IL37

Summary

IL37 (interleukin 37, HGNC:15563) is a protein-coding gene on chromosome 2q14.1, encoding Interleukin-37 (Q9NZH6). Immune regulatory cytokine that acts as a suppressor of innate inflammatory and immune responses involved in curbing excessive inflammation.

The protein encoded by this gene is a member of the interleukin 1 cytokine family. This cytokine can bind to, and may be a ligand for interleukin 18 receptor (IL18R1/IL-1Rrp). This cytokine also binds to interleukin 18 binding protein (IL18BP), an inhibitory binding protein of interleukin 18 (IL18), and subsequently forms a complex with IL18 receptor beta subunit, and through which it inhibits the activity of IL18. This gene along with eight other interleukin 1 family genes form a cytokine gene cluster on chromosome 2. Five alternatively spliced transcript variants encoding distinct isoforms have been reported.

Source: NCBI Gene 27178 — RefSeq curated summary.

At a glance

• Gene–disease (curated): inflammatory bowel disease (infantile ulcerative colitis) 31, autosomal recessive (Limited, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 33 total — 1 pathogenic
• Phenotypes (HPO): 9
• MANE Select transcript: NM_014439

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15563
Approved symbol	IL37
Name	interleukin 37
Location	2q14.1
Locus type	gene with protein product
Status	Approved
Aliases	FIL1, FIL1Z, FIL1(ZETA), IL-1H4, IL-1RP1, IL-1F7
Ensembl gene	ENSG00000125571
Ensembl biotype	protein_coding
OMIM	605510
Entrez	27178

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000263326, ENST00000311328, ENST00000349806, ENST00000352179, ENST00000353225, ENST00000885704

RefSeq mRNA: 5 — MANE Select: NM_014439 NM_014439, NM_173202, NM_173203, NM_173204, NM_173205

CCDS: CCDS2103, CCDS2104, CCDS2105, CCDS2106, CCDS2107

Canonical transcript exons

ENST00000263326 — 6 exons

Exon	Start	End
ENSE00000856851	112917129	112917248
ENSE00000856853	112917635	112917777
ENSE00000856855	112918561	112918882
ENSE00000963812	112913792	112913854
ENSE00003918954	112911165	112911248
ENSE00003921601	112912963	112913094

Expression profiles

Bgee: expression breadth ubiquitous, 141 present calls, max score 95.53.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1384 / max 94.9929, expressed in 21 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
22070	0.0820	15
22071	0.0564	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper arm skin	UBERON:0004263	95.53	gold quality
skin of leg	UBERON:0001511	93.22	gold quality
upper leg skin	UBERON:0004262	92.90	gold quality
zone of skin	UBERON:0000014	91.91	gold quality
nipple	UBERON:0002030	91.00	gold quality
skin of abdomen	UBERON:0001416	90.77	gold quality
vena cava	UBERON:0004087	88.34	silver quality
skin of hip	UBERON:0001554	86.48	gold quality
subthalamic nucleus	UBERON:0001906	86.35	silver quality
body of tongue	UBERON:0011876	85.70	silver quality
ventral tegmental area	UBERON:0002691	85.64	silver quality
cerebellar vermis	UBERON:0004720	85.39	gold quality
pylorus	UBERON:0001166	85.33	silver quality
pharyngeal mucosa	UBERON:0000355	85.15	silver quality
penis	UBERON:0000989	84.98	gold quality
lateral globus pallidus	UBERON:0002476	84.71	silver quality
superior surface of tongue	UBERON:0007371	84.53	silver quality
superior vestibular nucleus	UBERON:0007227	84.46	silver quality
substantia nigra pars reticulata	UBERON:0001966	84.28	silver quality
pericardium	UBERON:0002407	84.21	silver quality
substantia nigra pars compacta	UBERON:0001965	83.95	silver quality
dorsal root ganglion	UBERON:0000044	83.66	silver quality
saphenous vein	UBERON:0007318	83.56	silver quality
tongue	UBERON:0001723	83.48	silver quality
sperm	CL:0000019	83.41	gold quality
renal medulla	UBERON:0000362	82.92	silver quality
trigeminal ganglion	UBERON:0001675	82.80	silver quality
dorsal plus ventral thalamus	UBERON:0001897	82.73	silver quality
pons	UBERON:0000988	82.63	gold quality
male germ cell	CL:0000015	82.30	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.79

