IL1RAP

Summary

IL1RAP (interleukin 1 receptor accessory protein, HGNC:5995) is a protein-coding gene on chromosome 3q28, encoding Interleukin-1 receptor accessory protein (Q9NPH3). Coreceptor for IL1RL2 in the IL-36 signaling system.

This gene encodes a component of the interleukin 1 receptor complex, which initiates signalling events that result in the activation of interleukin 1-responsive genes. Alternative splicing of this gene results in membrane-bound and soluble isoforms differing in their C-terminus. The ratio of soluble to membrane-bound forms increases during acute-phase induction or stress.

Source: NCBI Gene 3556 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nephrotic syndrome of childhood - steroid sensitive (Limited, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 63 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_002182

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5995
Approved symbol	IL1RAP
Name	interleukin 1 receptor accessory protein
Location	3q28
Locus type	gene with protein product
Status	Approved
Aliases	IL-1RAcP, IL1R3, C3orf13
Ensembl gene	ENSG00000196083
Ensembl biotype	protein_coding
OMIM	602626
Entrez	3556

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 18 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000072516, ENST00000317757, ENST00000342550, ENST00000412080, ENST00000413869, ENST00000422485, ENST00000422625, ENST00000422940, ENST00000434491, ENST00000439062, ENST00000447382, ENST00000453359, ENST00000461629, ENST00000465496, ENST00000473566, ENST00000476929, ENST00000482913, ENST00000903528, ENST00000903529, ENST00000903530, ENST00000903531, ENST00000922987, ENST00000922988, ENST00000970339, ENST00000970340

RefSeq mRNA: 9 — MANE Select: NM_002182 NM_001167928, NM_001167929, NM_001167930, NM_001167931, NM_001364879, NM_001364880, NM_001364881, NM_002182, NM_134470

CCDS: CCDS3298, CCDS46982, CCDS54696

Canonical transcript exons

ENST00000447382 — 12 exons

Exon	Start	End
ENSE00000382207	190604128	190604413
ENSE00000781639	190620275	190620440
ENSE00000781640	190623344	190623415
ENSE00000781641	190627323	190627449
ENSE00001176756	190629350	190629498
ENSE00001380307	190564289	190564353
ENSE00001595112	190556130	190556216
ENSE00003493587	190648338	190651514
ENSE00003515969	190644248	190644397
ENSE00003672838	190645699	190645842
ENSE00003685479	190608995	190609181
ENSE00003844081	190514085	190514219

Expression profiles

Bgee: expression breadth ubiquitous, 230 present calls, max score 93.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.2441 / max 1103.1815, expressed in 1598 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
40563	13.5857	1572
40564	0.8782	273
40562	0.4756	255
40561	0.1627	50
40570	0.0602	7
40571	0.0601	6
40568	0.0215	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	93.87	gold quality
liver	UBERON:0002107	93.82	gold quality
placenta	UBERON:0001987	90.14	gold quality
tongue squamous epithelium	UBERON:0006919	89.37	gold quality
blood	UBERON:0000178	89.13	gold quality
calcaneal tendon	UBERON:0003701	86.45	gold quality
esophagus squamous epithelium	UBERON:0006920	86.06	gold quality
hair follicle	UBERON:0002073	85.13	silver quality
adrenal tissue	UBERON:0018303	85.05	gold quality
epithelium of esophagus	UBERON:0001976	84.07	gold quality
gingival epithelium	UBERON:0001949	83.89	gold quality
esophagus mucosa	UBERON:0002469	83.86	gold quality
squamous epithelium	UBERON:0006914	83.79	gold quality
gingiva	UBERON:0001828	83.61	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	82.94	gold quality
gall bladder	UBERON:0002110	82.89	gold quality
germinal epithelium of ovary	UBERON:0001304	82.70	gold quality
monocyte	CL:0000576	82.62	gold quality
oral cavity	UBERON:0000167	82.61	gold quality
mononuclear cell	CL:0000842	82.14	gold quality
leukocyte	CL:0000738	82.05	gold quality
decidua	UBERON:0002450	81.90	gold quality
sural nerve	UBERON:0015488	81.71	gold quality
stromal cell of endometrium	CL:0002255	81.52	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.38	gold quality
right lung	UBERON:0002167	81.25	gold quality
skin of abdomen	UBERON:0001416	81.15	gold quality
upper lobe of left lung	UBERON:0008952	80.83	gold quality
palpebral conjunctiva	UBERON:0001812	80.66	gold quality
upper lobe of lung	UBERON:0008948	80.51	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-ENAD-20	yes	438.78
E-MTAB-6701	yes	75.46
E-MTAB-6678	yes	16.46
E-ANND-3	yes	11.19
E-MTAB-5061	no	3.77

