IL4R

Summary

IL4R (interleukin 4 receptor, HGNC:6015) is a protein-coding gene on chromosome 16p12.1, encoding Interleukin-4 receptor subunit alpha (P24394). Receptor for both interleukin 4 and interleukin 13.

This gene encodes the alpha chain of the interleukin-4 receptor, a type I transmembrane protein that can bind interleukin 4 and interleukin 13 to regulate IgE production. The encoded protein also can bind interleukin 4 to promote differentiation of Th2 cells. A soluble form of the encoded protein can be produced by proteolysis of the membrane-bound protein, and this soluble form can inhibit IL4-mediated cell proliferation and IL5 upregulation by T-cells. Allelic variations in this gene have been associated with atopy, a condition that can manifest itself as allergic rhinitis, sinusitus, asthma, or eczema. Polymorphisms in this gene are also associated with resistance to human immunodeficiency virus type-1 infection. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 3566 — RefSeq curated summary.

At a glance

• Gene–disease (curated): IgE responsiveness, atopic (No Known Disease Relationship, GenCC)
• GWAS associations: 33
• Clinical variants (ClinVar): 159 total
• Druggable target: yes
• MANE Select transcript: NM_000418

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6015
Approved symbol	IL4R
Name	interleukin 4 receptor
Location	16p12.1
Locus type	gene with protein product
Status	Approved
Aliases	CD124
Ensembl gene	ENSG00000077238
Ensembl biotype	protein_coding
OMIM	147781
Entrez	3566

Gene structure

Transcript identifiers

Ensembl transcripts: 49 — 41 protein_coding, 4 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000170630, ENST00000395762, ENST00000543915, ENST00000561742, ENST00000561946, ENST00000562142, ENST00000562968, ENST00000563002, ENST00000563787, ENST00000563886, ENST00000563926, ENST00000565179, ENST00000565352, ENST00000565696, ENST00000565915, ENST00000566117, ENST00000566318, ENST00000568746, ENST00000628578, ENST00000856359, ENST00000856360, ENST00000856361, ENST00000856362, ENST00000856363, ENST00000856364, ENST00000856365, ENST00000856366, ENST00000856367, ENST00000856368, ENST00000856369, ENST00000856370, ENST00000856371, ENST00000856372, ENST00000856373, ENST00000856374, ENST00000856375, ENST00000856376, ENST00000856377, ENST00000856378, ENST00000912074, ENST00000912075, ENST00000912076, ENST00000944738, ENST00000944739, ENST00000944740, ENST00000944741, ENST00000944742, ENST00000944743, ENST00000944744

RefSeq mRNA: 4 — MANE Select: NM_000418 NM_000418, NM_001257406, NM_001257407, NM_001257997

CCDS: CCDS10629, CCDS58441

Canonical transcript exons

ENST00000395762 — 11 exons

Exon	Start	End
ENSE00001522736	27362252	27364778
ENSE00001522738	27330066	27330198
ENSE00002591980	27313974	27314020
ENSE00003530547	27358916	27358994
ENSE00003540849	27355808	27355907
ENSE00003560869	27340186	27340273
ENSE00003574656	27342121	27342259
ENSE00003610754	27346467	27346618
ENSE00003614300	27352540	27352696
ENSE00003680872	27360766	27360815
ENSE00003787415	27344869	27345020

Expression profiles

Bgee: expression breadth ubiquitous, 245 present calls, max score 98.14.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.5868 / max 774.5483, expressed in 1751 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
153320	19.0173	1710
153319	4.9809	1118
153316	2.1827	996
153315	0.4701	214
153323	0.3642	113
153318	0.3588	191
153317	0.2045	93
153325	0.0084	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.14	gold quality
mucosa of stomach	UBERON:0001199	98.04	gold quality
right lung	UBERON:0002167	98.04	gold quality
upper lobe of left lung	UBERON:0008952	97.82	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.57	gold quality
upper lobe of lung	UBERON:0008948	97.42	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.36	gold quality
lower esophagus	UBERON:0013473	97.34	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.33	gold quality
vermiform appendix	UBERON:0001154	96.74	gold quality
spleen	UBERON:0002106	96.66	gold quality
transverse colon	UBERON:0001157	96.64	gold quality
esophagus	UBERON:0001043	96.62	gold quality
right lobe of liver	UBERON:0001114	96.49	gold quality
lymph node	UBERON:0000029	96.17	gold quality
esophagus mucosa	UBERON:0002469	96.06	gold quality
left uterine tube	UBERON:0001303	96.04	gold quality
lower esophagus mucosa	UBERON:0035834	95.91	gold quality
gall bladder	UBERON:0002110	95.83	gold quality
blood	UBERON:0000178	95.82	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.35	gold quality
mucosa of transverse colon	UBERON:0004991	95.30	gold quality
rectum	UBERON:0001052	95.22	gold quality
caecum	UBERON:0001153	95.17	gold quality
colon	UBERON:0001155	95.13	gold quality
sigmoid colon	UBERON:0001159	95.07	gold quality
right coronary artery	UBERON:0001625	94.89	gold quality
omental fat pad	UBERON:0010414	94.81	gold quality
large intestine	UBERON:0000059	94.78	gold quality
peritoneum	UBERON:0002358	94.77	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-122	yes	58.90
E-GEOD-135922	yes	34.39
E-CURD-119	yes	24.73
E-ANND-3	yes	14.96
E-MTAB-6386	no	411.55