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, IRF3, TBX21

Literature-anchored findings (GeneRIF, showing 40)

• caspase-1 cleaves IL-1F7b at the predicted site to generate mature IL-1F7b (PMID:12096920)
• after binding to IL-18BP, IL-1F7b forms a complex with IL-18Rbeta, depriving the beta-chain of forming a functional receptor complex with IL-18Ralpha and thus inhibiting IL-18 activity (PMID:12381835)
• IL-1F7 plays an important role in the link between innate and adaptive immunity and has the ability to inhibit tumor growth following adenovirus-mediated gene transfer. (PMID:12496389)
• results demonstrate that IL-1F7b translocates to the nucleus after caspase-1 processing and may act as a transcriptional modulator reducing the production of LPS-stimulated proinflammatory cytokines (PMID:18390730)
• IL-37 thus emerges as a natural suppressor of innate inflammatory and immune responses (PMID:20935647)
• Data show that weight loss led to a significant reduction in liver IL-1beta, IL-18 and IL-1Ra expression, whereas hepatic IL-37 expression remained stable, adipose/liver NLRP3 inflammasome and IL-1alpha expression were not affected by weight loss. (PMID:21394384)
• IL-37 is a key modulator of intestinal inflammation, and its expression protects mice from experimental colitis. (PMID:21873195)
• IL-37 is protective against hepatic ischemia-reperfusion injury. (PMID:22646996)
• Data indicate that IL-1alpha binds stronger to nuclear structures than IL-33 and IL-37. (PMID:23159404)
• the A allele of IL-1F7 gene (rs3811047) may have a protective effect on rheumatoid arthritis. (PMID:23171316)
• IL37 may play a role in the pathogenesis of atopic dermatitis by modulating innate immune reactions. (PMID:23182761)
• IL-37b may be involved in the pathophysiology of inflammatory bowel disease as an anti-inflammatory cytokine and an inhibitor of both innate and acquired immune responses. (PMID:23600829)
• that IL-37 may play a significant role in the immune response of CHB patients with HBeAg seroconversion. The serum levels of IL-37 are associated with liver damage in CHB patients. (PMID:23697556)
• cerebrospinal fluid and plasma interleukin-37 are elevated and may play a role in Guillain-Barre syndrome (PMID:24174711)
• functional polymorphism, IL1f7 rs3811047 G>A, might contribute to gastric cardiac adenocarcinoma (GCA) susceptibility. (PMID:24357513)
• these studies strongly indicate that IL-37 plays a potent immunosuppressive role in the pathogenesis of both experimental psoriasis models in vitro and in vivo by downregulating proinflammatory cytokines. (PMID:24453242)
• Although caspase-1 is required for nuclear translocation of intracellular IL-37 and for secretion of mature IL-37, the release of the IL-37 precursor is independent of caspase-1 activation. (PMID:24481253)
• Downregulation of IL-37 expression appeared to result in overexpression of pro-inflammatory cytokines in degenerative disc disease. (PMID:24551286)
• IL-37 associated with SLE disease activity, especially related with systemic Lupus erythematosus renal disease activity. (PMID:24629023)
• We conclude that a decreased IL-37 expression in active BD patients may trigger the production of pro-inflammatory cytokines and ROS in association with activation of Th1 and Th17 cells by DCs. (PMID:24730521)
• plasma IL-37 levels are associated with the onset of acute coronary syndrome (PMID:24733959)
• show here that IL1A, IL1B and IL1F7 regulatory regions come in close proximity in LPS stimulated cells but not in resting human monocytes (PMID:24787052)
• IL-37 expression in RA and during DMARD treatment appears to be controlled by the level of pro-inflammatory cytokines. This results in a strong correlation between plasma levels of IL-37 and disease activity in RA patients. (PMID:24788826)
• Data indicate that anti-IL-37 antibody with high titer and specificity was successfully prepared. (PMID:24796748)
• Low Interleukin-37 expression is associated with hepatocellular carcinoma. (PMID:24898887)
• IL-37 as an important anti-inflammatory modulator during obesity-induced inflammation and insulin resistance. (PMID:25182023)
• tubular epithelial cells express the IL-18 contra-regulatory protein IL-37 as an endogenous control mechanism to reduce inflammation (PMID:25207880)
• IL-35 and IL-37 protein expressions were higher in IBD patients compared with controls. (PMID:25214710)
• the expression of IL-37 is correlated with the disease activity of GD, and contribute to suppress inflammation cytokines TNF-alpha, IL-6, and IL-17 during GD pathogenesis. (PMID:25226272)
• DCs expressing IL-37 are tolerogenic, thereby impairing activation of effector T-cell responses and inducing Treg cells (PMID:25294929)
• research demonstrated, for the first time, that anti-inflammatory active components (triptolide and triptonide) upregulated the expression of IL-37 most likely via activation of the ERK1/2 and p38 MAPK pathways. (PMID:25308753)
• hBD-3 stimulates IL-37 expression through CCR6 in keratinocytes (PMID:25541254)
• IL-37 requires IL-18Ralpha and SIGIRR/IL-1R8 to diminish allergic airway inflammation in mice (PMID:25557042)
• Thus, this method provides an efficient way to obtain an active IL-37 with high yield and high purity. (PMID:25559248)
• Higher levels of IL-37 were found in ankylosing spondylitis patients, which were correlated with disease activity. (PMID:25627863)
• IL-37 acts as an extracellular cytokine by binding to the IL-18 receptor but using the IL-1R8 for its anti-inflammatory properties. (PMID:25654981)
• IL-37 requires the receptors IL-18Ralpha and IL-1R8 to carry out its multifaceted anti-inflammatory program upon innate signal transduction. (PMID:25729923)
• Patients with active pulmonary tuberculosis present with significantly increased level of plasma IL-37. (PMID:25854573)
• our data shows that the level of IL-37 mRNA is affected by chronic HIV-1-infection. (PMID:25879630)
• IL-37 plays a potent immunosuppressive role in the pathogenesis of human rheumatoid arthritis and mouse collagen-induced arthritis models via the downregulation of IL-17 and IL-17-triggering cytokine production and the curbing of Th17 cell proliferation. (PMID:25917106)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
danio_rerio	il1fma	ENSDARG00000089383
danio_rerio	il1b	ENSDARG00000098700

