TNFRSF18

Summary

TNFRSF18 (TNF receptor superfamily member 18, HGNC:11914) is a protein-coding gene on chromosome 1p36.33, encoding Tumor necrosis factor receptor superfamily member 18 (Q9Y5U5). Receptor for TNFSF18.

This gene encodes a member of the TNF-receptor superfamily. The encoded receptor has been shown to have increased expression upon T-cell activation, and it is thought to play a key role in dominant immunological self-tolerance maintained by CD25(+)CD4(+) regulatory T cells. Knockout studies in mice also suggest the role of this receptor is in the regulation of CD3-driven T-cell activation and programmed cell death. Three alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported.

Source: NCBI Gene 8784 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 90 total
• Druggable target: yes
• MANE Select transcript: NM_004195

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11914
Approved symbol	TNFRSF18
Name	TNF receptor superfamily member 18
Location	1p36.33
Locus type	gene with protein product
Status	Approved
Aliases	AITR, GITR, CD357
Ensembl gene	ENSG00000186891
Ensembl biotype	protein_coding
OMIM	603905
Entrez	8784

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000328596, ENST00000379265, ENST00000379268, ENST00000486728

RefSeq mRNA: 3 — MANE Select: NM_004195 NM_004195, NM_148901, NM_148902

CCDS: CCDS10, CCDS30552, CCDS9

Canonical transcript exons

ENST00000379268 — 5 exons

Exon	Start	End
ENSE00001333104	1204034	1204236
ENSE00001333105	1204399	1204486
ENSE00001333111	1205370	1205492
ENSE00001333116	1206385	1206592
ENSE00001827758	1203508	1203968

Expression profiles

Bgee: expression breadth ubiquitous, 173 present calls, max score 87.23.

FANTOM5 (CAGE): breadth broad, TPM avg 4.5272 / max 590.7785, expressed in 431 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
9715	3.0061	411
9718	0.7902	36
9717	0.3047	68
9714	0.2310	34
9716	0.1395	43
9713	0.0557	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of abdomen	UBERON:0001416	87.23	gold quality
granulocyte	CL:0000094	86.68	gold quality
skin of leg	UBERON:0001511	85.53	gold quality
pancreatic ductal cell	CL:0002079	84.30	silver quality
zone of skin	UBERON:0000014	83.96	gold quality
cartilage tissue	UBERON:0002418	83.81	gold quality
lower esophagus mucosa	UBERON:0035834	83.12	gold quality
nasal cavity epithelium	UBERON:0005384	82.55	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.17	silver quality
upper arm skin	UBERON:0004263	82.03	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	79.50	gold quality
tibialis anterior	UBERON:0001385	79.20	silver quality
mucosa of transverse colon	UBERON:0004991	78.40	gold quality
nasal cavity mucosa	UBERON:0001826	77.94	gold quality
spleen	UBERON:0002106	77.52	gold quality
blood	UBERON:0000178	76.68	gold quality
vermiform appendix	UBERON:0001154	76.37	gold quality
buccal mucosa cell	CL:0002336	75.70	silver quality
tendon of biceps brachii	UBERON:0008188	74.85	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	74.82	gold quality
bone marrow cell	CL:0002092	74.76	gold quality
minor salivary gland	UBERON:0001830	74.17	gold quality
endocervix	UBERON:0000458	74.02	gold quality
small intestine Peyer’s patch	UBERON:0003454	73.66	gold quality
esophagus mucosa	UBERON:0002469	73.25	gold quality
caecum	UBERON:0001153	73.23	gold quality
mouth mucosa	UBERON:0003729	72.83	gold quality
transverse colon	UBERON:0001157	72.78	gold quality
lymph node	UBERON:0000029	72.52	gold quality
small intestine	UBERON:0002108	71.65	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-GEOD-139324	yes	1590.52
E-CURD-120	yes	1167.57
E-HCAD-8	yes	969.90
E-CURD-95	yes	937.38
E-CURD-89	yes	704.33
E-MTAB-6701	yes	129.69
E-MTAB-8142	yes	65.15
E-MTAB-6678	yes	29.97
E-MTAB-8410	yes	29.37
E-HCAD-11	yes	27.71
E-CURD-46	yes	25.46
E-HCAD-1	yes	16.49
E-CURD-122	yes	13.61
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTCF, FOXP3, NFKB1, NFKB, REL, RELA, RUNX1

miRNA regulators (miRDB)