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOS, GATA3, STAT6, TP53

miRNA regulators (miRDB)

29 targeting IL4R, 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-513B-5P	99.99	69.96	2150
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-7974	99.24	65.48	1137
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-7153-3P	99.00	65.35	608
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-5581-3P	98.55	70.31	1161
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-5581-5P	97.91	66.50	965
HSA-MIR-4690-3P	97.02	64.72	981
HSA-MIR-5685	97.02	64.34	1004
HSA-MIR-4486	96.96	60.61	931
HSA-MIR-125B-2-3P	96.69	68.38	1210
HSA-MIR-552-3P	96.68	64.12	1026
HSA-MIR-654-5P	96.07	66.18	1280
HSA-MIR-541-3P	96.07	66.11	1271
HSA-MIR-2861	95.24	65.47	1056
HSA-MIR-3622B-5P	94.62	64.58	835

Literature-anchored findings (GeneRIF, showing 40)

• gene-gene interaction in asthma: IL4RA and IL13 in a Dutch population with asthma (PMID:11709756)
• Tyrosine-phosphorylated IL4R peptides coprecipitate SH2-containing tyrosine phosphatase-1, SH2-containing tyrosine phosphatase-2, and SH2-containing inositol 5’-phosphatase, demonstrating a regulatory role for the ITIM motif in IL-4-induced proliferation. (PMID:11714803)
• high-affinity interaction of human IL-4 and the receptor alpha chain is constituted by two independent binding clusters (PMID:11786020)
• internalization of interleukin 4 receptor alpha increases cytotoxic effect of interleukin 4-receptor-targeted cytotoxin in cancer cells. (PMID:11801567)
• Characterization of IL-4 receptor components expressed on monocytes and monocyte-derived macrophages: variation associated with differential signaling by IL-4 (PMID:11811777)
• These results suggest TXA2 receptor polymorphism strongly interacts with IL-4R alpha polymorphism as a major determinant of high serum immunoglobulin E levels in atopic dermatitis. (PMID:11922633)
• Endogenous interferon-alpha production by differentiating human monocytes regulates expression and function of the IL-2/IL-4 receptor gamma chain (PMID:11991671)
• a single gene effect of IL4Ralpha variants or any other gene on chromosome 16 could not be shown in a selected population of children with asthma (PMID:12047364)
• no evidence for linkage of the IL4R gene locus with sarcoidosis (PMID:12047365)
• association of haplotype with type 1 diabetes (PMID:12401728)
• up-regulated 5-fold in B cell chronic lymphocytic leukemia cells, probably leading to increased responsiveness to IL4 and resistance to apoptosis (PMID:12454749)
• role of Tyr-713 in the interleukin-4 receptor alpha in regulating dephosphorylation of Stat6 (PMID:12459556)
• Allele frequency of IL4RA polymorphism was associated with rapid decline of lung function in smokers. (PMID:12594065)
• IL4R is associated with diabetes mellitus, type 1 in Filipinos. (PMID:12748907)
• Th2 cytokines enhance TARC expression in human airway smooth muscle cells in IL-4Ralpha genotype-dependent fashion. (PMID:12871855)
• No genotypic effects on total serum IgE levels. (PMID:12897746)
• IL-4R alpha chain 576R/R genotypes confer genetic susceptibility to allergic asthma in Chinese. (PMID:12940513)
• The prevalence of the mutant variant of the IL-4ra gene was lower in neonates with necrotizing enterocolitis (NEC) compared with those without NEC, suggesting that this mutation might protect against the development of NEC in VLBW infants. (PMID:14523823)
• functional variants within the IL4R gene predispose to hip osteoarthritis in Caucasian females (PMID:14745651)
• investigated the frequency and genotypes of S503P and Q576R SNPs and their association with traits of allergic asthma in a Hawaii population (PMID:14984008)
• polymorphisms of IL1A (G/T at +4845) and IL4RA (T/C at +22446) show an epistatic effect on the risk of atopy (PMID:15007345)
• variants in the IL4, IL13, and IL4RA genes play an important role in controlling specific IgE response in atopy (PMID:15007352)
• Certain interstitial pneumonia patients can be modulated in a manner that is dependent on the IL-4 and IL-13 receptor subunit expression by these cells. (PMID:15161635)
• V50R551 IL-4R alpha variant has enhanced function alone, but with Q110 IL-13 variant the 2 have a synergistic effect on IL-13-dependent gene induction. (PMID:15356556)
• Polymorphisms of IL-4R previously associated with other immune mediated diseases, do not confer susceptibility to Graves’ disease in white Caucasians in the United Kingdom. (PMID:15497451)
• differences in the potency of IL-13- and IL-4-mediated induction of eotaxin-3 might be explained by expression of types 1 and 2 IL-4 receptors in bronchial epithelium (PMID:15521376)
• The IL-4RalphaQ576R polymorphism may involve in the development of penicillins allergy, and through modulating specific serum IgE levels. (PMID:15969687)
• IL$R alpha V50 homozygosity associates with slow progression and that exon 12 U-haplotypes might be associated with both susceptibility to infection via parenteral route and resistance to infection via sexual exposure. (PMID:16189667)
• The soluble receptor balance (sIL-2R/sIL-4R) in patients with severe hemolytic uremic syndrome may shift, depending on the disease state of the patients (PMID:16226465)
• In conclusion, these results suggest that viral airway infection may enhance interleukin-4-induced eotaxin-3 production through upregulation of the interleukin-4 receptor in airway epithelial cells. (PMID:16264039)
• No association between type 1 diabetes and any SNP or haplotype was found by the transmission disequilibrium test. (PMID:16538488)
• This is the first demonstration of sex-specific association of the two foremost genes of the IL-4 signalling cascade with chronic inflammatory arthropathies. (PMID:16551465)
• Multifactor dimensionality reduction (MDR) test was applied to detect epistasis, and identified single-IL4R(Q576R)- and three-IL4R(Q576R), IL5RA(-80), CD14(-260)- locus association models that predict multiple sclerosis risk with 75-76% accuracy. (PMID:16625214)
• A structure/function analysis of the IL-4 ligand-receptor interaction, using various mutations of both the ligand and the receptor, is reported. (PMID:16640778)
• Results show sequence variations as a possible way of altering alternative splicing selection of IL4R in vivo. (PMID:16917945)
• Homozygotes with the low activity allele of the A398G polymorphism in the IL4R gene had a modest increase in risk of atrophic gastritis (OR = 1.52, 95% CI: 1.05-2.21), compared with homozygotes of the high activity allele. (PMID:17006724)
• The Ile50Val polymorphism of IL-4R alpha gene is not associated with bronchial asthma in Han nationality patients. (PMID:17045041)
• Variants in the IL4RA gene alone may not exert any major influence on susceptibility to asthma-related diseases in childhood, but in combination with other genes, such as IL9R, IL4RA may be an important gene for disease susceptibility (PMID:17083349)
• Our findings of higher frequency of IL4 and IL4RA genotypes and alleles with rheumatoid arthritis. (PMID:17143971)
• SNPs in IL4Ralpha, which are more common in African Americans, are associated with severe asthma exacerbations, lower lung function, and increased mast cell-related tissue inflammation (PMID:17170387)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Il4ra	ENSMUSG00000030748
rattus_norvegicus	Il4r	ENSRNOG00000015441

