IL36RN

Summary

IL36RN (interleukin 36 receptor antagonist, HGNC:15561) is a protein-coding gene on chromosome 2q14.1, encoding Interleukin-36 receptor antagonist protein (Q9UBH0). Inhibits the activity of interleukin-36 (IL36A,IL36B and IL36G) by binding to receptor IL1RL2 and preventing its association with the coreceptor IL1RAP for signaling.

The protein encoded by this gene is a member of the interleukin 1 cytokine family. This cytokine was shown to specifically inhibit the activation of NF-kappaB induced by interleukin 1 family, member 6 (IL1F6). This gene and eight other interleukin 1 family genes form a cytokine gene cluster on chromosome 2. Two alternatively spliced transcript variants encoding the same protein have been reported.

Source: NCBI Gene 26525 — RefSeq curated summary.

At a glance

• Gene–disease (curated): psoriasis 14, pustular (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 216 total — 10 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 43
• MANE Select transcript: NM_012275

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15561
Approved symbol	IL36RN
Name	interleukin 36 receptor antagonist
Location	2q14.1
Locus type	gene with protein product
Status	Approved
Aliases	FIL1, FIL1(DELTA), FIL1D, IL1HY1, IL1RP3, IL1L1, IL-1F5, IL36RA, MGC29840
Ensembl gene	ENSG00000136695
Ensembl biotype	protein_coding
OMIM	605507
Entrez	26525

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000346807, ENST00000393200, ENST00000437409, ENST00000514072

RefSeq mRNA: 2 — MANE Select: NM_012275 NM_012275, NM_173170

CCDS: CCDS2111

Canonical transcript exons

ENST00000393200 — 5 exons

Exon	Start	End
ENSE00001128476	113059412	113059467
ENSE00001144904	113062124	113062251
ENSE00001144910	113060852	113060937
ENSE00001514447	113059198	113059241
ENSE00003896815	113062453	113064744

Expression profiles

Bgee: expression breadth ubiquitous, 106 present calls, max score 98.54.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5425 / max 100.7060, expressed in 142 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
22077	0.4326	119
22076	0.1099	49

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
amniotic fluid	UBERON:0000173	98.54	gold quality
upper arm skin	UBERON:0004263	95.11	gold quality
gingiva	UBERON:0001828	94.44	gold quality
gingival epithelium	UBERON:0001949	94.19	gold quality
tongue squamous epithelium	UBERON:0006919	92.71	gold quality
skin of leg	UBERON:0001511	92.29	gold quality
esophagus squamous epithelium	UBERON:0006920	91.61	gold quality
squamous epithelium	UBERON:0006914	91.42	gold quality
lower esophagus mucosa	UBERON:0035834	90.51	gold quality
epithelium of esophagus	UBERON:0001976	90.33	gold quality
zone of skin	UBERON:0000014	89.89	gold quality
skin of abdomen	UBERON:0001416	89.09	gold quality
cervix epithelium	UBERON:0004801	85.99	gold quality
oral cavity	UBERON:0000167	85.31	gold quality
esophagus mucosa	UBERON:0002469	83.90	gold quality
cervix squamous epithelium	UBERON:0006922	83.84	silver quality
buccal mucosa cell	CL:0002336	81.59	gold quality
cartilage tissue	UBERON:0002418	78.98	gold quality
sperm	CL:0000019	74.58	silver quality
male germ cell	CL:0000015	73.61	silver quality
placenta	UBERON:0001987	73.27	gold quality
upper leg skin	UBERON:0004262	72.53	gold quality
epithelium of nasopharynx	UBERON:0001951	72.33	silver quality
penis	UBERON:0000989	72.21	gold quality
mammalian vulva	UBERON:0000997	71.71	gold quality
periodontal ligament	UBERON:0008266	70.20	silver quality
oviduct epithelium	UBERON:0004804	68.41	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	68.16	gold quality
skin of hip	UBERON:0001554	67.08	gold quality
body of tongue	UBERON:0011876	66.28	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.94

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

78 targeting IL36RN, 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-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-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-646	99.68	67.84	1645

Literature-anchored findings (GeneRIF, showing 40)