10 targeting TNFRSF18, 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-6763-5P	99.76	64.68	1767
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-6810-3P	97.96	64.57	1023
HSA-MIR-4638-3P	97.90	65.75	905
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-4726-5P	97.24	65.67	1299
HSA-MIR-939-5P	97.10	65.80	1579
HSA-MIR-1343-5P	96.48	66.06	1506
HSA-MIR-3918	96.13	64.65	1300

Literature-anchored findings (GeneRIF, showing 40)

• GITR rapidly recruits TNF receptor-associated factor 2 (TRAF2) in a ligand-dependent manner; data indicate that the cytoplasmic domain of GITR contains a single TRAF binding site where acidic residues 202/203 and 211-213 are critical for this interaction. (PMID:15944293)
• Since regulatory T-cells are localized in the vicinity of GITRL-expressing cells in atopic dermatitis skin, the GITR/GITRL interaction may serve to perpetuate the inflammation locally. (PMID:16955181)
• This protein has been shown to stimulate T cell-mediated antitumor immunity in mice, and now in a human tumor cell line. (PMID:17360848)
• These data suggest that, despite abnormal GITR expression during HIV infection, GITR triggering enhances HIV-specific CD4(+) T cell cytokine expression and protects HIV-specific CD4(+) T cells from apoptosis. (PMID:17538882)
• although GITR is an activation marker for NK cells similar to that for T cells, GITR serves as a negative regulator for NK cell activation (PMID:18230609)
• CD4(+)CD25(+) effector memory T-cells expressing CD134 and GITR seem to play a role in disease mechanisms, as suggested by their close association with disease activity and their participation in the inflammatory process in Wegener’s granulomatosis. (PMID:18723571)
• mechanism of IgG4 induction by regulatory cells involves GITR-GITR-L interactions, IL-10 and TGF-beta. (PMID:18924213)
• Data show that in humans GITRL expression subverts NK cell immunosurveillance of AML. (PMID:19155305)
• mRNA level for CTLA-4, ICOS1, IL-23, IL-27, SMAD3 and GITR were lower in T regulatory cells of children with diabetes compared to the control patients (PMID:19547759)
• The regulatory SNPs identified in this study will provide useful information for understanding the relevance of sequence polymorphisms in populations of different background and may serve as a basis to study parasite susceptibility in association studies (PMID:21445534)
• Data indicate that CD4(+) CD25(low) GITR(+) cells represent a low percentage of the CD4(+) T-cell population (0.32-1.74%) and are mostly memory cells. (PMID:21557210)
• study concludes, the rs3753348 C/G SNP in the GITR is associated with Hashimoto’s disease prognosis and expression on T(reg) and T(eff) cells (PMID:21592113)
• GITR, which transmits a signal that abrogates regulatory T cell functions, was elevated in early rheumatoid arthritis. (PMID:21670968)
• Findings suggest that GITR-expression of TILs is associated with cancer progression. (PMID:21694467)
• Although GITR transgene costimulation can therapeutically enhance T helper (Th) type 2 cell responses, GITR-GITR ligand interactions are not required for development of Th2-mediated resistance or pathology. (PMID:21705620)
• DCs transfected with mRNA encoding a humanized anti-CTLA-4 mAb and mRNA encoding a soluble human GITR fusion protein enhance the induction of anti-tumor CTLs in response to DCs. (PMID:22028176)
• GITRL may contribute to disease pathophysiology and resistance to direct and Rituximab-induced NK reactivity in CLL (PMID:22064350)
• Results suggest that GITR expression might indicate a molecular link between steroid use and complicated acute sigmoid diverticulitis. Increased MMP-9 expression by GITR signalling might explain morphological changes in the colonic wall in diverticulitis. (PMID:22309286)