Paralogs (7): CSF2RB (ENSG00000100368), IL2RB (ENSG00000100385), IL21R (ENSG00000103522), MPL (ENSG00000117400), IL9R (ENSG00000124334), IL7R (ENSG00000168685), EPOR (ENSG00000187266)

Protein

Protein identifiers

Interleukin-4 receptor subunit alpha — P24394 (reviewed: P24394)

All UniProt accessions (9): P24394, A0A0G2JLA1, H3BRH7, H3BSE7, H3BTD9, I3L4H7, I3L4W9, J9JII2, Q5FC08

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for both interleukin 4 and interleukin 13. Couples to the JAK1/2/3-STAT6 pathway. The IL4 response is involved in promoting Th2 differentiation. The IL4/IL13 responses are involved in regulating IgE production and, chemokine and mucus production at sites of allergic inflammation. In certain cell types, can signal through activation of insulin receptor substrates, IRS1/IRS2. Soluble IL4R (sIL4R) inhibits IL4-mediated cell proliferation and IL5 up-regulation by T-cells.

Subunit / interactions. The functional IL4 receptor is formed by initial binding of IL4 to IL4R. Subsequent recruitment to the complex of the common gamma chain, in immune cells, creates a type I receptor and, in non-immune cells, of IL13RA1 forms a type II receptor. IL4R can also interact with the IL13/IL13RA1 complex to form a similar type II receptor. Interacts with PIK3C3. Interacts with the SH2-containing phosphatases, PTPN6/SHIP1, PTPN11/SHIP2 and INPP5D/SHIP. Interacts with JAK1 through a Box 1-containing region; inhibited by SOCS5. Interacts with SOCS5; inhibits IL4 signaling. Interacts with JAK3. Interacts with CLM1. Interacts with IL13RA2.

Subcellular location. Cell membrane Secreted.

Tissue specificity. Isoform 1 and isoform 2 are highly expressed in activated T-cells.

Post-translational modifications. On IL4 binding, phosphorylated on C-terminal tyrosine residues. Phosphorylation on any one of tyrosine residues, Tyr-575, Tyr-603 or Tyr-631, is required for STAT6-induced gene induction. The soluble form (sIL4R/IL4BP) can also be produced by proteolytic cleavage at the cell surface (shedding) by a metalloproteinase.

Domain organisation. The extracellular domain represents the IL4 binding protein (IL4BP). The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding. The box 1 motif is required for JAK interaction and/or activation. Contains 1 copy of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM). This motif is involved in modulation of cellular responses. The phosphorylated ITIM motif can bind the SH2 domain of several SH2-containing phosphatases.