Paralogs (7): IL1B (ENSG00000125538), IL36G (ENSG00000136688), IL1RN (ENSG00000136689), IL36A (ENSG00000136694), IL36RN (ENSG00000136695), IL36B (ENSG00000136696), IL1F10 (ENSG00000136697)

Protein

Protein identifiers

Interleukin-37 — Q9NZH6 (reviewed: Q9NZH6)

Alternative names: FIL1 zeta, IL-1X, Interleukin-1 family member 7, Interleukin-1 homolog 4, Interleukin-1 zeta, Interleukin-1-related protein

All UniProt accessions (1): Q9NZH6

UniProt curated annotations — full annotation on UniProt →

Function. Immune regulatory cytokine that acts as a suppressor of innate inflammatory and immune responses involved in curbing excessive inflammation. Signaling can occur via two mechanisms, intracellularly through nuclear translocation with SMAD3 and extracellularly after secretion and binding to its receptor composed of IL18R1 and IL18RAP. Suppresses, or reduces, pro-inflammatory cytokine production, including IL1A and IL6, as well as CCL12, CSF1, CSF2, CXCL13, IL1B, IL23A and IL1RN, but spares anti-inflammatory cytokines. Inhibits dendritic cell activation.

Subunit / interactions. Interacts with SMAD3. Binds IL18R1, but not to IL1R1, with lower affinity than IL18, and does not seem to act as a receptor antagonist for IL18. 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. Cytosol. Nucleus. Secreted.