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR2

miRNA regulators (miRDB)

193 targeting IL1RAP, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3924	100.00	72.09	2394
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-8485	100.00	77.57	4731
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-513A-5P	100.00	69.77	2465
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-6133	100.00	66.48	2064
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753

Literature-anchored findings (GeneRIF, showing 40)

• Identification of essential regions in the cytoplasmic tail of interleukin-1 receptor accessory protein critical for interleukin-1 signaling (PMID:11880380)
• soluble form of IL-1R AcP contributes to the antagonism of IL-1 action by the type II decoy receptor (PMID:12530978)
• The dramatic changes in levels of IL-1RAcP mRNAs suggest important functions in regulating sensitivity to IL-1 during stress and may play a role in oncogenic processes that are engaged during chronic inflammation. (PMID:12781872)
• IL-1F6, IL-1F8, and IL-1F9 signal through IL-1Rrp2 and IL-1RAcP in Jurkat cells (PMID:14734551)
• Specific destabilization of membrane-bound IL-1 receptor accessory protein mRNA in HepG2 hepatoma cells is mediated by its 2.8-kilobase 3’-untranslated region. (PMID:15528363)
• Analysis of a three-dimensional docking model of the TIR-TIR interaction between MyD88 and IL1RAcP (PMID:15849357)
• IL-1RAcP, MyD88, and IRAK-4 are the stable components of the endogenous type I interleukin-1 (IL-1) receptor signaling complex (PMID:17507369)
• IL-1RAcP687 functions in the IL-1 signal transduction and response. Furthermore, IL-1RAcP687 can associate with proteins involved in the upstream IL-1 signaling pathway such as IL-1RI, Tollip, and MyD88. (PMID:17949817)
• IL-1ra is associated with preserved beta-cell capacity in type 1 diabetes. (PMID:18299313)
• an isoform of the IL-1 receptor accessory protein (termed AcPb) was identified that is expressed exclusively in the CNS. (PMID:19481478)
• identifies IL1RAP as a unique cell surface biomarker distinguishing Ph(+) from Ph(-) candidate chronic myeloid leukemia (CML) stem cells and opens up a previously unexplored avenue for therapy of CML (PMID:20805474)
• This study showed a significant downregulation of soluble interleukin-1 receptor accessory protein expression in the endometrium of women with endometriosis. (PMID:21272866)
• Studies indicate that new targets have recently been investigated as potential modulators in myeloid leukemia pathogenesis, including miR-328, BMI1, FOXOs and IL1RAP. (PMID:21373837)
• decreased protein levels in the peritoneal fluid of women with endometriosis (PMID:21958553)
• The genetic polymorphisms of IL-1ss-2023 C allele, IL- 1RAcP -8261 T allele and -8183 A allele are probable host factors for persistent HBV infection. (PMID:22251538)
• Knockdown of IL1RAP decreased clonogenicity and increased cell death of AML cells. (PMID:22723552)
• Interleukin-1R3 mediates interleukin-1-induced potassium current increase through fast activation of Akt kinase. (PMID:22778412)
• MARCH8-mediated polyubiquitination and degradation of IL1RAP is an important mechanism for negative regulation of IL-1beta-induced signaling pathways. (PMID:22904187)
• Combined crystallography and small-angle X-ray-scattering studies reveal that ST2 possesses hinge flexibility between the D3 domain and D1D2 module, whereas IL-1RAcP exhibits a rigid conformation in the unbound state in solution. (PMID:23980170)