Polymorphism. Allelic variants in IL4RA are associated with a susceptibility to atopy, an immunological condition that can lead to clinical symptoms such as allergic rhinitis, sinusitis, asthma and eczema. Allelic variants in IL4RA are associated with cedar pollen sensitization. Individuals develop Japanese cedar pollinosis with increased exposure to cedar pollen. Japanese cedar pollinosis is a type I allergic disease with ocular and nasal symptoms that develop paroxysmally on contact with Japanese cedar pollen. These symptoms, which occur seasonally each year, are typical features of allergic rhinitis, such as sneezing, excessive nasal secretion, nasal congestion, and conjunctival itching.

Similarity. Belongs to the type I cytokine receptor family. Type 4 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P24394-1	1, Membrane-bound form	yes
P24394-2	2, Soluble form, sIL4Ralpha/splice
P24394-3	3

RefSeq proteins (4): NP_000409, NP_001244335, NP_001244336, NP_001244926 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003531	Hempt_rcpt_S_F1_CS	Conserved_site
IPR003961	FN3_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015319	IL-4_rcpt-alpha_N	Domain
IPR036116	FN3_sf	Homologous_superfamily

Pfam: PF09238

UniProt features (113 total): mutagenesis site 33, strand 16, sequence variant 15, site 8, region of interest 6, helix 6, glycosylation site 6, modified residue 4, short sequence motif 3, compositionally biased region 3, splice variant 3, chain 2, topological domain 2, disulfide bond 2, signal peptide 1, turn 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
1IAR	X-RAY DIFFRACTION	2.3
8K4Q	X-RAY DIFFRACTION	2.59
6WGL	X-RAY DIFFRACTION	2.82
3BPL	X-RAY DIFFRACTION	2.93
3BPO	X-RAY DIFFRACTION	3
5E4E	X-RAY DIFFRACTION	3
3BPN	X-RAY DIFFRACTION	3.02
6OEL	X-RAY DIFFRACTION	3.1
8Z8L	X-RAY DIFFRACTION	3.96
1IRS	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P24394-F1	55.73	0.24

Antibody-complex structures (SAbDab): 4 — 6OEL, 6WGL, 8K4Q, 8Z8L

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 (8): 38 (major il4 binding determinant); 64 (minor il4 binding determinant); 66 (minor il4 binding determinant); 92 (minor il4 binding determinant); 94 (minor il4 binding determinant); 97 (major il4 binding determinant); 152 (minor il4 binding determinant); 208 (major il4 binding determinant)

Post-translational modifications (4): 497, 575, 603, 631

Disulfide bonds (2): 34–44, 74–86

Glycosylation sites (6): 53, 98, 128, 134, 176, 209

Mutagenesis-validated functional residues (33):

Position	Phenotype
38	700-fold reduction in il4 binding.
38	25-fold reduction in il4 binding.
39	no effect on il4 binding.
40	no effect on il4 binding.
64	100-fold reduction in il4 binding.
66	45-fold reduction in il4 binding.
67	no effect on il4 binding.
68	no effect on il4 binding.
91	little effect on il4 binding.
92	50-fold reduction in il4 binding.
93	little effect on il4 binding.
94	35-fold reduction in il4 binding.
95	no effect on il4 binding.
97	>150-fold reduction in il4 binding.
98	no effect on il4 binding.
99	10-fold reduction in il4 binding.
116	little effect on il4 binding.
117	little effect on il4 binding.
118	no effect on il4 binding.
119	no effect on il4 binding.
150	little effect on il4 binding.
151	little effect on il4 binding.
152	40-fold reduction in il4 binding.
152	no effect on il4 binding.
153	little effect on il4 binding.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-9976102	Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)

MSigDB gene sets: 455 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_MACROPHAGE_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, BOYAULT_LIVER_CANCER_SUBCLASS_G56_DN, LU_IL4_SIGNALING, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_INTERLEUKIN_4, GOBP_RESPONSE_TO_PEPTIDE, MODULE_45, MODULE_64, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, HALMOS_CEBPA_TARGETS_UP, GOBP_REGULATION_OF_MACROPHAGE_ACTIVATION

GO Biological Process (19): production of molecular mediator involved in inflammatory response (GO:0002532), positive regulation of immunoglobulin production (GO:0002639), immune response (GO:0006955), signal transduction (GO:0007165), immunoglobulin mediated immune response (GO:0016064), positive regulation of chemokine production (GO:0032722), interleukin-4-mediated signaling pathway (GO:0035771), defense response to protozoan (GO:0042832), positive regulation of macrophage activation (GO:0043032), positive regulation of mast cell degranulation (GO:0043306), T-helper 1 cell differentiation (GO:0045063), T-helper 2 cell differentiation (GO:0045064), negative regulation of T-helper 1 cell differentiation (GO:0045626), positive regulation of T-helper 2 cell differentiation (GO:0045630), positive regulation of cold-induced thermogenesis (GO:0120162), positive regulation of myoblast fusion (GO:1901741), immune system process (GO:0002376), cell surface receptor signaling pathway (GO:0007166), cytokine-mediated signaling pathway (GO:0019221)