Tissue specificity. In general, low constitutive expression, if any, in healthy tissues; high expression in inflammatory counterparts, including in synovial tissues from individuals with active rheumatoid arthritis. Isoform A, isoform B and isoform C are expressed in testis, colon, placenta, lung and lymph node. Isoform D and isoform E were found only in testis and bone marrow. Whereas only isoform A is found in brain, only isoform B in kidney and only isoform C in heart.

Post-translational modifications. Proteolytically converted to the mature form by CASP1.

Disease relevance. Inflammatory bowel disease 31, autosomal recessive (IBD31) [MIM:619398] A form of inflammatory bowel disease, a chronic, relapsing inflammation of the gastrointestinal tract with a complex etiology and a multifactorial inheritance pattern. It is subdivided into Crohn disease and ulcerative colitis phenotypes. Crohn disease may affect any part of the gastrointestinal tract from the mouth to the anus, but most frequently it involves the terminal ileum and colon. Bowel inflammation is transmural and discontinuous; it may contain granulomas or be associated with intestinal or perianal fistulas. In contrast, in ulcerative colitis, the inflammation is continuous and limited to rectal and colonic mucosal layers; fistulas and granulomas are not observed. Both diseases include extraintestinal inflammation of the skin, eyes, or joints. IBD31 patients suffer from infantile ulcerative colitis and present with recurrent bloody diarrhea with anemia and leukocytosis, extensive lymphoplasmocytic infiltration, cryptitis, and apoptotic crypt abcesses throughout the colon and rectum. The disease is caused by variants affecting the gene represented in this entry.

Induction. Highly induced by bacterial lipopolysaccharides (LPS) and TGFB1, more moderately by IFNG, IL18, IL1B, TNF and the dinucleotide CpG (at protein level). Constitutive expression in bone marrow macrophages is down-regulated in the presence of IL4 and CSF2. Induced by phorbol myristate acetate (PMA) in different cell lines.

Miscellaneous. The name IL-HL refers to isoform B containing polymorphisms Val-31 and Ala-42.

Similarity. Belongs to the IL-1 family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9NZH6-1	B, IL-1F7b, IL-HLa	yes
Q9NZH6-2	A
Q9NZH6-3	C, IL-HS
Q9NZH6-4	D, IL1F7d
Q9NZH6-5	E, IL1F7e

RefSeq proteins (5): NP_055254, NP_775294, NP_775295, NP_775296, NP_775297 (=MANE)

Domains & families (InterPro)

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

Pfam: PF00340

UniProt features (36 total): strand 14, sequence variant 9, helix 4, splice variant 4, propeptide 1, chain 1, region of interest 1, turn 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5HN1	X-RAY DIFFRACTION	2.25
6NCU	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZH6-F1	82.35	0.63

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9008059	Interleukin-37 signaling
R-HSA-9012546	Interleukin-18 signaling

MSigDB gene sets: 99 (showing top): 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, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_CYTOKINE_PRODUCTION, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_NEGATIVE_REGULATION_OF_DEFENSE_RESPONSE, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_REGULATION_OF_LIPOPOLYSACCHARIDE_MEDIATED_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_INFLAMMATORY_RESPONSE

GO Biological Process (7): inflammatory response (GO:0006954), immune response (GO:0006955), cytokine-mediated signaling pathway (GO:0019221), negative regulation of interleukin-6 production (GO:0032715), negative regulation of tumor necrosis factor production (GO:0032720), regulation of inflammatory response (GO:0050727), cellular response to lipopolysaccharide (GO:0071222)

GO Molecular Function (4): cytokine activity (GO:0005125), interleukin-1 receptor binding (GO:0005149), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (6): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleoplasm (GO:0005654), cytosol (GO:0005829), nucleus (GO:0005634), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Interleukin-1 family signaling	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
defense response	1
immune system process	1
response to stimulus	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
negative regulation of cytokine production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
negative regulation of tumor necrosis factor superfamily cytokine production	1
inflammatory response	1
regulation of defense response	1
regulation of response to external stimulus	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
receptor ligand activity	1
cytokine receptor binding	1
growth factor receptor binding	1
protein binding	1
binding	1
nuclear lumen	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