• IL-1 delta, which shows striking homology to IL-1 receptor antagonist, specifically and potently inhibits NF-kappa B activation through the orphan IL-1 receptor-related protein 2. (PMID:11466363)
• results suggest that polymorphisms within IL1RN and IL1L1 themselves or a gene in linkage disequilibrium with IL1RN and IL1L1 predispose to the more severe forms of alopecia areata (PMID:11841485)
• The commnon variants in the IL-1 cluster gene are not associated with incidence of restenosis in patients after PTCA. (PMID:14644395)
• IL-1beta-511T was associated with reflux esophagitis having hyperacidity. (PMID:16211343)
• Data show that the gene expression for interleukin-8, IL-10, and IL-1Ra, but not IL-6, is increased in blood leukocytes taken from athletes following 2 hours of intensive cycling and is not influenced by carbohydrate compared with placebo ingestion. (PMID:16978071)
• Expression of IL-1F5 is increased in human plaque psoriasis skin and is overexpressed in the lesional psoriatic skin of transgenic mice. (PMID:21242515)
• Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. (PMID:21839423)
• Interleukin-36 (IL-36) ligands require processing for full agonist (IL-36alpha, IL-36beta, and IL-36gamma) or antagonist (IL-36Ra) activity (PMID:21965679)
• These data provide evidence that IL-38 binds to the IL-36R, as does IL-36Ra. (PMID:22315422)
• The mutation in the interleukin-36-receptor antagonist gene plays a role in generalised pustular psoriasis (PMID:22325761)
• Results indicate that IL36RN mutations are not associated with pustular psoriasis in Chinese populations. (PMID:22862555)
• Data indicate that IL36RN mutations were identified in 2 of 14 Japanese generalized pustular psoriasis (GPP) patients. (PMID:22903787)
• Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes. (PMID:23303454)
• IL36RN missense mutations may underlie some forms of acute generalized exanthematous pustulosis. (PMID:23358093)
• Acrodermatitis is a clinical phenotype of DITRA: evidence a variant of pustular psoriasis… recessively inherited mutations in the IL36RN gene, which encodes interleukin-36 receptor antagonist… the cause of familial GPP, a condition termed DITRA (PMID:23428889)
• Our rate of 38.9% IL36RN mutations provides further evidence that generalized pustular psoriasis is heterogenous. (PMID:23648549)
• The majority of generalized pustular psoriasis alone is caused by deficiency of the interleukin-36 receptor antagonist due to IL36RN mutations. (PMID:23698098)
• IL36RN variants are unlikely to confer significant disease risk for psoriasis vulgaris. (PMID:23792462)
• The percentage of IL36RN mutations of pediatric generalized pustular psoriasis patients was much higher than that of adult onset patients. (PMID:23863864)
• Individuals with IL36RN mutations are very susceptible to Generalized pustular psoriasis (GPP) or GPP-related generalized pustulosis induced by drugs. [review] (PMID:24656634)
• We report two cases of impetigo herpetiformis with homozygous and heterozygous IL36RN mutations. (PMID:24717243)
• IL-36 promotes myeloid cell infiltration, activation, and inflammatory activity in skin (PMID:24829417)
• in a Chinese Daur family with generalized pustular psoriasis, identified a homozygous splice site mutation c.115+6T>C in intron 3 in both patients; other 4 family members and 7 healthy controls carried heterozygous c.115+6T>C mutations (PMID:24979538)
• found 2 new variants and 4 known IL36RN variants in 29 generalized pustular psoriasis patients (PMID:25212972)
• The study found that IL36RN alleles define a generalized pustular psoriasis phenotype characterized by early onset, high risk of systemic inflammation, and low prevalence of psoriasis vulgaris. (PMID:25458002)
• identified a novel IL36RN missense mutation, c.334G > A in exon 5, that caused p.E112K substitution and was located adjacent to a 113 amino acid residue in generalized pustular psoriasis (PMID:25468355)
• we report T123M and 115+6T>C mutations, both homozygous in nature, in two Japanese individuals with Zumbusch type of generalized pustular psoriasis. (PMID:25615897)
• We identified a novel homozygous missense mutation in IL36RN in two siblings, and showed the molecular basis of the condition to be both distinct from psoriasis and distinct between the two families studied. (PMID:25688670)
• IL36RN was identified as strong regulators of skin pathology in both lesional and non-lesional skin samples. (PMID:25897967)
• IL36RN missense mutation was not associated with psoriasis. (PMID:25989471)
• The authors present a case of strikingly distinct phenotypes seen in two IL36RN mutation carriers from the same nonconsanguineous pedigree. This mutation it appears may influence the age of onset. (PMID:26147717)
• generalized pustular psoriasis and early onset, ever generalized pustular psoriasis (more than two attacks), ever acrodermatitis continua of Hallopeau, inverse psoriasis, and a family history of pustular psoriasis were associated with IL36RN mutation. (PMID:26589685)
• Case Report: short-term infliximab for treatment of juvenile generalized pustular psoriasis with IL36RN mutation. (PMID:26627198)
• The present study identified IL-36RN in various species and investigated the associations between IL-36RN and cancer prognosis. (PMID:26676204)
• The findings indicate that IL36RN mutations do not seem to contribute to the pathogenesis of common, nonpustular forms of psoriasis, but to the rarer pustular manifestations such as GPP, acrodermatitis continua suppurativa of Hallopeau and acute generalized exanthematous pustulosis. (PMID:27038307)
• Using different blood leukocyte and skin resident cell preparations, and recombinant proteins, the authors have identified that neutrophil elastase, but not other neutrophil derived proteases, cleaves IL-36Ra into its highly active antagonistic form. (PMID:27101808)
• A study on the association of IL36RN mutations that affect protein expression and function with phenotype in patients with generalized pustular psoriasis. (PMID:27220475)
• Study data and the previous European study suggest that palmoplantar pustulosis is not associated with mutations of the IL36RN gene. (PMID:27542682)
• Some cases of geographic tongue are caused by IL36RN mutations, while those lacking mutations are associated with an imbalance in expression between IL-36Ra and IL-36gamma proteins in tongue tissue. (PMID:27900482)
• Mutation in IL36RN impairs the processing and regulatory function of the interleukin-36-receptor antagonist and is associated with DITRA syndrome. (PMID:28603914)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	il1fma	ENSDARG00000089383
danio_rerio	il1b	ENSDARG00000098700
mus_musculus	Il36rn	ENSMUSG00000026983
rattus_norvegicus	Il36rn	ENSRNOG00000005751