GO Molecular Function (3): interleukin-4 receptor activity (GO:0004913), cytokine receptor activity (GO:0004896), protein binding (GO:0005515)

GO Cellular Component (7): extracellular region (GO:0005576), nucleoplasm (GO:0005654), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), centriolar satellite (GO:0034451), signaling receptor complex (GO:0043235), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by Interleukins	1
Differentiation of T cells	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytokine-mediated signaling pathway	2
alpha-beta T cell activation involved in immune response	2
T cell differentiation involved in immune response	2
T-helper cell differentiation	2
inflammatory response	1
multicellular organismal process	1
immunoglobulin production	1
regulation of immunoglobulin production	1
positive regulation of production of molecular mediator of immune 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
B cell mediated immunity	1
positive regulation of cytokine production	1
chemokine production	1
regulation of chemokine production	1
cellular response to interleukin-4	1
response to protozoan	1
defense response to other organism	1
positive regulation of leukocyte activation	1
macrophage activation	1
regulation of macrophage activation	1
positive regulation of leukocyte degranulation	1
mast cell degranulation	1
regulation of mast cell degranulation	1
T-helper 1 type immune response	1
type 2 immune response	1
negative regulation of immune effector process	1
negative regulation of T-helper 1 type immune response	1
T-helper 1 cell differentiation	1
negative regulation of T-helper cell differentiation	1
regulation of T-helper 1 cell differentiation	1
positive regulation of immune effector process	1
positive regulation of type 2 immune response	1
T-helper 2 cell differentiation	1

Protein interactions and networks

STRING

2865 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL4R	IL4	P05112	999
IL4R	IL13	P35225	999
IL4R	IL13RA1	P78552	999
IL4R	IL2RG	P31785	997
IL4R	IL13RA2	Q14627	996
IL4R	JAK1	P23458	993
IL4R	STAT6	P42226	968
IL4R	SOCS5	O75159	914
IL4R	IL10	P22301	904
IL4R	IFNG	P01579	876
IL4R	JAK3	P52333	850
IL4R	IL7	P13232	845
IL4R	IL7R	P16871	824
IL4R	IL5	P05113	817
IL4R	IL6R	P08887	817

IntAct

33 interactions, top by confidence:

A	B	Type	Score
IL4	IL4R	psi-mi:“MI:0407”(direct interaction)	0.810
IL4R	IL4	psi-mi:“MI:0915”(physical association)	0.810
IL4R	IL4	psi-mi:“MI:0914”(association)	0.810
IL4	IL4R	psi-mi:“MI:0915”(physical association)	0.810
IL2RG	IL4	psi-mi:“MI:0407”(direct interaction)	0.670
IL2RG	IL4	psi-mi:“MI:0914”(association)	0.670
STAT6	IL4R	psi-mi:“MI:0914”(association)	0.640
IL13RA1	IL4	psi-mi:“MI:0407”(direct interaction)	0.610
IL13RA1	IL4R	psi-mi:“MI:0407”(direct interaction)	0.560
IL4R	RHOBTB3	psi-mi:“MI:0914”(association)	0.530
PTPN6	IL4R	psi-mi:“MI:0914”(association)	0.530
IRS1	IL4R	psi-mi:“MI:0407”(direct interaction)	0.440
IL4R	IL4R	psi-mi:“MI:0407”(direct interaction)	0.440
PIBF1	IL4R	psi-mi:“MI:0915”(physical association)	0.400
TNFRSF10A	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.350
IL4R	DHRS3	psi-mi:“MI:0914”(association)	0.350
MYC	PDZD2	psi-mi:“MI:0914”(association)	0.350
IL13	SPTB	psi-mi:“MI:0914”(association)	0.350
INPP5D	IL4R	psi-mi:“MI:0914”(association)	0.350
	IL4R	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (72): RHBDF2 (Affinity Capture-MS), ANKLE2 (Affinity Capture-MS), JAK1 (Affinity Capture-MS), NET1 (Affinity Capture-MS), PRR11 (Affinity Capture-MS), TYK2 (Affinity Capture-MS), UTP6 (Affinity Capture-MS), KCNT2 (Affinity Capture-MS), PKMYT1 (Affinity Capture-MS), STX5 (Affinity Capture-MS), GOLGA2 (Affinity Capture-MS), DHRS3 (Affinity Capture-MS), RHOBTB3 (Affinity Capture-MS), ACVR2B (Affinity Capture-MS), PLEKHH3 (Affinity Capture-MS)

ESM2 similar proteins: A1KXC4, B2RQL2, B2RTN2, O35188, O55145, O60667, O95196, P06484, P07141, P16382, P24394, P25918, P78423, Q29RT9, Q3SYS8, Q58CT8, Q5BK39, Q5FVQ5, Q5M871, Q5U2P6, Q63257, Q64322, Q68CR7, Q68DV7, Q6AXU5, Q6P1B3, Q6PNM1, Q6RFH4, Q71M36, Q863Z5, Q8BHB3, Q8BHE4, Q8BHW6, Q8BSU2, Q8C708, Q8IXW0, Q8JZQ0, Q8K0B3, Q8NET5, Q8R183

Diamond homologs: P16382, P24394, Q63257, Q6WG24, Q863Z5

SIGNOR signaling

16 interactions.

