IL1RAPL2

Summary

IL1RAPL2 (interleukin 1 receptor accessory protein like 2, HGNC:5997) is a protein-coding gene on chromosome Xq22.3, encoding X-linked interleukin-1 receptor accessory protein-like 2 (Q9NP60).

The protein encoded by this gene is a member of the interleukin 1 receptor family. This protein is similar to the interleukin 1 accessory proteins, and is most closely related to interleukin 1 receptor accessory protein-like 1 (IL1RAPL1). This gene and IL1RAPL1 are located at a region on chromosome X that is associated with X-linked non-syndromic cognitive disability.

Source: NCBI Gene 26280 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 165 total
• MANE Select transcript: NM_017416

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5997
Approved symbol	IL1RAPL2
Name	interleukin 1 receptor accessory protein like 2
Location	Xq22.3
Locus type	gene with protein product
Status	Approved
Aliases	IL-1R9, TIGIRR-1, IL1RAPL-2, IL1R9
Ensembl gene	ENSG00000189108
Ensembl biotype	protein_coding
OMIM	300277
Entrez	26280

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000372582, ENST00000485671

RefSeq mRNA: 1 — MANE Select: NM_017416 NM_017416

CCDS: CCDS14517

Canonical transcript exons

ENST00000372582 — 11 exons

Exon	Start	End
ENSE00001375319	105484313	105484387
ENSE00001383286	105740546	105740691
ENSE00001384097	105717367	105717496
ENSE00001384938	105195475	105195748
ENSE00001387672	105267388	105267541
ENSE00001388693	105233818	105234004
ENSE00001458147	105766964	105767829
ENSE00001458155	104658895	104658995
ENSE00001458156	104566199	104567051
ENSE00003610200	105748960	105749103
ENSE00003625059	105755177	105755347

Expression profiles

Bgee: expression breadth ubiquitous, 109 present calls, max score 80.49.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1106 / max 17.9515, expressed in 50 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197135	0.1106	50

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.49	gold quality
diaphragm	UBERON:0001103	78.87	gold quality
olfactory bulb	UBERON:0002264	76.64	gold quality
type B pancreatic cell	CL:0000169	74.39	gold quality
tibialis anterior	UBERON:0001385	73.83	silver quality
cortical plate	UBERON:0005343	72.34	gold quality
pancreatic ductal cell	CL:0002079	67.82	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	65.73	gold quality
epithelial cell of pancreas	CL:0000083	65.19	gold quality
quadriceps femoris	UBERON:0001377	64.85	gold quality
cervix squamous epithelium	UBERON:0006922	64.63	gold quality
vastus lateralis	UBERON:0001379	64.17	gold quality
hair follicle	UBERON:0002073	63.21	gold quality
prefrontal cortex	UBERON:0000451	61.28	gold quality
orbitofrontal cortex	UBERON:0004167	60.51	gold quality
ileal mucosa	UBERON:0000331	60.22	silver quality
tongue squamous epithelium	UBERON:0006919	59.63	gold quality
right lobe of liver	UBERON:0001114	59.25	gold quality
mucosa of urinary bladder	UBERON:0001259	58.38	gold quality
Brodmann (1909) area 46	UBERON:0006483	57.20	gold quality
decidua	UBERON:0002450	56.55	gold quality
kidney epithelium	UBERON:0004819	55.34	gold quality
thymus	UBERON:0002370	54.71	gold quality
liver	UBERON:0002107	54.06	gold quality
endothelial cell	CL:0000115	53.99	gold quality
skin of hip	UBERON:0001554	53.25	gold quality
frontal cortex	UBERON:0001870	52.68	gold quality
cervix epithelium	UBERON:0004801	52.59	gold quality
Brodmann (1909) area 9	UBERON:0013540	52.42	gold quality
left ventricle myocardium	UBERON:0006566	51.14	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-25	yes	996.36
E-HCAD-35	yes	985.04
E-HCAD-30	yes	879.83
E-ANND-3	yes	3.56

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

19 targeting IL1RAPL2, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-26A-1-3P	99.64	66.81	788
HSA-MIR-26A-2-3P	99.64	66.82	786
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-4782-5P	98.35	69.33	1474
HSA-MIR-5706	98.35	69.33	1463
HSA-MIR-4778-5P	97.96	68.06	1634
HSA-MIR-6847-5P	97.93	66.74	1808