Paralogs (7): IL1B (ENSG00000125538), IL37 (ENSG00000125571), IL36G (ENSG00000136688), IL1RN (ENSG00000136689), IL36A (ENSG00000136694), IL36B (ENSG00000136696), IL1F10 (ENSG00000136697)

Protein

Protein identifiers

Interleukin-36 receptor antagonist protein — Q9UBH0 (reviewed: Q9UBH0)

Alternative names: FIL1 delta, IL-1-related protein 3, Interleukin-1 HY1, Interleukin-1 delta, Interleukin-1 family member 5, Interleukin-1 receptor antagonist homolog 1, Interleukin-1-like protein 1

All UniProt accessions (3): C9JTH1, Q9UBH0, U3KPW9

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits the activity of interleukin-36 (IL36A,IL36B and IL36G) by binding to receptor IL1RL2 and preventing its association with the coreceptor IL1RAP for signaling. Part of the IL-36 signaling system that is thought to be present in epithelial barriers and to take part in local inflammatory response; similar to the IL-1 system with which it shares the coreceptor. Proposed to play a role in skin inflammation. May be involved in the innate immune response to fungal pathogens, such as Aspergillus fumigatus. May activate an anti-inflammatory signaling pathway by recruiting SIGIRR.

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

Subcellular location. Cytoplasm. Secreted.

Tissue specificity. Predominantly expressed in skin keratinocytes but not in fibroblasts, endothelial cells or melanocytes. Detected also in the spleen, brain leukocyte and macrophage cell types. Increased in lesional psoriasis skin.

Disease relevance. Psoriasis 14, pustular (PSORS14) [MIM:614204] A life-threatening disease defined by repeated flares of sudden onset consisting of diffuse erythematous skin eruption characterized by rapid coverage with pustules, high-grade fever, asthenia, marked leukocytosis, and elevated serum levels of C-reactive protein. The disease is caused by variants affecting the gene represented in this entry.

Induction. By phorbol ester (PMA) and bacterial lipopolysaccharides (LPS) treatment in macrophage cell line. By Aspergillus fumigatus conidia in peripheral blood mnonocytes.

Similarity. Belongs to the IL-1 family.

RefSeq proteins (2): NP_036407, NP_775262 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000975	IL-1_fam	Family
IPR003297	IL-1RA/IL-36	Family
IPR008996	IL1/FGF	Homologous_superfamily
IPR020877	IL-1_CS	Conserved_site

Pfam: PF00340

UniProt features (25 total): strand 13, sequence variant 5, helix 3, initiator methionine 1, chain 1, turn 1, disulfide bond 1

Structure

Experimental structures (PDB)

3 structures.