A	Effect	B	Mechanism
IL13	up-regulates	IL4R	binding
IL4	up-regulates	IL4R	binding
IL4R	up-regulates	IL2RG	binding
IL4R	up-regulates	IRS1	phosphorylation
IL4R	up-regulates	IRS2	phosphorylation
IL4R	up-regulates	JAK1	binding
IL4	“up-regulates activity”	IL4R	binding
IL13	“up-regulates activity”	IL4R	binding
IL4R	“up-regulates activity”	JAK1	phosphorylation
IL4R	“up-regulates activity”	JAK2	phosphorylation
IL4R	up-regulates	STAT5A
IL4R	up-regulates	JAK3
IL4R	up-regulates	JAK1
IL4R	“up-regulates activity”	Proliferation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 17 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Interleukin-4 and Interleukin-13 signaling	6	44.1×	3e-07

GO biological processes:

GO term	Partners	Fold	FDR
cytokine-mediated signaling pathway	5	38.4×	2e-05

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	96
Likely benign	25
Benign	17

Top pathogenic / likely-pathogenic (0)

SpliceAI

2444 predictions. Top by Δscore:

Variant	Effect	Δscore
16:27318765:G:GT	donor_gain	1.0000
16:27340180:CTGCA:C	acceptor_loss	1.0000
16:27340181:TGCAG:T	acceptor_loss	1.0000
16:27340182:GCAG:G	acceptor_loss	1.0000
16:27340183:CAGG:C	acceptor_loss	1.0000
16:27340184:A:AG	acceptor_gain	1.0000
16:27340184:A:C	acceptor_loss	1.0000
16:27340185:G:GA	acceptor_gain	1.0000
16:27340185:GGT:G	acceptor_gain	1.0000
16:27340185:GGTGC:G	acceptor_gain	1.0000
16:27340272:TGGT:T	donor_loss	1.0000
16:27340274:G:GG	donor_gain	1.0000
16:27340274:GTAA:G	donor_loss	1.0000
16:27340275:T:A	donor_loss	1.0000
16:27342260:G:GG	donor_gain	1.0000
16:27344867:A:AG	acceptor_gain	1.0000
16:27344868:G:GG	acceptor_gain	1.0000
16:27344868:GA:G	acceptor_gain	1.0000
16:27345016:GCATG:G	donor_gain	1.0000
16:27345018:ATGG:A	donor_loss	1.0000
16:27345019:TGGTG:T	donor_loss	1.0000
16:27345020:GGTG:G	donor_loss	1.0000
16:27345021:G:GA	donor_loss	1.0000
16:27345022:T:G	donor_loss	1.0000
16:27346465:A:AG	acceptor_gain	1.0000
16:27346466:G:GG	acceptor_gain	1.0000
16:27346466:GT:G	acceptor_gain	1.0000
16:27346616:GAT:G	donor_gain	1.0000
16:27346619:G:GG	donor_gain	1.0000
16:27352538:A:AG	acceptor_gain	1.0000

AlphaMissense

5402 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:27342188:G:C	W46C	0.999
16:27342188:G:T	W46C	0.999
16:27342186:T:A	W46R	0.998
16:27342186:T:C	W46R	0.998
16:27346532:T:A	W143R	0.998
16:27346532:T:C	W143R	0.998
16:27346534:G:C	W143C	0.997
16:27346534:G:T	W143C	0.997
16:27352669:T:A	W215R	0.996
16:27352669:T:C	W215R	0.996
16:27352671:G:C	W215C	0.996
16:27352671:G:T	W215C	0.996
16:27352672:A:C	S216R	0.995
16:27352674:C:A	S216R	0.995
16:27352674:C:G	S216R	0.995
16:27352663:A:C	S213R	0.994
16:27352665:T:A	S213R	0.994
16:27352665:T:G	S213R	0.994
16:27342180:T:A	C44S	0.993
16:27342181:G:C	C44S	0.993
16:27346587:T:A	V161D	0.993
16:27342180:T:C	C44R	0.992
16:27342187:G:C	W46S	0.992
16:27342181:G:A	C44Y	0.991
16:27344915:T:C	C86R	0.991
16:27344967:T:C	L103P	0.991
16:27344992:G:C	W111C	0.991
16:27344992:G:T	W111C	0.991
16:27345002:T:C	F115L	0.991
16:27345004:C:A	F115L	0.991

dbSNP variants (sampled 300 via entrez): RS1000044741 (16:27354016 T>G), RS1000058651 (16:27356886 C>T), RS1000100850 (16:27331055 C>G,T), RS1000120537 (16:27314299 G>C,T), RS1000217383 (16:27322821 A>G), RS1000241316 (16:27355018 A>G), RS1000316987 (16:27347749 C>T), RS1000318052 (16:27320039 G>A), RS1000376678 (16:27349118 G>A), RS1000447239 (16:27364861 G>T), RS1000449115 (16:27325181 C>A), RS1000492520 (16:27314003 T>C), RS1000557673 (16:27331540 T>C), RS1000577919 (16:27318257 T>C), RS1000653145 (16:27318585 A>C,G)