• Plasma sIL1RAP levels are reduced in obesity and can potentially act as biomarkers of obesity. (PMID:24915116)
• Data suggest serum levels of soluble IL1RAP (from alternative splicing) are down-regulated in endometriosis throughout menstrual cycle; IL1RAP levels (which peak in proliferative phase in fertile women) exhibit minor variations in endometriosis. (PMID:24935223)
• The SNP rs4624606 in IL-1RAcP was nominally associated with CAD risk. (PMID:25517029)
• The findings of this study support IL1RAP as a novel potential Alzheimer’s disease target and highlight the use of amyloid PET as a valuable Alzheimer’s disease endophenotype, particularly in a longitudinal framework. (PMID:26268530)
• Reconstitution of ST2 (IL-1R4) specific for IL-33 activity; no suppression by IL-1Ra though a common chain IL-1R3 (IL-1RAcP) shared with IL-1. (PMID:27031441)
• single nucleotide polymorphism A471T in the Toll-interleukin 1 receptor domain (TIR) of the IL-1Rrp2 that is present in approximately 2% of the human population, down-regulated IL-36R signaling by a decrease of interaction with IL-1RAcP. (PMID:27307043)
• These results provide novel insights into the role of IL1RAP in CML and a strong rationale for the development of an IL1RAP antibody therapy to target residual CML stem cells. (PMID:27621309)
• Expression level of sIL1RAP may become one of the potential indexes for determining the prognosis of low-grade gliomas (PMID:29238884)
• IL1RAP Polymorphism is Associated With acute Anterior Uveitis. (PMID:29424312)
• This study provides a new mechanistic basis for the efficacy of IL1RAP targeting in acute myeloid leukemia. (PMID:29773641)
• A regulatory network in the PSG10P/miR-19a-3p/IL1RAP pathway may contribute to preeclampsia pathogenesis during pregnancy. (PMID:30370628)
• Association of IL1RAP-related genetic variation with cerebrospinal fluid concentration of Alzheimer-associated tau protein. (PMID:30792413)
• in diseases driven by multiple cytokines, blocking IL-1R3 is a therapy to limit activities from six members of the IL-1 family. (PMID:31427775)
• Associations of IL1RAP and IL1RL1 gene polymorphisms with obesity and inflammation mediators. (PMID:31897507)
• Biallelic variants/mutations of IL1RAP in patients with steroid-sensitive nephrotic syndrome. (PMID:31954058)
• IL1RAP regulated by PRPRD promotes gliomas progression via inducing neuronal synapse development and neuron differentiation in vitro. (PMID:32829106)
• The Role of SNPs in IL1RL1 and IL1RAP Genes in Age-related Macular Degeneration Development and Treatment Efficacy. (PMID:32871771)
• The Potential Role of IL1RAP on Tumor Microenvironment-Related Inflammatory Factors in Stomach Adenocarcinoma. (PMID:33602046)
• Proteomic Screens for Suppressors of Anoikis Identify IL1RAP as a Promising Surface Target in Ewing Sarcoma. (PMID:34021002)
• Novel IL1RAP mutation associated with schizophrenia interferes with neuronal growth and related NF-kappaB signal pathways. (PMID:35181481)
• Innate immune mediator, Interleukin-1 receptor accessory protein (IL1RAP), is expressed and pro-tumorigenic in pancreatic cancer. (PMID:35606824)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000114719
mus_musculus	Il1rap	ENSMUSG00000022514
rattus_norvegicus	Il1rap	ENSRNOG00000001928

Paralogs (10): LAG3 (ENSG00000089692), IL1R2 (ENSG00000115590), IL1R1 (ENSG00000115594), IL1RL2 (ENSG00000115598), IL1RL1 (ENSG00000115602), IL18R1 (ENSG00000115604), IL18RAP (ENSG00000115607), IL1RAPL1 (ENSG00000169306), SIGIRR (ENSG00000185187), IL1RAPL2 (ENSG00000189108)