Literature-anchored findings (GeneRIF, showing 4)

• Increased circulating levels of IL-1 accessory protein is associated with Hepatitis C virus positive patients (PMID:16596202)
• The increased expression of IL-1 receptor and the colocalization with reciprocal ligands in patients with myositis but not in healthy controls support the hypothesis of a crucial role of IL-1 in the pathogenesis of polymyositis and dermatomyositis. (PMID:17265504)
• A total of six novel and 11 known single nucleotide polymorphisms were identified. Further studies are warranted to analyze the candidate genes at Xq11.1-q21.33. (PMID:21384559)
• Crystal structure of the Toll/interleukin-1 receptor (TIR) domain of IL-1R10 provides structural insights into TIR domain signalling. (PMID:35038778)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	il1rapl2	ENSDARG00000037553
mus_musculus	Il1rapl2	ENSMUSG00000059203
rattus_norvegicus	Il1rapl2	ENSRNOG00000062221

Paralogs (10): LAG3 (ENSG00000089692), IL1R2 (ENSG00000115590), IL1R1 (ENSG00000115594), IL1RL2 (ENSG00000115598), IL1RL1 (ENSG00000115602), IL18R1 (ENSG00000115604), IL18RAP (ENSG00000115607), IL1RAPL1 (ENSG00000169306), SIGIRR (ENSG00000185187), IL1RAP (ENSG00000196083)

Protein

Protein identifiers

X-linked interleukin-1 receptor accessory protein-like 2 — Q9NP60 (reviewed: Q9NP60)

Alternative names: IL1RAPL-2-related protein, Interleukin-1 receptor 9, Three immunoglobulin domain-containing IL-1 receptor-related 1

All UniProt accessions (1): Q9NP60

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Membrane.

Tissue specificity. Detected at low levels in fetal and adult brain, in particular in the frontal lobe, temporal lobe and cerebellum. Detected at very low levels in skin, liver, fetal ovary and in placenta.

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

Similarity. Belongs to the interleukin-1 receptor family.

RefSeq proteins (1): NP_059112* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000157	TIR_dom	Domain
IPR003599	Ig_sub	Domain
IPR004077	IL-1_rcpt_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, PF13895

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (35 total): helix 10, glycosylation site 5, strand 5, domain 4, disulfide bond 3, topological domain 2, signal peptide 1, chain 1, sequence variant 1, turn 1, transmembrane region 1, active site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7SZL	X-RAY DIFFRACTION	2.3
7FD3	X-RAY DIFFRACTION	2.99

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NP60-F1	75.74	0.41

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): 488

Disulfide bonds (3): 53–116, 162–214, 265–331

Glycosylation sites (5): 63, 120, 136, 211, 328

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-388844	Receptor-type tyrosine-protein phosphatases
R-HSA-112316	Neuronal System
R-HSA-6794362	Protein-protein interactions at synapses

MSigDB gene sets: 82 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, BENPORATH_ES_WITH_H3K27ME3, GOBP_SYNAPSE_ASSEMBLY, GOBP_RESPONSE_TO_PEPTIDE, GOCC_CELL_SURFACE, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, CAGCTG_AP4_Q5, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_REGULATION_OF_SYNAPSE_ASSEMBLY, GOBP_REGULATION_OF_SYNAPSE_STRUCTURE_OR_ACTIVITY, AACTTT_UNKNOWN, AFFAR_YY1_TARGETS_DN, GOBP_CELL_JUNCTION_ASSEMBLY, GOCC_SYNAPSE

GO Biological Process (6): cell surface receptor signaling pathway (GO:0007166), central nervous system development (GO:0007417), regulation of presynapse assembly (GO:1905606), signal transduction (GO:0007165), nervous system development (GO:0007399), cytokine-mediated signaling pathway (GO:0019221)

GO Molecular Function (5): interleukin-1 receptor activity (GO:0004908), interleukin-1, type II, blocking receptor activity (GO:0004910), NAD+ nucleosidase activity, cyclic ADP-ribose generating (GO:0061809), cytokine receptor activity (GO:0004896), hydrolase activity (GO:0016787)