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

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBH0-F1	92.62	0.82

Functional residue map

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

Disulfide bonds (1): 8–154

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9014826	Interleukin-36 pathway

MSigDB gene sets: 217 (showing top): GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_INTERLEUKIN_6_PRODUCTION, MARTINEZ_RB1_TARGETS_UP, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GOBP_NEGATIVE_REGULATION_OF_TYPE_II_INTERFERON_PRODUCTION, GOBP_CYTOKINE_PRODUCTION, GOBP_REGULATION_OF_RESPONSE_TO_STRESS

GO Biological Process (11): negative regulation of cytokine-mediated signaling pathway (GO:0001960), inflammatory response (GO:0006954), immune response (GO:0006955), antifungal humoral response (GO:0019732), negative regulation of type II interferon production (GO:0032689), negative regulation of interleukin-17 production (GO:0032700), negative regulation of interleukin-6 production (GO:0032715), innate immune response (GO:0045087), cellular response to lipopolysaccharide (GO:0071222), immune system process (GO:0002376), signal transduction (GO:0007165)

GO Molecular Function (4): cytokine activity (GO:0005125), interleukin-1 receptor binding (GO:0005149), interleukin-1 receptor antagonist activity (GO:0005152), protein binding (GO:0005515)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Interleukin-1 family signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of cytokine production	3
cytokine receptor binding	2
cellular anatomical structure	2
regulation of cytokine-mediated signaling pathway	1
negative regulation of signal transduction	1
cytokine-mediated signaling pathway	1
negative regulation of response to cytokine stimulus	1
defense response	1
immune system process	1
response to stimulus	1
antimicrobial humoral response	1
defense response to fungus	1
type II interferon production	1
regulation of type II interferon production	1
interleukin-17 production	1
regulation of interleukin-17 production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
immune response	1
defense response to symbiont	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
biological_process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
receptor ligand activity	1
growth factor receptor binding	1
negative regulation of cytokine-mediated signaling pathway	1
interleukin-1 binding	1
receptor antagonist activity	1
binding	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

996 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL36RN	IL1RL2	Q9HB29	993
IL36RN	IL36B	Q9NZH7	965
IL36RN	IL1R1	P14778	923
IL36RN	IL1A	P01583	815
IL36RN	IL1B	P01584	783
IL36RN	CARD14	Q9BXL6	771
IL36RN	SIGIRR	Q6IA17	745
IL36RN	AP1S3	Q96PC3	726
IL36RN	IL1RAP	Q9NPH3	720
IL36RN	IL18R1	Q13478	687
IL36RN	IL33	O95760	620
IL36RN	IL6	P05231	604
IL36RN	IL18	Q14116	582
IL36RN	IFNG	P01579	572
IL36RN	IL1RAPL2	Q9NP60	570

IntAct

87 interactions, top by confidence:

A	B	Type	Score
IL36RN	SSBP3	psi-mi:“MI:0915”(physical association)	0.720
SSBP3	IL36RN	psi-mi:“MI:0915”(physical association)	0.720
SSBP4	IL36RN	psi-mi:“MI:0915”(physical association)	0.670
IL36RN	SSBP4	psi-mi:“MI:0915”(physical association)	0.670
REL	IL36RN	psi-mi:“MI:0915”(physical association)	0.560
IL36RN	REL	psi-mi:“MI:0915”(physical association)	0.560
IL36RN	HPCA	psi-mi:“MI:0915”(physical association)	0.560
CRACR2B	IL36RN	psi-mi:“MI:0915”(physical association)	0.560
CNOT4	IL36RN	psi-mi:“MI:0915”(physical association)	0.560
SH2B2	IL36RN	psi-mi:“MI:0915”(physical association)	0.560
IRAK4	IL36RN	psi-mi:“MI:0915”(physical association)	0.560
DDIT4L	IL36RN	psi-mi:“MI:0915”(physical association)	0.560
INCA1	IL36RN	psi-mi:“MI:0915”(physical association)	0.560
ZKSCAN4	IL36RN	psi-mi:“MI:0915”(physical association)	0.560
AGR2	IL36RN	psi-mi:“MI:0915”(physical association)	0.560
IL36RN	AP3M1	psi-mi:“MI:0915”(physical association)	0.560
UBL4B	IL36RN	psi-mi:“MI:0915”(physical association)	0.560
HPCA	IL36RN	psi-mi:“MI:0915”(physical association)	0.560
SSBP2	IL36RN	psi-mi:“MI:0915”(physical association)	0.550
TBC1D22B	A2ML1	psi-mi:“MI:0914”(association)	0.530
IL36RN	UBB	psi-mi:“MI:0914”(association)	0.530
SSBP2	CLEC18A	psi-mi:“MI:0914”(association)	0.530
IL36RN	TXN2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (54): IL36RN (Two-hybrid), IL36RN (Two-hybrid), IL36RN (Two-hybrid), SSBP4 (Two-hybrid), IL36RN (Two-hybrid), IL36RN (Affinity Capture-MS), IL36RN (Affinity Capture-MS), RRAS (Affinity Capture-MS), SRC (Affinity Capture-MS), UBB (Affinity Capture-MS), SRSF8 (Affinity Capture-MS), HNRNPLL (Affinity Capture-MS), IL36RN (Affinity Capture-MS), IL36RN (Two-hybrid), IL36RN (Two-hybrid)