Protein

Protein identifiers

Interleukin-1 receptor accessory protein — Q9NPH3 (reviewed: Q9NPH3)

Alternative names: Interleukin-1 receptor 3

All UniProt accessions (5): C9J1D9, C9J9W1, C9JT28, Q9NPH3, H7C3W4

UniProt curated annotations — full annotation on UniProt →

Function. Coreceptor for IL1RL2 in the IL-36 signaling system. Coreceptor with IL1R1 in the IL-1 signaling system. Associates with IL1R1 bound to IL1B to form the high affinity interleukin-1 receptor complex which mediates interleukin-1-dependent activation of NF-kappa-B and other pathways. Signaling involves the recruitment of adapter molecules such as TOLLIP, MYD88, and IRAK1 or IRAK2 via the respective TIR domains of the receptor/coreceptor subunits. Recruits TOLLIP to the signaling complex. Does not bind to interleukin-1 alone; binding of IL1RN to IL1R1, prevents its association with IL1R1 to form a signaling complex. The cellular response is modulated through a non-signaling association with the membrane IL1R2 decoy receptor. Coreceptor for IL1RL1 in the IL-33 signaling system. Can bidirectionally induce pre- and postsynaptic differentiation of neurons by trans-synaptically binding to PTPRD. May play a role in IL1B-mediated costimulation of IFNG production from T-helper 1 (Th1) cells. Associates with secreted ligand-bound IL1R2 and increases the affinity of secreted IL1R2 for IL1B; this complex formation may be the dominant mechanism for neutralization of IL1B by secreted/soluble receptors. Enhances the ability of secreted IL1R1 to inhibit IL-33 signaling. Unable to mediate canonical IL-1 signaling. Required for Src phosphorylation by IL1B. May be involved in IL1B-potentiated NMDA-induced calcium influx in neurons.

Subunit / interactions. The interleukin-36 receptor complex is a heterodimer of IL1RL2 and IL1RAP; the association is inhibited by IL36RN. The interleukin-1 receptor complex is a heterodimer of IL1R1 and IL1RAP. Associates with IL1R2 to form a non-signaling interleukin-1 receptor complex. Isoform 4 interacts with IL1R1 in an interleukin-1-dependent manner. Interacts with IL-33-bound IL1RL1 to form the minimal interleukin-33 signaling complex with a 1:1:1 stoichiometry. Interacts with KIT (independently of stimulation with KITLG/SCF). A mast cell-specific KITLG/SCF-induced interleukin-33 signaling complex contains IL1RL1, IL1RAP, KIT and MYD88. Interacts (via the first immunoglobilin domain) with PTPRD (via the third immunoglobilin domain); induces pre- and postsynaptic differentiation of neurons.

Subcellular location. Cell membrane Secreted Secreted.

Tissue specificity. Detected in liver, skin, placenta, thymus and lung. Isoform 4 is predominantly expressed in brain. Overexpressed on candidate chronic myeloid leukemia (CML) stem cells, hematopoietic stem cells and mononuclear cells of patients with acute myeloid leukemia (AML). Overexpressed in patients with chronic obstructive pulmonary disease (COPD). Expressed in T-helper 1 (Th1) and T-helper 2 (Th2) cell subsets.

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

Induction. Isoform 1 is down-regulated by phorbol ester treatment. Isoform 2 is induced by phorbol ester treatment.