928 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL37	IL18R1	Q13478	994
IL37	IL18BP	O95998	906
IL37	SIGIRR	Q6IA17	891
IL37	IL1B	P01584	851
IL37	IL1A	P01583	805
IL37	CASP1	P29466	771
IL37	SMAD3	P84022	739
IL37	IL1R1	P14778	721
IL37	IL33	O95760	697
IL37	IL6	P05231	678
IL37	IL18	Q14116	668
IL37	IL1RL2	Q9HB29	645
IL37	IL10	P22301	594
IL37	TNF	P01375	583
IL37	IL1RAP	Q9NPH3	572

IntAct

44 interactions, top by confidence:

A	B	Type	Score
CCNC	MED19	psi-mi:“MI:0914”(association)	0.640
ALDH3A1	RCCD1	psi-mi:“MI:0914”(association)	0.640
PRKAB2	IL37	psi-mi:“MI:0915”(physical association)	0.560
IL37	CHAT	psi-mi:“MI:0915”(physical association)	0.560
IL37	FGFR3	psi-mi:“MI:0915”(physical association)	0.560
GRIN2C	IL37	psi-mi:“MI:0915”(physical association)	0.560
IL37	GSN	psi-mi:“MI:0915”(physical association)	0.560
IL37		psi-mi:“MI:0915”(physical association)	0.560
IL37	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
FTH1	A2ML1	psi-mi:“MI:0914”(association)	0.530
DNAAF19	KLK10	psi-mi:“MI:0914”(association)	0.530
FADD	THAP12	psi-mi:“MI:0914”(association)	0.530
IL37	SMAD3	psi-mi:“MI:0403”(colocalization)	0.460
SMAD3	IL37	psi-mi:“MI:0915”(physical association)	0.460
GSG1	IL37	psi-mi:“MI:0915”(physical association)	0.400
IL37	SLC9A4	psi-mi:“MI:0915”(physical association)	0.400
P2RY11	IL37	psi-mi:“MI:0915”(physical association)	0.400
BEX5	A2ML1	psi-mi:“MI:0914”(association)	0.350

BioGRID (33): IL37 (Affinity Capture-MS), IL37 (Affinity Capture-MS), IL37 (Affinity Capture-MS), IL37 (Affinity Capture-MS), IL37 (Affinity Capture-MS), IL37 (Affinity Capture-MS), IL37 (Affinity Capture-MS), IL37 (Affinity Capture-MS), PRKAB2 (Two-hybrid), IL37 (Two-hybrid), IL37 (Two-hybrid), IL37 (Affinity Capture-MS), IL37 (Affinity Capture-MS), IL37 (Affinity Capture-MS), IL37 (Affinity Capture-MS)

ESM2 similar proteins: A4UYK8, O46612, O46613, P01582, P01583, P01584, P04822, P08831, P09428, P10749, P14628, P16598, P18430, P21621, P26889, P41687, P46648, P48089, P48090, P51493, P51745, P79161, P79162, P79182, P79340, Q14D04, Q28292, Q28385, Q28386, Q28579, Q2HZH0, Q2MH07, Q32NG6, Q3HWU1, Q3UIR3, Q63264, Q6PUD2, Q6R2X3, Q6ZUJ8, Q865X7

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, Q6R2X3, Q8R460, Q9XS77, Q9NZH8, Q865X8, Q9JLA2, Q9NZH7, P14628, P26889, A4UYK8, P01584, P10749, P41687, P46648, P48090, P51493

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
IL37	“down-regulates activity”	“Interleukin-37 receptor-ligand complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	24
Likely benign	4
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1174126	NM_014439.4(IL37):c.530T>C (p.Ile177Thr)	Pathogenic

SpliceAI

782 predictions. Top by Δscore:

Variant	Effect	Δscore
2:112917126:TA:T	acceptor_loss	0.9900
2:112917127:A:AT	acceptor_loss	0.9900
2:112917228:A:G	donor_gain	0.9900
2:112917291:GGG:G	donor_gain	0.9900
2:112917292:GGG:G	donor_gain	0.9900
2:112917244:CCCAG:C	donor_loss	0.9800
2:112917245:CCAG:C	donor_loss	0.9800
2:112917247:AG:A	donor_loss	0.9800
2:112917248:GGTGA:G	donor_loss	0.9800
2:112917249:G:C	donor_loss	0.9800
2:112917250:T:G	donor_loss	0.9800
2:112917633:A:AG	acceptor_gain	0.9800
2:112917634:G:GG	acceptor_gain	0.9800
2:112917634:GA:G	acceptor_gain	0.9800
2:112917717:G:T	donor_gain	0.9800
2:112918440:G:GT	donor_gain	0.9800
2:112918559:A:AG	acceptor_gain	0.9800
2:112918560:G:GG	acceptor_gain	0.9800
2:112913855:G:GG	donor_gain	0.9700
2:112917773:TGAAG:T	donor_loss	0.9700
2:112917774:GAAGG:G	donor_loss	0.9700
2:112917775:AAG:A	donor_loss	0.9700
2:112917777:GGTG:G	donor_loss	0.9700
2:112917778:GTGAG:G	donor_loss	0.9700
2:112917779:T:A	donor_loss	0.9700
2:112913090:AGAAG:A	donor_loss	0.9600
2:112913091:GAAGG:G	donor_loss	0.9600
2:112913092:AAGGT:A	donor_loss	0.9600
2:112913093:AGGT:A	donor_loss	0.9600
2:112913094:GGT:G	donor_loss	0.9600

AlphaMissense

1452 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:112918612:T:C	F154L	0.984
2:112918614:C:A	F154L	0.984
2:112918614:C:G	F154L	0.984
2:112918753:T:C	F201L	0.983
2:112918755:T:A	F201L	0.983
2:112918755:T:G	F201L	0.983
2:112917161:T:C	F60L	0.978
2:112917163:C:A	F60L	0.978
2:112917163:C:G	F60L	0.978
2:112918618:T:C	F156L	0.976
2:112918620:T:A	F156L	0.976
2:112918620:T:G	F156L	0.976
2:112918678:T:C	F176L	0.973
2:112918680:C:A	F176L	0.973
2:112918680:C:G	F176L	0.973
2:112918759:T:C	F203L	0.970
2:112918761:T:A	F203L	0.970
2:112918761:T:G	F203L	0.970
2:112918619:T:C	F156S	0.959
2:112918754:T:C	F201S	0.957
2:112918712:T:A	V187D	0.955
2:112917168:T:C	I62T	0.946
2:112917213:T:A	L77H	0.944
2:112918656:G:C	E168D	0.943
2:112918656:G:T	E168D	0.943
2:112918760:T:C	F203S	0.942
2:112917640:T:C	F91L	0.941
2:112917642:C:A	F91L	0.941
2:112917642:C:G	F91L	0.941
2:112917219:C:A	A79E	0.940

dbSNP variants (sampled 300 via entrez): RS1000272376 (2:112914573 G>A), RS1000387037 (2:112917383 G>C,T), RS1000569633 (2:112915408 G>A), RS1000705713 (2:112909430 C>T), RS1001003781 (2:112915872 G>A), RS1001062662 (2:112916668 C>T), RS1002324515 (2:112915214 G>A), RS1002373193 (2:112911026 G>A,C), RS1002578205 (2:112918365 G>T), RS1002747640 (2:112912499 T>A), RS1002777745 (2:112912844 T>C), RS1004425559 (2:112913942 G>A,C,T), RS1004448138 (2:112915046 A>G), RS1005147392 (2:112910429 G>T), RS1005221305 (2:112910732 A>G)

Disease associations

OMIM: gene MIM:605510 | disease phenotypes: MIM:266600, MIM:619398

GenCC curated gene-disease

Disease	Classification	Inheritance
inflammatory bowel disease (infantile ulcerative colitis) 31, autosomal recessive	Limited	Unknown

Mondo (2): inflammatory bowel disease (MONDO:0005265), inflammatory bowel disease (infantile ulcerative colitis) 31, autosomal recessive (MONDO:0030314)