GO Cellular Component (4): plasma membrane (GO:0005886), cell surface (GO:0009986), glutamatergic synapse (GO:0098978), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Protein-protein interactions at synapses	1
Neuronal System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
system development	2
cellular anatomical structure	2
signal transduction	1
nervous system development	1
regulation of synapse assembly	1
presynapse assembly	1
regulation of presynapse organization	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
cytokine receptor activity	1
interleukin-1 binding	1
interleukin-1 receptor activity	1
hydrolase activity, hydrolyzing N-glycosyl compounds	1
transmembrane signaling receptor activity	1
cytokine-mediated signaling pathway	1
cytokine binding	1
immune receptor activity	1
catalytic activity	1
membrane	1
cell periphery	1
synapse	1

Protein interactions and networks

STRING

944 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL1RAPL2	IL1A	P01583	597
IL1RAPL2	IL18	Q14116	590
IL1RAPL2	IL1F10	Q8WWZ1	583
IL1RAPL2	IL36RN	Q9UBH0	570
IL1RAPL2	IL37	Q9NZH6	568
IL1RAPL2	DACH2	Q96NX9	542
IL1RAPL2	NCS1	P36610	508
IL1RAPL2	IL18R1	Q13478	505
IL1RAPL2	PTPRF	P10586	489
IL1RAPL2	IL18BP	O95998	436
IL1RAPL2	IL13RA1	P78552	431
IL1RAPL2	NME8	Q8N427	428
IL1RAPL2	PTPRD	P23468	428
IL1RAPL2	IL1RL2	Q9HB29	425
IL1RAPL2	OPALIN	Q96PE5	416

IntAct

12 interactions, top by confidence:

A	B	Type	Score
FGFR3	IL1RAPL2	psi-mi:“MI:0915”(physical association)	0.540
IL1RAPL2	FGFR3	psi-mi:“MI:0915”(physical association)	0.540
PTPRS	IL1RAPL2	psi-mi:“MI:0915”(physical association)	0.540
IL1RAPL2	PTPRS	psi-mi:“MI:0915”(physical association)	0.540
FGFR3	IL1RAPL2	psi-mi:“MI:0407”(direct interaction)	0.540
IL1RAPL2	PTPRS	psi-mi:“MI:0407”(direct interaction)	0.540
IL1RAPL2	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
PTPRD	IL1RAPL2	psi-mi:“MI:0915”(physical association)	0.400
LEP	IL1RAPL2	psi-mi:“MI:0915”(physical association)	0.400
IL1RAPL2	PRTG	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (5): IL1RAPL2 (Affinity Capture-MS), IL1RAPL2 (Proximity Label-MS), IL1RAPL2 (Reconstituted Complex), IL1RAPL2 (Positive Genetic), IL1RAPL2 (Co-fractionation)

ESM2 similar proteins: A0JM41, A2VD98, A6QQC6, A8MVW5, B0CLX4, B6ZK76, B6ZK77, O60487, O70255, O88324, O88775, O95976, P01832, P03228, P06907, P08920, P08921, P09619, P0C6B7, P0C6N0, P0CW72, P10522, P20938, P21995, P25189, P27573, P37301, P37998, P59823, P59824, P86176, Q01151, Q4VAH7, Q5EAB0, Q5R804, Q640U3, Q6PCB8, Q6WEB5, Q80UL9, Q86XK7

Diamond homologs: B6ZK76, B6ZK77, P08953, P59822, P59823, P59824, P60029, Q61730, Q63621, Q7YQL9, Q9ERS6, Q9NP60, Q9NPH3, Q9NZN1, O95256, Q9Z2B1, P13504, P14778, P27930, P27931, Q02955, Q29612, Q62929, Q9ERS7, Q9HB29, P22366, Q13478, Q4V892, Q6IA17, Q6Y1S1, Q9JLZ8, A8QMS7, B2LT61, B2LT62, B2LT64, B2LT65, B3SRQ2, B3Y613, B3Y614, B3Y615

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
IL1RAPL2	“up-regulates activity”	NCS1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	88
Likely benign	14
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

3713 predictions. Top by Δscore:

Variant	Effect	Δscore
X:104658893:A:AG	acceptor_gain	1.0000
X:104658894:G:GA	acceptor_gain	1.0000
X:104658894:GCT:G	acceptor_gain	1.0000
X:104658996:G:GA	donor_loss	1.0000
X:104658996:G:GG	donor_gain	1.0000
X:104658997:TAA:T	donor_loss	1.0000
X:104658884:T:TA	acceptor_gain	0.9900
X:104658890:TTCA:T	acceptor_loss	0.9900
X:104658891:TCAGC:T	acceptor_loss	0.9900
X:104658892:CA:C	acceptor_loss	0.9900
X:104658893:A:AT	acceptor_loss	0.9900
X:104658893:AGCT:A	acceptor_gain	0.9900
X:104658894:GC:G	acceptor_gain	0.9900
X:104658894:GCTG:G	acceptor_gain	0.9900
X:104658894:GCTGT:G	acceptor_gain	0.9900
X:104658998:AAGTT:A	donor_loss	0.9900
X:104790388:C:CA	acceptor_gain	0.9900
X:104790388:C:G	acceptor_gain	0.9900
X:104990519:A:G	acceptor_gain	0.9900
X:104566368:G:GT	donor_gain	0.9800
X:104658991:TTCTG:T	donor_gain	0.9800
X:105110047:A:T	donor_gain	0.9800
X:104658992:TCTG:T	donor_gain	0.9700
X:104666554:A:G	acceptor_gain	0.9700
X:104878856:A:AG	acceptor_gain	0.9700
X:104878857:A:G	acceptor_gain	0.9700
X:104990518:A:AG	acceptor_gain	0.9700
X:104990518:AAG:A	acceptor_gain	0.9700
X:104567047:CTCAG:C	donor_loss	0.9600
X:104567048:TCAGG:T	donor_loss	0.9600

AlphaMissense

4524 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:105195483:T:A	C31S	1.000
X:105195483:T:C	C31R	1.000
X:105195484:G:C	C31S	1.000
X:105195494:G:C	W34C	1.000
X:105195494:G:T	W34C	1.000
X:105195549:T:A	C53S	1.000
X:105195549:T:C	C53R	1.000
X:105195550:G:A	C53Y	1.000
X:105195550:G:C	C53S	1.000
X:105195551:T:G	C53W	1.000
X:105195618:T:A	W76R	1.000
X:105195618:T:C	W76R	1.000
X:105195620:G:C	W76C	1.000
X:105195620:G:T	W76C	1.000
X:105195738:T:C	C116R	1.000
X:105195739:G:A	C116Y	1.000
X:105195740:T:G	C116W	1.000
X:105233832:G:A	C124Y	1.000
X:105233996:T:A	W179R	1.000
X:105233996:T:C	W179R	1.000
X:105233998:G:C	W179C	1.000
X:105233998:G:T	W179C	1.000
X:105267478:T:G	Y212D	1.000
X:105267518:G:C	R225P	1.000
X:105717387:T:A	C265S	1.000
X:105717387:T:C	C265R	1.000
X:105717388:G:A	C265Y	1.000
X:105717388:G:C	C265S	1.000
X:105717389:C:G	C265W	1.000
X:105717437:G:C	W281C	1.000

dbSNP variants (sampled 300 via entrez): RS1000001535 (X:104868028 G>A,T), RS1000001648 (X:105116061 G>A), RS1000004044 (X:104880414 C>A), RS1000005274 (X:105397590 T>C), RS1000017600 (X:105448523 C>T), RS1000017840 (X:104601145 A>G), RS1000018367 (X:104763259 C>T), RS1000018579 (X:104871583 T>A,C), RS1000019553 (X:105065784 A>T), RS1000025763 (X:105577333 G>A), RS1000027078 (X:105697227 A>G), RS1000027402 (X:104945991 A>G), RS1000028058 (X:105319056 G>C), RS1000030305 (X:105502479 T>C,G), RS1000035297 (X:104880735 G>A)

Disease associations

OMIM: gene MIM:300277 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases methylation	2
FR900359	increases phosphorylation	1
sodium arsenite	decreases expression	1
zinc sulfide	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
Aripiprazole	affects cotreatment, increases expression	1
Amphotericin B	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	affects cotreatment, decreases expression	1
Endosulfan	decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Lead	decreases expression	1
Ozone	affects cotreatment, increases expression	1
Selenium	affects cotreatment, decreases expression	1
Tetradecanoylphorbol Acetate	affects cotreatment, affects expression	1
Tobacco Smoke Pollution	increases expression	1
Zinc	affects cotreatment, affects expression	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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