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?
Q9NPH3-1	1, Membrane-bound IL-1RAcP, mIL-1RAcP	yes
Q9NPH3-2	2, Soluble IL-1RAcP, sIL-1RAcP
Q9NPH3-3	3, Soluble IL-1RAcP-beta, sIL-1RAcP-beta
Q9NPH3-5	4, AcPb, mIL-1RAcP687

RefSeq proteins (9): NP_001161400, NP_001161401, NP_001161402, NP_001161403, NP_001351808, NP_001351809, NP_001351810, NP_002173, NP_608273 (=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
IPR041416	IL-1RAcP-like_ig	Domain

Pfam: PF01582, PF18452

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (78 total): strand 31, helix 14, glycosylation site 7, disulfide bond 5, splice variant 4, domain 4, region of interest 2, topological domain 2, turn 2, signal peptide 1, chain 1, compositionally biased region 1, active site 1, modified residue 1, transmembrane region 1, sequence variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
7FCC	X-RAY DIFFRACTION	2.14
4DEP	X-RAY DIFFRACTION	3.1
3O4O	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NPH3-F1	86.16	0.59

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): 482

Post-translational modifications (1): 557

Disulfide bonds (5): 24–122, 47–114, 137–181, 160–212, 266–332

Glycosylation sites (7): 57, 107, 111, 118, 196, 209, 299

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-388844	Receptor-type tyrosine-protein phosphatases
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-9014826	Interleukin-36 pathway
R-HSA-9014843	Interleukin-33 signaling
R-HSA-9020702	Interleukin-1 signaling

MSigDB gene sets: 465 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, VALK_AML_WITH_FLT3_ITD, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, TGGTGCT_MIR29A_MIR29B_MIR29C, MODULE_52, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_NEGATIVE_REGULATION_OF_INTERLEUKIN_1_PRODUCTION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_SYNAPSE_ASSEMBLY, GOBP_RESPONSE_TO_PEPTIDE, MODULE_545, GOBP_MACROPHAGE_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, MODULE_45

GO Biological Process (18): inflammatory response (GO:0006954), immune response (GO:0006955), cytokine-mediated signaling pathway (GO:0019221), positive regulation of interleukin-13 production (GO:0032736), positive regulation of interleukin-4 production (GO:0032753), positive regulation of interleukin-5 production (GO:0032754), positive regulation of interleukin-6 production (GO:0032755), interleukin-33-mediated signaling pathway (GO:0038172), innate immune response (GO:0045087), positive regulation of synapse assembly (GO:0051965), protein-containing complex assembly (GO:0065003), interleukin-1-mediated signaling pathway (GO:0070498), regulation of postsynaptic density assembly (GO:0099151), trans-synaptic signaling by trans-synaptic complex (GO:0099545), synaptic membrane adhesion (GO:0099560), regulation of presynapse assembly (GO:1905606), immune system process (GO:0002376), signal transduction (GO:0007165)

GO Molecular Function (6): interleukin-33 receptor activity (GO:0002114), interleukin-1 receptor activity (GO:0004908), coreceptor activity (GO:0015026), NAD+ nucleosidase activity, cyclic ADP-ribose generating (GO:0061809), hydrolase activity (GO:0016787), signaling receptor activity (GO:0038023)

GO Cellular Component (6): extracellular region (GO:0005576), plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020), glutamatergic synapse (GO:0098978), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Interleukin-1 family signaling	3
Intracellular signaling by second messengers	1
Protein-protein interactions at synapses	1
Negative regulation of the PI3K/AKT network	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of cytokine production	4
cellular anatomical structure	3
cytokine-mediated signaling pathway	2
regulation of synapse assembly	2
cytokine receptor activity	2
defense response	1
immune system process	1
response to stimulus	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
interleukin-13 production	1
regulation of interleukin-13 production	1
interleukin-4 production	1
regulation of interleukin-4 production	1
interleukin-5 production	1
regulation of interleukin-5 production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
immune response	1
defense response to symbiont	1
synapse assembly	1
positive regulation of nervous system development	1
positive regulation of cell junction assembly	1
cellular component assembly	1
protein-containing complex organization	1
cellular response to interleukin-1	1
postsynaptic density assembly	1
regulation of postsynaptic specialization assembly	1
regulation of excitatory synapse assembly	1
regulation of postsynaptic density organization	1
trans-synaptic signaling	1
synapse organization	1
cell-cell adhesion	1
presynapse assembly	1
regulation of presynapse organization	1
biological_process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1