• GITR is pathologically expressed on Treg cells in systemic lupus erythematosus. (PMID:22516990)
• Liver tumor Tregs up-regulate the expression of glucocorticoid-induced tumor necrosis factor receptor compared with Tregs in tumor-free liver tissue and blood. (PMID:22911397)
• Data indicate that the mRNAs of CTLA-4 and GITR genes were expressed at lower levels in CVID patients compared to control group. (PMID:23432692)
• GITR acts as a potential tumor suppressor in MM. (PMID:23785514)
• these results show a higher susceptibility to apoptosis in patients’ versus controls’ T(reg) cells, suggesting that GITR is a T(reg)-cell marker that would be primarily involved in T(reg)-cell survival rather than in their suppressor function. (PMID:23929911)
• Our findings indicate the possible involvement of GITR-GITRL pathway in the pathogenesis of pSS. (PMID:23935647)
• Data may suggest a key role of regulatory GITR+CD25 low/-CD4+ T cells subset in the modulation of the abnormal immune response in lupus erythematosus (SLE) patients. (PMID:25256257)
• Aberrant expression of GITR may contribute to systemic lupus erithematosus pathogenesis. Glucocorticoid may achieve its therapeutic effect partly by inducing GITR expression on Tresps rather than Tregs, which initiates the apoptosis of Tresp cells in SLE patients. (PMID:25293713)
• results suggest that the GITR rs3753348 polymorphism may be involved in the development and susceptibility of CWP. (PMID:25445616)
• GITR is a crucial player in differentiation of thymic regulatory T cells and expansion of regulatory T cells, including both thymic regulatory T cells and peripheral regulatory T cells. (PMID:25961057)
• GITR expression can enhance the sensitivity to Bortezomib by inhibiting Bortezomib-induced NF-kappaB activation. (PMID:25973846)
• HTLV-1 infection can modify the expression of main functional transcription factors, FOXP3 and GITR (PMID:28101786)
• a novel molecular mechanism by which MBD4 inhibits GITR expression in a DNMT1-dependent manner (PMID:28542810)
• GITR cosignal in ILC2s controls allergic lung inflammation. (PMID:29427641)
• The increased expression of FOXP3, CTLA-4 and GITR represent higher activity of Treg cells. (PMID:30484986)
• Agonistic targeting of GITR can enhance functionality of HCC TIL. (PMID:30719701)
• Authors demonstrate that GITR engagement of activated, but not naive, ILC2s improves glucose homeostasis, resulting in both protection against insulin resistance onset and amelioration of established insulin- resistance. (PMID:30755607)
• This work demonstrates abnormal changes in Helios(+) Tregs and soluble GITR in myasthenia gravis, as well as direct regulation of Helios by GITR in the context of Tregulatory cells. (PMID:31118027)
• Characterization and Comparison of GITR Expression in Solid Tumors. (PMID:31358539)
• GITR shapes humoral immunity by controlling the balance between follicular T helper cells and regulatory T follicular cells. (PMID:32259529)
• Glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) drives atherosclerosis in mice and is associated with an unstable plaque phenotype and cerebrovascular events in humans. (PMID:32728688)
• Interleukin 3-induced GITR promotes the activation of human basophils. (PMID:32889153)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	hdr	ENSDARG00000004392
danio_rerio	tnfrsfa	ENSDARG00000004451
danio_rerio	cd40	ENSDARG00000054968
danio_rerio	nradd	ENSDARG00000057143
danio_rerio	tnfrsf1b	ENSDARG00000070165
danio_rerio	tnfrsf11a	ENSDARG00000087804
mus_musculus	Tnfrsf18	ENSMUSG00000041954
rattus_norvegicus	Tnfrsf18	ENSRNOG00000022012