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

Diamond homologs: O18999, O77482, P09428, P18510, P21621, P25085, P25086, P26890, P51745, P79162, Q29056, Q2MH07, Q866R8, Q8R459, Q8WNR2, Q8WWZ1, Q9BEH0, Q9D6Z6, Q9GMZ4, Q9NZH6, Q9QYY1, Q9UBH0, Q9UHA7, Q9YGD3, A4UYK8, P01584, P10749, P14628, P26889, P41687, P46648, P48090, P51493, P79182, Q28292, Q28386, Q2HZH0, Q63264, Q6PUD2, Q6R2X3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
IL1F10	“down-regulates activity”	IL36RN	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	4
Uncertain significance	100
Likely benign	59
Benign	17

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1071715	NC_000002.11:g.(?113816996)(113820274_?)del	Pathogenic
1459348	NC_000002.11:g.(?113817016)(113890448_?)del	Pathogenic
2183544	NM_012275.3(IL36RN):c.420_426del (p.Gly141fs)	Pathogenic
2779032	NM_012275.3(IL36RN):c.184C>T (p.Gln62Ter)	Pathogenic
30489	NM_012275.3(IL36RN):c.80T>C (p.Leu27Pro)	Pathogenic
3640207	NM_012275.3(IL36RN):c.16del (p.Ala6fs)	Pathogenic
3725838	NM_012275.3(IL36RN):c.273del (p.Ala92fs)	Pathogenic
3776767	NM_012275.3(IL36RN):c.205_212del (p.Ser69fs)	Pathogenic
40006	NM_012275.3(IL36RN):c.368C>G (p.Thr123Arg)	Pathogenic
4747025	NM_012275.3(IL36RN):c.41C>A (p.Ser14Ter)	Pathogenic
1066220	NM_012275.3(IL36RN):c.29+1G>A	Likely pathogenic
2000447	NM_012275.3(IL36RN):c.30-2A>G	Likely pathogenic
2579641	NM_012275.3(IL36RN):c.338C>A (p.Ser113Ter)	Likely pathogenic
2712028	NM_012275.3(IL36RN):c.30-1G>T	Likely pathogenic

SpliceAI

940 predictions. Top by Δscore:

Variant	Effect	Δscore
2:113059411:GGGGA:G	acceptor_gain	1.0000
2:113059410:AGG:A	acceptor_gain	0.9900
2:113059411:GGG:G	acceptor_gain	0.9900
2:113060850:A:AG	acceptor_gain	0.9900
2:113060851:G:GG	acceptor_gain	0.9900
2:113060924:G:T	donor_gain	0.9900
2:113062197:TGG:T	donor_gain	0.9900
2:113062447:C:A	acceptor_gain	0.9900
2:113062451:A:AG	acceptor_gain	0.9900
2:113062452:G:GG	acceptor_gain	0.9900
2:113062452:GCCA:G	acceptor_gain	0.9900
2:113059410:AG:A	acceptor_gain	0.9800
2:113059411:GG:G	acceptor_gain	0.9800
2:113059464:TCCG:T	donor_loss	0.9800
2:113059465:CCGG:C	donor_loss	0.9800
2:113059466:CG:C	donor_loss	0.9800
2:113059467:GGT:G	donor_loss	0.9800
2:113059468:G:GT	donor_loss	0.9800
2:113059469:TGAG:T	donor_loss	0.9800
2:113059470:GA:G	donor_loss	0.9800
2:113059471:AGTG:A	donor_loss	0.9800
2:113059472:G:C	donor_loss	0.9800
2:113062118:CCACA:C	acceptor_loss	0.9800
2:113062119:CACA:C	acceptor_loss	0.9800
2:113062120:ACAGG:A	acceptor_loss	0.9800
2:113062121:CAGG:C	acceptor_loss	0.9800
2:113062122:A:G	acceptor_loss	0.9800
2:113062123:G:GA	acceptor_loss	0.9800
2:113062452:GCC:G	acceptor_gain	0.9800
2:113058741:AAGG:A	donor_loss	0.9700

