 (2:102313975 T>C), RS1000297701 (2:102327893 C>T), RS1000307004 (2:102340989 T>C), RS1000503299 (2:102351104 G>A,C), RS1000649731 (2:102312923 G>A), RS1000695614 (2:102314081 G>T), RS1000718406 (2:102348586 T>C), RS1000721754 (2:102321726 C>G,T), RS1000760656 (2:102314552 C>T), RS1000971724 (2:102321559 G>A), RS1000990252 (2:102336511 C>T), RS1001064299 (2:102351366 A>G), RS1001125618 (2:102313086 A>G), RS1001255928 (2:102343920 T>A), RS1001402987 (2:102319066 T>C,G)

Disease associations

OMIM: gene MIM:601203 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

65 associations (top):

Study	Trait	p-value
GCST000157_6	Celiac disease	4.000000e-09
GCST000339_6	Eosinophil count	5.000000e-14
GCST000612_30	Celiac disease	1.000000e-15
GCST000879_29	Crohn’s disease	2.000000e-12
GCST001182_1	Asthma	2.000000e-15
GCST001701_1	Asthma	1.000000e-09
GCST001709_2	Atopic dermatitis	8.000000e-18
GCST001725_46	Inflammatory bowel disease	3.000000e-20
GCST002083_12	Self-reported allergy	2.000000e-16
GCST002084_2	Allergic sensitization	5.000000e-11
GCST002137_6	Waist circumference	5.000000e-06
GCST002166_1	Serum protein levels (sST2)	2.000000e-27
GCST002166_14	Serum protein levels (sST2)	7.000000e-94
GCST002166_5	Serum protein levels (sST2)	7.000000e-11
GCST002166_6	Serum protein levels (sST2)	2.000000e-39
GCST002166_7	Serum protein levels (sST2)	1.000000e-35
GCST002166_9	Serum protein levels (sST2)	2.000000e-30
GCST002322_4	Asthma and hay fever	4.000000e-11
GCST003129_29	Primary biliary cholangitis	5.000000e-09
GCST003176_2	Asthma	2.000000e-06
GCST003184_24	Atopic dermatitis	2.000000e-12
GCST003987_5	Asthma	5.000000e-31
GCST003990_26	Allergy	6.000000e-27
GCST004131_93	Inflammatory bowel disease	5.000000e-11
GCST004132_63	Crohn’s disease	6.000000e-11
GCST005212_18	Asthma	4.000000e-21
GCST005213_1	Asthma (childhood onset)	5.000000e-13
GCST005851_3	Delirium	1.000000e-08
GCST005975_7	Eosinophil count	6.000000e-25
GCST006408_6	Allergic sensitization	3.000000e-09

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004842	eosinophil count
EFO:0005298	allergic sensitization measurement
EFO:0004713	FEV/FVC ratio
EFO:0004314	forced expiratory volume
EFO:0004847	age at onset
EFO:1002011	adult onset asthma
EFO:0008168	interleukin 1 receptor-like 1 measurement
EFO:0007614	asthma exacerbation measurement
EFO:0007991	eosinophil percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4804256 (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

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, increases expression	8
sodium arsenite	decreases expression, affects cotreatment, increases abundance	5
Cyclosporine	increases expression	4
Cadmium Chloride	decreases expression, increases expression	4
Arsenic	affects cotreatment, decreases expression, increases expression, increases abundance	3
Calcitriol	increases expression, increases reaction	3
Methotrexate	decreases expression, increases expression	3
Aflatoxin B1	decreases methylation, increases expression	3
Particulate Matter	decreases expression, increases abundance, increases expression	3
Air Pollutants	affects expression, increases abundance, increases expression	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Cadmium	increases expression	2
Endosulfan	increases expression	2
Estradiol	increases expression, affects cotreatment	2
Nickel	increases expression	2
Ozone	increases expression, affects expression, increases abundance, affects cotreatment	2
Progesterone	increases expression, affects cotreatment	2
Silicon Dioxide	increases expression	2
Asbestos, Crocidolite	affects expression, increases expression	2
Glupearl 19S	increases expression	1
methyleugenol	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
lead acetate	decreases expression	1
sodium arsenate	increases abundance, increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
hydroxyhydroquinone	increases expression	1
dimethylselenide	increases expression, increases oxidation	1
3,4-dichloroaniline	increases expression	1
2-amino-9H-pyrido(2,3-b)indole	increases expression	1
cobaltous chloride	decreases expression	1

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_D1WW	Abcam A-549 IL1RL1 KO	Cancer cell line	Male
CVCL_D2B7	Abcam HCT 116 IL1RL1 KO	Cancer cell line	Male
CVCL_E6U8	Genomeditech HEK-293 H_IL33 Reporter	Transformed cell line	Female
CVCL_UF59	HEK-Blue IL-33	Transformed cell line	Female

Clinical trials (associated diseases)

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