Disease associations

OMIM: gene MIM:147781 | disease phenotypes: MIM:147050, MIM:609423

GenCC curated gene-disease

Disease	Classification	Inheritance
IgE responsiveness, atopic	No Known Disease Relationship	Unknown

Mondo (2): IgE responsiveness, atopic (MONDO:0007817), susceptibility to HIV infection (MONDO:0004951)

Orphanet (0):

HPO phenotypes

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

GWAS associations

33 associations (top):

Study	Trait	p-value
GCST001316_10	IgE levels	1.000000e-07
GCST002083_31	Self-reported allergy	3.000000e-07
GCST002717_2	Serum IgE levels	2.000000e-06
GCST003129_4	Primary biliary cholangitis	2.000000e-07
GCST003542_67	Night sleep phenotypes	4.000000e-06
GCST004009_6	Leprosy	6.000000e-07
GCST004302_15	Primary biliary cholangitis	4.000000e-16
GCST004600_132	Eosinophil percentage of white cells	3.000000e-10
GCST004606_90	Eosinophil count	2.000000e-12
GCST004624_166	Sum eosinophil basophil counts	2.000000e-10
GCST007797_29	Asthma onset (childhood vs adult)	5.000000e-09
GCST007798_158	Asthma	3.000000e-14
GCST007798_159	Asthma	4.000000e-20
GCST007799_37	Asthma (adult onset)	1.000000e-11
GCST007800_11	Asthma (childhood onset)	9.000000e-27
GCST007941_55	Medication use (adrenergics, inhalants)	1.000000e-13
GCST007995_47	Asthma (childhood onset)	6.000000e-13
GCST008838_8	Asthma (time to onset)	8.000000e-07
GCST008916_121	Asthma	2.000000e-17
GCST008916_15	Asthma	1.000000e-13
GCST008916_3	Asthma	1.000000e-12
GCST009720_64	Asthma	6.000000e-17
GCST009798_29	Asthma	3.000000e-08
GCST009798_58	Asthma	3.000000e-09
GCST009798_64	Asthma	4.000000e-17
GCST009798_67	Asthma	5.000000e-11
GCST010042_19	Asthma	7.000000e-22
GCST010043_28	Asthma	6.000000e-25
GCST90002381_82	Eosinophil count	4.000000e-31
GCST90002381_83	Eosinophil count	2.000000e-13

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0007827	nighttime rest measurement
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0005090	basophil count
EFO:0004847	age at onset
EFO:1002011	adult onset asthma
EFO:0009941	Inhalant adrenergic use measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C564133	Ige Responsiveness, Atopic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3580490 (SINGLE PROTEIN), CHEMBL3831285 (PROTEIN COMPLEX)

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

PharmGKB clinical annotations

7 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1029489	Efficacy	3	pitrakinra	Asthma
rs1110470	Efficacy	3	pitrakinra	Asthma
rs1805010	Efficacy	3	pitrakinra	Asthma
rs1805015	Efficacy	3	Hepatitis vaccines
rs2239347	Efficacy	3	pitrakinra	Asthma
rs3024530	Efficacy	3	pitrakinra	Asthma
rs8832	Efficacy	3	pitrakinra	Asthma

PharmGKB variants

8 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs8832	IL4R	3	3.00	1	pitrakinra
rs1029489	IL4R	3	3.00	1	pitrakinra
rs1110470	IL4R	3	2.00	1	pitrakinra
rs1805010	IL4R	3	2.00	1	pitrakinra
rs1805015	IL4R	3	2.25	1	Hepatitis vaccines
rs2239347	IL4R	3	2.00	1	pitrakinra
rs3024530	IL4R	3	2.50	1	pitrakinra
rs1801275	IL4R		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — IL-2 receptor family

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
dupilumab	Binding	11.06	pIC50
stapokibart	Antagonist	9.4	pIC50

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	decreases expression, affects expression, affects cotreatment, increases expression	5
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression, increases methylation	4
sodium arsenite	increases expression, decreases expression, affects cotreatment, increases abundance	3
Benzene	increases expression	3
bisphenol A	decreases methylation, affects expression	2
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression, increases expression	2
Acetaminophen	affects cotreatment, increases expression	2
Arsenic	affects cotreatment, decreases expression, increases abundance, affects methylation	2
Calcitriol	increases expression, affects cotreatment	2
Cisplatin	increases expression, increases reaction, affects binding	2
Nickel	increases expression	2
Genistein	decreases expression, increases expression	2
Particulate Matter	decreases reaction, increases expression	2
bisphenol F	decreases methylation	1
triphenyl phosphate	affects expression	1
citral	increases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	decreases expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
benzo(e)pyrene	increases methylation	1
4-phenylenediamine	affects expression	1
resorcinol	increases expression	1
diallyl trisulfide	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
allergovit	decreases expression	1
GW 4064	increases expression	1