Orphanet (1): Rare inflammatory bowel disease (Orphanet:104012)

HPO phenotypes

9 total (9 of 9 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001270	Motor delay
HP:0001903	Anemia
HP:0001974	Increased total leukocyte count
HP:0003565	Elevated erythrocyte sedimentation rate
HP:0003593	Infantile onset
HP:0011227	Elevated circulating C-reactive protein concentration
HP:0025085	Bloody diarrhea
HP:0100279	Ulcerative colitis

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002113_1	Pulmonary function	7.000000e-06
GCST002365_5	Response to anti-retroviral therapy (ddI/d4T) in HIV-1 infection (Grade 2 peripheral neuropathy)	3.000000e-06
GCST006636_1	Menstruation quality of life impact (dysmenorrhea)	3.000000e-12
GCST006637_3	Pain medicine use during menstruation	2.000000e-09
GCST006656_2	Dysmenorrheic pain severity	2.000000e-16
GCST90011898_66	Alanine aminotransferase levels	6.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0004314	forced expiratory volume
EFO:0000180	HIV-1 infection
EFO:0007889	dysmenorrheic pain measurement
EFO:0007010	drug use measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D015212	Inflammatory Bowel Diseases	C06.405.205.731; C06.405.469.432

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
3,4,5,3’,4’-pentachlorobiphenyl	affects expression, decreases expression	2
zinc sulfide	affects cotreatment, increases expression	2
Lipopolysaccharides	affects cotreatment, increases expression, decreases reaction	2
propionaldehyde	decreases expression	1
bisphenol A	decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
titanium dioxide	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
zinc chloride	decreases expression	1
ferrous sulfate	decreases expression	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	decreases expression	1
1-nitropyrene	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
cadmium selenide	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
brevetoxin 2	increases expression	1
Acetaminophen	increases expression	1
Ethanol	increases expression, affects cotreatment	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Cadmium	affects cotreatment, increases expression	1
Folic Acid	affects cotreatment, increases expression	1
Nickel	decreases expression	1
Rifampin	increases expression	1
Selenium	increases expression, affects cotreatment	1
Silicon Dioxide	decreases expression	1
Silver	affects expression	1
Triclosan	decreases reaction, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00167882	PHASE4	COMPLETED	The Influence of 5-Aminosalicylates on Thiopurine Metabolite Levels
NCT00205062	PHASE4	TERMINATED	Positron Emission Tomography (PET)-Computed Tomography (CT) in Inflammatory Bowel Disease (IBD)
NCT00567593	PHASE4	COMPLETED	Gene Regulation by Thiazolidinediones
NCT00746395	PHASE4	COMPLETED	Randomized, Placebo-controlled Trial of Lubiprostone as a Preparation for Capsule Endoscopy
NCT01034358	PHASE4	COMPLETED	Immune Response to the Human Papillomavirus Vaccine in Young Women With Inflammatory Bowel Disease
NCT01056913	PHASE4	COMPLETED	NITI CAR27 (ColonRing) Compression Anastomosis in Colorectal Surgery
NCT01067547	PHASE4	COMPLETED	A Trial of Iron Replacement in Patients With Iron Deficiency.
NCT01341808	PHASE4	COMPLETED	Immunogenicity of Hepatitis A Vaccine in Inflammatory Bowel Disease (IBD) Patients
NCT01908283	PHASE4	COMPLETED	Induction of Immunity Against Streptococcus Pneumoniae in Adults With Inflammatory Bowel Disease