AlphaMissense

1000 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:113059463:T:C	F9L	0.988
2:113059465:C:A	F9L	0.988
2:113059465:C:G	F9L	0.988
2:113062541:T:C	F111S	0.984
2:113062142:T:A	V45D	0.983
2:113062507:T:C	F100L	0.983
2:113062509:C:A	F100L	0.983
2:113062509:C:G	F100L	0.983
2:113062501:T:C	F98L	0.982
2:113062503:C:A	F98L	0.982
2:113062503:C:G	F98L	0.982
2:113062178:T:A	V57D	0.981
2:113062601:T:A	V131D	0.981
2:113062508:T:C	F100S	0.976
2:113062567:T:C	F120L	0.973
2:113062569:C:A	F120L	0.973
2:113062569:C:G	F120L	0.973
2:113062207:T:C	C67R	0.972
2:113060859:G:C	D13H	0.969
2:113062133:T:C	I42T	0.967
2:113062133:T:G	I42S	0.967
2:113062655:T:C	F149S	0.967
2:113062534:T:C	S109P	0.966
2:113062654:T:C	F149L	0.966
2:113062656:C:A	F149L	0.966
2:113062656:C:G	F149L	0.966
2:113062187:G:A	G60D	0.965
2:113060854:T:C	M11T	0.963
2:113062571:T:A	L121Q	0.963
2:113062149:T:A	N47K	0.961

dbSNP variants (sampled 300 via entrez): RS1001141325 (2:113060053 G>A), RS1001300675 (2:113060218 CT>C), RS1001768930 (2:113064948 G>C), RS1001792864 (2:113060678 C>T), RS1001863818 (2:113058829 G>A), RS1002052807 (2:113059689 G>A,C), RS1002179174 (2:113065008 C>T), RS1002236433 (2:113064693 T>C), RS1002812818 (2:113057994 TAATA>T), RS1003049582 (2:113057717 A>G), RS1003198889 (2:113061930 T>C), RS1004388903 (2:113063624 A>G), RS1004955140 (2:113057549 T>C), RS1005465926 (2:113063431 C>T), RS1005658151 (2:113062250 A>C)

Disease associations

OMIM: gene MIM:605507 | disease phenotypes: MIM:614204, MIM:612852

GenCC curated gene-disease

Disease	Classification	Inheritance
psoriasis 14, pustular	Strong	Autosomal recessive
autoinflammatory syndrome	Strong	Semidominant
palmoplantar pustulosis	Supportive	Autosomal dominant

Mondo (5): generalized pustular psoriasis (MONDO:0100491), autoinflammatory syndrome (MONDO:0019751), psoriasis 14, pustular (MONDO:0013626), sterile multifocal osteomyelitis with periostitis and pustulosis (MONDO:0013021), palmoplantar pustulosis (MONDO:0015597)

Orphanet (5): Generalized pustular psoriasis (Orphanet:247353), Autoinflammatory syndrome (Orphanet:93665), Acrodermatitis continua of Hallopeau (Orphanet:163931), Sterile multifocal osteomyelitis with periostitis and pustulosis (Orphanet:210115), DITRA (Orphanet:404546)

HPO phenotypes

43 total (30 of 43 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000221	Furrowed tongue
HP:0000554	Uveitis
HP:0001019	Erythroderma
HP:0001036	Parakeratosis
HP:0001369	Arthritis
HP:0001513	Obesity
HP:0001597	Abnormal nail morphology
HP:0001635	Congestive heart failure
HP:0001888	Decreased total lymphocyte count
HP:0001945	Fever
HP:0001974	Increased total leukocyte count
HP:0002829	Arthralgia
HP:0002901	Hypocalcemia
HP:0002902	Hyponatremia
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003073	Hypoalbuminemia
HP:0003565	Elevated erythrocyte sedimentation rate
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0003623	Neonatal onset
HP:0003765	Psoriasiform dermatitis
HP:0005764	Polyarticular arthritis
HP:0008404	Nail dystrophy
HP:0010741	Pedal edema
HP:0010783	Erythema
HP:0011227	Elevated circulating C-reactive protein concentration
HP:0011462	Young adult onset
HP:0011463	Childhood onset