Cellosaurus cell lines

8 cell lines: 5 cancer cell line, 2 transformed cell line, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2ZA	Abcam HEK293T IL4R KO	Transformed cell line	Female
CVCL_D7S6	Ubigene A-549 IL4R KO	Cancer cell line	Male
CVCL_D8N7	Ubigene HCT 116 IL4R KO	Cancer cell line	Male
CVCL_D9H4	Ubigene HEK293 IL4R KO	Transformed cell line	Female
CVCL_E0F3	Ubigene HeLa IL4R KO	Cancer cell line	Female
CVCL_E6QU	Genomeditech CHO-K1 H_IL4R	Spontaneously immortalized cell line	Female
CVCL_SS45	HAP1 IL4R (-) 1	Cancer cell line	Male
CVCL_XP79	HAP1 IL4R (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00414141	PHASE3	COMPLETED	Efficacy and Safety/Tolerability of Grass MATA MPL
NCT00423787	PHASE3	COMPLETED	Efficacy and Safety/Tolerability of Ragweed MATA MPL
NCT00104377	PHASE2	COMPLETED	Induction of Immunogenicity With Different Doses of Grass MATA in Subjects Allergic to Grass and Rye Pollen
NCT00110786	PHASE2	COMPLETED	Investigation of Efficacy and Safety of Ragweed MATAMPL, Pollinex-R and Placebo in Patients With Ragweed Allergy
NCT00113750	PHASE2	COMPLETED	Induction of Immunogenicity With Different Doses of TreeMATA in Subjects Allergic to Tree Pollen
NCT00118612	PHASE2	COMPLETED	Different Doses of Tyrosine Adsorbed Tree Pollen Allergoid With Monophosphoryl Lipid A (MPL) in Patients Sensitized to Tree Pollen
NCT00118625	PHASE2	COMPLETED	Assessment of the Contribution of Monophosphoryl Lipid A (MPL) to a Tree Pollen Allergy Vaccine
NCT00133146	PHASE2	COMPLETED	Assessment of the Contribution of Monophosphoryl Lipid A (MPL) to a Grass Pollen Allergy Vaccine
NCT00133159	PHASE2	COMPLETED	Different Doses of Tyrosine Adsorbed Grass Pollen Allergoid With Monophosphoryl Lipid A (MPL) in Patients Sensitized to Grass Pollen
NCT00258635	PHASE2	COMPLETED	Investigation of Safety+Efficacy of Different Doses of RagweedMATAMPL;Assessment of Residual Allergenicity Using Skin Prick Test
NCT00325338	PHASE2	COMPLETED	Follow-up Investigation of Efficacy of Ragweed MATAMPL,and Placebo in Patients With Ragweed-induced Seasonal Allergic Rhinitis
NCT00387478	PHASE2	TERMINATED	Investigation of Efficacy and Safety of Tree MATAMPL,Tree MATA, and Placebo in Patients With Birch-Induced Seasonal Allergic Rhinitis
NCT00461097	PHASE2	COMPLETED	Oral Immunotherapy for Childhood Egg Allergy
NCT00104390	PHASE1	COMPLETED	Assessment of Residual Allergenicity of Grass/Rye Pollen Allergoid Using Skin Prick Testing
NCT00107705	PHASE1	COMPLETED	Assessment of Residual Allergenicity of Tree (Birch, Hazel, and Alder) Pollen Allergoid Using Skin Prick Testing
NCT00109759	PHASE1	WITHDRAWN	Evaluation of Safety and Tolerability of Tyrosine Adsorbed Ragweed Pollen Allergoid With MPL (Monophosphoryl Lipid A)
NCT00116285	PHASE1	COMPLETED	Assessment of Residual Allergenicity of Ragweed Pollen Allergoid With Monophosphoryl Lipid A (MPL) Using Skin Prick Testing
NCT00241410	PHASE1	COMPLETED	Safety, Immunological Effect and Efficacy of the Combined Application of MPL and Grass Pollen Allergen
NCT00850668	PHASE1	COMPLETED	Peanut Allergy Vaccine Study in Healthy and Peanut-allergic Adults
NCT00580606	PHASE1/PHASE2	COMPLETED	A Randomized, Double-Blind Placebo-Controlled Peanut Sublingual Immunotherapy Trial
NCT01084174	PHASE1/PHASE2	COMPLETED	A Randomized, Double-Blind, Placebo-Controlled Pilot Study of Sublingual/Oral Immunotherapy for the Treatment of Peanut Allergy
NCT05003804	PHASE1/PHASE2	COMPLETED	Allergic Disease Onset Prevention Study
NCT01407640	Not specified	COMPLETED	Diagnosis and Physiopathology of Insulin Allergy
NCT02561390	Not specified	COMPLETED	Comparison Between spIgE and Skin Prick Test of Local and Imported Aeroallergens
NCT02561429	Not specified	COMPLETED	Comparison of Difference Histamine Concentration (1, 5 and 10 mg/ml) for Skin Prick Test Positive Control
NCT02733926	Not specified	UNKNOWN	Effect of Vegetation in Kindergartens on the Immune Response of Children
NCT06065137	Not specified	COMPLETED	Standardised Drug Provocation Testing in Perioperative Hypersensitivity