NCT01934088	PHASE4	COMPLETED	Satisfaction With Nurse Administered Propofol Sedation vs. Midazolam With Fentanyl Sedation for Endoscopy
NCT02162862	PHASE4	COMPLETED	Treating Disrupted Sleep in Individuals With Inflammatory Bowel Disease
NCT02248337	PHASE4	COMPLETED	Low Volume Colon Preparation for IBD
NCT02281799	PHASE4	WITHDRAWN	Thiopurine Induced Pancreatitis in IBD Patients
NCT02392286	PHASE4	TERMINATED	Corticosteroid Dosage for Crohn’s Disease Flare
NCT02437591	PHASE4	COMPLETED	Study to Evaluate the Pharmacokinetics of Fidaxomicin in Inflammatory Bowel Disease (IBD) Subjects With Clostridium Difficile Infection (CDI)
NCT02453776	PHASE4	COMPLETED	Precision Dosing of Infliximab Versus Conventional Dosing of Infliximab
NCT02461758	PHASE4	COMPLETED	Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory Bowel Disease Patients
NCT02566889	PHASE4	TERMINATED	An Efficacy and Safety Study of Infliximab Dose Escalation in Pediatric Participants With Inflammatory Bowel Disease
NCT02774057	PHASE4	UNKNOWN	Trial of Captafer® vs. Oral Iron Sulfate in the Treatment of Iron Deficiency Anemia in Patients With IBD
NCT02806206	PHASE4	UNKNOWN	Prucalopride Prior to Small Bowel Capsule Endoscopy
NCT02946203	PHASE4	COMPLETED	Comparison of VoLumen and Breeza Oral Contrast Agents in Pediatric Patients
NCT02994836	PHASE4	COMPLETED	GIS-SUSANTI-TNF-2015 (Anti-TNF Discontinuation )
NCT03220841	PHASE4	UNKNOWN	Stricture Definition and Treatment (STRIDENT) Drug Therapy Study
NCT03351972	PHASE4	COMPLETED	Differences in Preparation for Small Bowel Capsule Endoscopy
NCT03466983	PHASE4	COMPLETED	A Trial Comparing the Incidence of Hypophosphatemia in Relation to Treatment With Iron Isomaltoside and Ferric Carboxymaltose in Subjects With Iron Deficiency Anaemia Due to Inflammatory Bowel Disease
NCT03591770	PHASE4	TERMINATED	Shingrix Vaccine in Patients With Moderate to Severe Ulcerative Colitis on Tofacitinib
NCT03629379	PHASE4	COMPLETED	Response to Ustekinumab for Anti-tnf Induced Psoriasiform Skin Lesions
NCT03723447	PHASE4	COMPLETED	Intraoperative TAP Block With Bupivacaine/Dexamethasone Against Liposomal Bupivacaine (Exparel®)
NCT03798691	PHASE4	COMPLETED	Immunogenicity of Herpes Zoster Subunit Vaccine in Inflammatory Bowel Disease Patients Treated With Vedolizumab
NCT03860012	PHASE4	UNKNOWN	Folic Acid in Pediatric Inflammatory Bowel Disease
NCT03885713	PHASE4	COMPLETED	Identification of Predictive Biomarkers for Response to Biologic Therapies and Tofacitinib in Inflammatory Bowel Disease
NCT03917303	PHASE4	RECRUITING	Control Crohn Safe Trial
NCT04045782	PHASE4	COMPLETED	Evaluation of the Safety and Effectiveness of Switching From Humira® to Imraldi® in Flanders
NCT04304950	PHASE4	COMPLETED	Chronotherapy in Inflammatory Bowel Disease
NCT04626947	PHASE4	TERMINATED	Prevention of Recurrent Clostridium Difficile Infection (CDI) in Patients With Inflammatory Bowel Disease (IBD).
NCT04646187	PHASE4	ENROLLING_BY_INVITATION	De-escalation of Anti-TNF Therapy in Inflammatory Bowel Disease
NCT04835506	PHASE4	ACTIVE_NOT_RECRUITING	Proactive Infliximab Optimization Using a Pharmacokinetic Dashboard Versus Standard of Care in Patients With Inflammatory Bowel Disease: The OPTIMIZE Trial
NCT04982172	PHASE4	COMPLETED	Model-informed Dose De-escalation of Infliximab in Patients With Inflammatory Bowel Diseases
NCT05180175	PHASE4	COMPLETED	The Nordic IBD Treatment Strategy Trial
NCT05280405	PHASE4	UNKNOWN	Early Proactive Therapeutic Drug Monitoring of Infliximab in Children: EPIC Study