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002987_16	Stroke	6.000000e-07
GCST006104_7	Interleukin-1-receptor antagonist levels	1.000000e-06
GCST006636_1	Menstruation quality of life impact (dysmenorrhea)	3.000000e-12
GCST006637_3	Pain medicine use during menstruation	2.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004754	interleukin 1 receptor antagonist measurement
EFO:0007889	dysmenorrheic pain measurement
EFO:0007010	drug use measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C557815	Deficiency of interleukin-1 receptor antagonist (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, decreases expression	2
Lipopolysaccharides	increases expression, affects response to substance, affects cotreatment, decreases reaction	2
Silicon Dioxide	decreases expression, increases expression	2
Particulate Matter	increases expression	2
sodium arsenate	decreases expression, increases abundance	1
ethyl-p-hydroxybenzoate	increases expression	1
trichostatin A	affects expression, decreases reaction	1
zinc chloride	decreases expression	1
ferrous sulfate	decreases expression	1
hydroquinone	increases expression	1
1-nitropyrene	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
paricalcitol	affects cotreatment, decreases expression	1
abrine	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Doxorubicin	decreases expression	1
Formaldehyde	increases expression	1
Nickel	affects expression, decreases reaction	1
Phosphorus	affects cotreatment, decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Sodium Dodecyl Sulfate	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Triclosan	decreases reaction, increases expression	1
Valproic Acid	increases methylation	1
Asbestos, Crocidolite	increases expression	1
Cadmium Chloride	increases expression	1
Soot	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05710185	PHASE4	TERMINATED	Deucravacitinib for the Treatment of Palmoplantar Pustulosis
NCT07503652	PHASE4	RECRUITING	Clinical Observation of Xeligekimab in the Treatment of Moderate to Severe Palmoplantar Pustulosis
NCT03942042	PHASE4	COMPLETED	A Study of Ixekizumab (LY2439821) in Participants in Japan With Generalized Pustular Psoriasis and Erythrodermic Psoriasis
NCT06013969	PHASE4	ACTIVE_NOT_RECRUITING	A Study to Test Whether Spesolimab Helps People With Generalized Pustular Psoriasis (GPP) Who Need Treatment for Repeated Flares
NCT02641730	PHASE3	COMPLETED	An Efficacy and Safety of Guselkumab in Participants With Palmoplantar Pustulosis
NCT04061252	PHASE3	COMPLETED	A Study of KHK4827 in Subjects With Palmoplantar Pustulosis
NCT04451720	PHASE3	COMPLETED	Study of Subcutaneous Risankizumab Injection to Assess Change in Palmoplantar Pustulosis Area and Severity Index [PPPASI] in Adult Japanese Participants With Palmoplantar Pustulosis
NCT05174065	PHASE3	COMPLETED	Phase 3, Randomized Study of Apremilast in Japanese Participants With Palmoplantar Pustulosis (PPP)
NCT07219420	PHASE3	RECRUITING	A Study to Evaluate the Efficacy and Safety of Bimekizumab in Study Participants With Palmoplantar Pustulosis
NCT07530367	PHASE3	NOT_YET_RECRUITING	A Phase III Randomized Controlled Trial Evaluating the Efficacy and Safety of Tofacitinib Combined With Imatinib in Patients With Moderate-to-Severe Palmoplantar Pustulosis
NCT02533375	PHASE3	COMPLETED	Study to Investigate Efficacy and Safety of Adalimumab in Japanese Subjects With Generalized Pustular Psoriasis (GPP)
NCT05200247	PHASE3	COMPLETED	An Expanded Access Trial in Japan to Provide Spesolimab to People With a Flare-up in Generalized Pustular Psoriasis Who Have no Other Treatment Options