Protein interactions and networks

STRING

894 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL1RAP	IL1A	P01583	997
IL1RAP	IL1B	P01584	997
IL1RAP	IL33	O95760	996
IL1RAP	IL1R1	P14778	988
IL1RAP	IL1RL1	Q01638	987
IL1RAP	IL1RL2	Q9HB29	987
IL1RAP	IL1R2	P27930	975
IL1RAP	IL18R1	Q13478	936
IL1RAP	PTPRS	Q13332	921
IL1RAP	KIT	P10721	919
IL1RAP	MYD88	P78397	901
IL1RAP	TRAF6	Q9Y4K3	871
IL1RAP	IRAK4	Q9NWZ3	864
IL1RAP	IL36A	Q9UHA7	824
IL1RAP	IRAK1	P51617	824

IntAct

62 interactions, top by confidence:

A	B	Type	Score
PIK3CA	PIK3R2	psi-mi:“MI:0914”(association)	0.900
IL1RAP	IL1B	psi-mi:“MI:0914”(association)	0.760
IL1RAP	IL1B	psi-mi:“MI:0915”(physical association)	0.760
IL1RAP	PTPRF	psi-mi:“MI:0915”(physical association)	0.730
IL1RAP	PTPRF	psi-mi:“MI:0407”(direct interaction)	0.730
PTPRF	IL1RAP	psi-mi:“MI:0407”(direct interaction)	0.730
IL1RAP	PTPRF	psi-mi:“MI:0403”(colocalization)	0.730
FGL1	LCMT2	psi-mi:“MI:0914”(association)	0.640
IL1RAP	PTPRS	psi-mi:“MI:0915”(physical association)	0.540
PTPRS	IL1RAP	psi-mi:“MI:0407”(direct interaction)	0.540
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
HAVCR2	TCAF2	psi-mi:“MI:0914”(association)	0.530
OPALIN	BTAF1	psi-mi:“MI:0914”(association)	0.530
IL1RAP	HIST2H2BF	psi-mi:“MI:0915”(physical association)	0.400
IL1RAP	TICAM2	psi-mi:“MI:0915”(physical association)	0.400
IL1RAP	PTPRD	psi-mi:“MI:0915”(physical association)	0.400
PTPRD	IL1RAP	psi-mi:“MI:0915”(physical association)	0.400
KPNA1	IL1RAP	psi-mi:“MI:0915”(physical association)	0.370
MC4R	IL1RAP	psi-mi:“MI:0915”(physical association)	0.370
IL1RAP	PRKCI	psi-mi:“MI:0915”(physical association)	0.370
CCNI	IL1RAP	psi-mi:“MI:0915”(physical association)	0.370
PRPF40A	IL1RAP	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (67): IL1RAP (Synthetic Lethality), IL1RAP (Affinity Capture-MS), IL1RAP (Affinity Capture-MS), IL1RAP (Affinity Capture-MS), TOLLIP (Two-hybrid), IL1RAP (Co-localization), IL1RAP (Co-localization), IL1RAP (Co-localization), PTPRD (Co-localization), PTPRD (Reconstituted Complex), PTPRD (Protein-peptide), IL1RAP (Affinity Capture-Western), IL1R1 (Affinity Capture-Western), IRAK1 (Affinity Capture-Western), IL1RAP (Affinity Capture-Western)

ESM2 similar proteins: A3KPA0, A5A6L6, A5D7C3, O60487, O70255, O88792, P01865, P01903, P01904, P01910, P04224, P04228, P14434, P14439, P14778, P15980, P22646, P23150, P53788, P57087, P59822, P97952, Q00954, Q02955, Q07699, Q17QN4, Q1WIM2, Q28740, Q2WGK2, Q30631, Q3TEW6, Q3V3F6, Q4PPC4, Q5EAB0, Q5R804, Q61730, Q62929, Q63621, Q66KX2, Q68FQ2

Diamond homologs: A2TF48, A5HNF6, A8QMS7, B3SRQ2, B3Y678, B3Y679, B3Y680, B3Y681, B3Y682, B3Y683, B6CJX2, C8BKC7, P22366, P59822, Q28DJ2, Q4LBC6, Q599T9, Q5FWM2, Q5XJ85, Q61098, Q61730, Q6IA17, Q6Y1S1, Q99836, Q9DF60, Q9JLZ8, Q9NPH3, Q9V477, V5NAL9, B6ZK76, B6ZK77, P08953, P59823, P59824, P60029, Q63621, Q7YQL9, Q9ERS6, Q9NP60, Q9NZN1

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
IL1RAP	“down-regulates activity”	TOLLIP	binding
IL1R1	“up-regulates activity”	IL1RAP	binding
IL1RL1	“up-regulates activity”	IL1RAP	binding
IL1B	up-regulates	IL1RAP	binding
IL1RAP	up-regulates	IL1R1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	31
Likely benign	4
Benign	5

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1326307	GRCh37/hg19 3q28-29(chr3:189608636-197532175)x1	Pathogenic

SpliceAI

2557 predictions. Top by Δscore:

Variant	Effect	Δscore
3:190527617:C:G	donor_gain	1.0000
3:190564280:T:TA	acceptor_gain	1.0000
3:190564352:AGGTA:A	donor_loss	1.0000
3:190564353:GGT:G	donor_loss	1.0000
3:190564354:GTA:G	donor_loss	1.0000
3:190564355:T:A	donor_loss	1.0000
3:190604116:T:TA	acceptor_gain	1.0000
3:190604341:G:GG	donor_gain	1.0000
3:190609179:ATG:A	donor_loss	1.0000
3:190609180:TGGTA:T	donor_loss	1.0000
3:190609182:G:A	donor_loss	1.0000
3:190609183:T:TC	donor_loss	1.0000
3:190627470:G:GT	donor_gain	1.0000
3:190629348:A:AG	acceptor_gain	1.0000
3:190629349:G:GA	acceptor_gain	1.0000
3:190629349:GT:G	acceptor_gain	1.0000
3:190629349:GTATA:G	acceptor_gain	1.0000
3:190644236:T:A	acceptor_gain	1.0000
3:190644241:A:AG	acceptor_gain	1.0000
3:190644244:CCA:C	acceptor_loss	1.0000
3:190644246:A:AC	acceptor_loss	1.0000
3:190644246:A:AG	acceptor_gain	1.0000
3:190644246:AGTGC:A	acceptor_gain	1.0000
3:190644247:G:GG	acceptor_gain	1.0000
3:190644247:GT:G	acceptor_gain	1.0000
3:190644247:GTGCC:G	acceptor_gain	1.0000
3:190644393:TTTAG:T	donor_gain	1.0000
3:190644394:TTAG:T	donor_gain	1.0000
3:190644396:AGG:A	donor_loss	1.0000
3:190644397:GGTA:G	donor_loss	1.0000

AlphaMissense

3760 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:190604133:T:A	C24S	1.000
3:190604134:G:C	C24S	1.000
3:190604144:G:C	W27C	1.000
3:190604144:G:T	W27C	1.000
3:190604202:T:C	C47R	1.000
3:190604271:T:A	W70R	1.000
3:190604271:T:C	W70R	1.000
3:190604403:T:C	C114R	1.000
3:190604404:G:A	C114Y	1.000
3:190604405:C:G	C114W	1.000
3:190620371:T:C	C212R	1.000
3:190627391:T:A	W282R	1.000
3:190627391:T:C	W282R	1.000
3:190627393:G:C	W282C	1.000
3:190627393:G:T	W282C	1.000
3:190629441:T:A	C332S	1.000
3:190629442:G:C	C332S	1.000
3:190645822:G:C	R442P	1.000
3:190648568:T:A	W526R	1.000
3:190648568:T:C	W526R	1.000
3:190604133:T:C	C24R	0.999
3:190604134:G:A	C24Y	0.999
3:190604202:T:A	C47S	0.999
3:190604203:G:A	C47Y	0.999
3:190604203:G:C	C47S	0.999
3:190604204:C:G	C47W	0.999
3:190604211:T:C	F50L	0.999
3:190604212:T:G	F50C	0.999
3:190604213:T:A	F50L	0.999
3:190604213:T:G	F50L	0.999