NCT05239039	PHASE3	COMPLETED	An Expanded Access Program in China to Provide Spesolimab to People With a Flare-up in Generalized Pustular Psoriasis Who Have no Other Treatment Options
NCT05352893	PHASE3	COMPLETED	Study to Evaluate the Efficacy and Safety of Imsidolimab (ANB019) in the Treatment of Subjects With GPP
NCT05366855	PHASE3	TERMINATED	Study to Evaluate the Long-Term Safety and Efficacy of Imsidolimab (ANB019) in the Treatment of Subjects With GPP
NCT06295692	PHASE3	ACTIVE_NOT_RECRUITING	A Study of JNJ-77242113 for the Treatment of Participants With Generalized Pustular Psoriasis or Erythrodermic Psoriasis
NCT06323356	PHASE3	ACTIVE_NOT_RECRUITING	A Study of TAK-279 in Adult Participants With Generalized Pustular Psoriasis or Erythrodermic Psoriasis
NCT01794117	PHASE2	COMPLETED	Anakinra for Inflammatory Pustular Skin Diseases
NCT03633396	PHASE2	COMPLETED	A Study to Evaluate the Efficacy and Safety of Imsidolimab (ANB019) in Adults With Palmoplantar Pustulosis
NCT03988335	PHASE2	COMPLETED	A Study to Evaluate RIST4721 in Palmoplantar Pustulosis (PPP)
NCT04015518	PHASE2	COMPLETED	A Study to Test How Effective and Safe Different Doses of BI 655130 Are in Patients With a Moderate to Severe Form of the Skin Disease Palmoplantar Pustulosis
NCT04493424	PHASE2	TERMINATED	A Study to Test Long-term Treatment With Spesolimab in People With Palmoplantar Pustulosis (PPP) Who Took Part in Previous Studies With Spesolimab
NCT04572997	PHASE2	COMPLETED	Apremilast in Patients With Moderate to Severe Palmoplantar Pustulosis (PPP) (APLANTUS)
NCT05194839	PHASE2	TERMINATED	A Phase 2b Study to Evaluate RIST4721 in Palmoplantar Pustulosis (PPP)
NCT07013201	PHASE2	RECRUITING	A 16-week Trial to Investigate the Efficacy and Safety of Delgocitinib Cream 20 mg/g in Adult Participants With Mild to Severe Palmoplantar Pustulosis
NCT00301002	PHASE2	COMPLETED	Study to Evaluate the Efficacy of Alefacept to Treat Palmar Plantar Pustulosis
NCT00442182	PHASE2	UNKNOWN	The Efficacy and Safety of ITF2357 in AIS
NCT03619902	PHASE2	COMPLETED	A Study to Evaluate the Efficacy and Safety of Imsidolimab (ANB019) in Adults With Generalized Pustular Psoriasis
NCT03782792	PHASE2	COMPLETED	Effisayil™ 1: A Study to Test Spesolimab (BI 655130) in Patients With a Flare-up of a Skin Disease Called Generalized Pustular Psoriasis
NCT03886246	PHASE2	ACTIVE_NOT_RECRUITING	Effisayil™ ON: A Study to Test Long-term Treatment With Spesolimab in People With Generalized Pustular Psoriasis Who Took Part in a Previous Study
NCT04399837	PHASE2	COMPLETED	A Study to Test Whether BI 655130 (Spesolimab) Prevents Flare-ups in Patients With Generalized Pustular Psoriasis
NCT06231381	PHASE2	RECRUITING	Efficacy and Safety of HB0034 in Patients with Generalized Pustular Psoriasis (GPP)
NCT07314060	PHASE2	RECRUITING	A Clinical Trial of TQH2929 Injection in Patients With Acute Flare-up of Generalized Pustular Psoriasis
NCT01801449	PHASE2	COMPLETED	Rilonacept for Deficiency of the Interleukin-1 Receptor Antagonist (DIRA)
NCT03972280	PHASE1	COMPLETED	Safety and Pharmacokinetics of Repeat Doses of CSL324 in Subjects With Hidradenitis Suppurativa and Palmoplantar Pustulosis
NCT05512598	PHASE1	COMPLETED	HB0034 in Patients With Generalized Pustular Psoriasis (GPP)
NCT06433531	PHASE1	ACTIVE_NOT_RECRUITING	A Clinical Study of TQH2929 Injection in Treatment With Generalized Pustular Psoriasis (GPP)
NCT01780857	Not specified	COMPLETED	Immune Signature of Palmoplantar Pustulosis
NCT04459507	Not specified	COMPLETED	A Registry Study of Palmoplantar Pustulosis (PPP) Treatment Patterns, Disease Burden and Treatment Outcomes in Japan
NCT04566471	Not specified	UNKNOWN	Palmoplantar Pustulosis and Generalized Pustular Psoriasis: A National Population-based Analysis of Prevalence