dbSNP variants (sampled 300 via entrez): RS1000012012 (3:190570438 T>C), RS1000049580 (3:190519288 T>G), RS1000055429 (3:190587238 G>A), RS1000085682 (3:190606263 G>A), RS1000116308 (3:190593351 T>C), RS1000142458 (3:190554987 C>G,T), RS1000149641 (3:190646480 T>A,C,G), RS1000152703 (3:190605894 T>TG), RS1000170560 (3:190593024 A>G), RS1000190197 (3:190606649 T>C), RS1000202292 (3:190562452 C>T), RS1000216352 (3:190555278 A>C,G), RS1000217351 (3:190625382 G>A), RS1000226347 (3:190640822 C>G), RS1000231954 (3:190564205 C>A,T)

Disease associations

OMIM: gene MIM:602626 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
nephrotic syndrome of childhood - steroid sensitive	Limited	Autosomal recessive

Mondo (1): nephrotic syndrome of childhood - steroid sensitive (MONDO:0044781)

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000172_2	Lung cancer	8.000000e-06
GCST000838_1	Waist circumference	4.000000e-06
GCST003082_3	Longitudinal change in brain amyloid plaque burden	1.000000e-09
GCST006585_490	Blood protein levels	0.000000e+00
GCST006585_499	Blood protein levels	0.000000e+00

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007646	amyloid plaque accumulation rate

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4665591 (PROTEIN COMPLEX), CHEMBL4804256 (PROTEIN COMPLEX)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	4
Arsenic	affects expression, affects methylation, decreases expression, increases abundance	3
sodium arsenite	increases abundance, decreases expression	2
Acetaminophen	affects cotreatment, decreases expression, increases expression	2
Lipopolysaccharides	affects cotreatment, decreases expression, increases expression, affects response to substance	2
Tobacco Smoke Pollution	affects expression, decreases expression, increases methylation	2
Aflatoxin B1	decreases methylation, increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
Asian ginseng	affects cotreatment, increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
titanium dioxide	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	affects expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	decreases expression	1
coumarin	affects phosphorylation	1
zinc sulfide	affects cotreatment, increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
mercuric bromide	affects cotreatment, decreases expression	1
pinosylvin	decreases expression	1
cadmium selenide	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
Am 580	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
quinocetone	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_B1UF	Abcam HeLa IL1RAP KO	Cancer cell line	Female
CVCL_E6U8	Genomeditech HEK-293 H_IL33 Reporter	Transformed cell line	Female
CVCL_E6U9	Genomeditech HEK-293 H_IL36 Reporter	Transformed cell line	Female
CVCL_E8EH	HEK-Blue IL-36	Transformed cell line	Female
CVCL_F1UX	HyCyte U-937 KO-hIL1RAP	Cancer cell line	Male
CVCL_UF33	HEK-Blue IL-18	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04536181	PHASE3	WITHDRAWN	Study of Initial Steroid Treatment in Young Children With Nephrotic Syndrome
NCT05850546	PHASE3	NOT_YET_RECRUITING	Rituximab in the First Episode of Paediatric Nephrotic Syndrome
NCT04783675	PHASE2	COMPLETED	Efficacy and Safety of Rituximab in the First Episode of Pediatric Idiopathic Nephrotic Syndrome
NCT05786768	PHASE2/PHASE3	RECRUITING	Efficacy and Safety of Obinutuzumab Versus Rituximab in Childhood Steroid Dependant and Frequent Relapsing Nephrotic Syndrome
NCT04713410	Not specified	UNKNOWN	Comparison of Relapse Rate After 12 Weeks Verses 20 Weeks Steroid Therapy for the Management of First Episode of Steroid Sensitive Nephrotic Syndrome
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases
NCT06860620	Not specified	COMPLETED	Efficacy of Zinc Supplementation in Maintaining Sustained Remission in Children With Steroid-sensitive Nephrotic Syndrome