Paralogs (21): FAS (ENSG00000026103), TNFRSF1B (ENSG00000028137), TNFRSF9 (ENSG00000049249), RELT (ENSG00000054967), NGFR (ENSG00000064300), TNFRSF1A (ENSG00000067182), CD40 (ENSG00000101017), TNFRSF10A (ENSG00000104689), LTBR (ENSG00000111321), TNFRSF10B (ENSG00000120889), TNFRSF8 (ENSG00000120949), CD27 (ENSG00000139193), TNFRSF11A (ENSG00000141655), TNFRSF21 (ENSG00000146072), TNFRSF14 (ENSG00000157873), TNFRSF11B (ENSG00000164761), TNFRSF10D (ENSG00000173530), TNFRSF10C (ENSG00000173535), TNFRSF4 (ENSG00000186827), TNFRSF25 (ENSG00000215788), TNFRSF6B (ENSG00000243509)

Protein

Protein identifiers

Tumor necrosis factor receptor superfamily member 18 — Q9Y5U5 (reviewed: Q9Y5U5)

Alternative names: Activation-inducible TNFR family receptor, Glucocorticoid-induced TNFR-related protein

All UniProt accessions (2): Q9Y5U5, J3KT02

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for TNFSF18. Seems to be involved in interactions between activated T-lymphocytes and endothelial cells and in the regulation of T-cell receptor-mediated cell death. Mediated NF-kappa-B activation via the TRAF2/NIK pathway.

Subunit / interactions. Binds to TRAF1, TRAF2, and TRAF3, but not TRAF5 and TRAF6. Binds through its C-terminus to SIVA1/SIVA.

Subcellular location. Cell membrane Secreted.

Tissue specificity. Expressed in lymph node, peripheral blood leukocytes and weakly in spleen.

Induction. Up-regulated in peripherical mononuclear cells after antigen stimulation/lymphocyte activation.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y5U5-1	1	yes
Q9Y5U5-2	2, GITR-D
Q9Y5U5-3	3

RefSeq proteins (3): NP_004186, NP_683699, NP_683700 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001368	TNFR/NGFR_Cys_rich_reg	Domain
IPR022318	TNFR_18	Family
IPR034018	TNFRSF18_N	Domain
IPR053107	TNFRSF18	Family

UniProt features (35 total): strand 11, disulfide bond 5, sequence variant 4, repeat 3, splice variant 2, topological domain 2, helix 2, signal peptide 1, chain 1, glycosylation site 1, transmembrane region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
7LAW	X-RAY DIFFRACTION	2.75
9P8X	X-RAY DIFFRACTION	2.86
7KHD	X-RAY DIFFRACTION	2.96

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5U5-F1	73.72	0.41

Functional residue map

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

Disulfide bonds (5): 34–49, 74–86, 81–94, 115–134, 128–153

Glycosylation sites (1): 146

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5669034	TNFs bind their physiological receptors
R-HSA-8877330	RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)

MSigDB gene sets: 242 (showing top): GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOCC_CELL_SURFACE, GOBP_CELL_SURFACE_RECEPTOR_SIGNALING_PATHWAY_VIA_JAK_STAT, GOBP_REGULATION_OF_LEUKOCYTE_MIGRATION, GOBP_POSITIVE_REGULATION_OF_PEPTIDYL_TYROSINE_PHOSPHORYLATION, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, GOBP_LEUKOCYTE_MIGRATION, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_MIGRATION, WANG_LMO4_TARGETS_DN, GOBP_POSITIVE_REGULATION_OF_PHOSPHORUS_METABOLIC_PROCESS, GOBP_TUMOR_NECROSIS_FACTOR_MEDIATED_SIGNALING_PATHWAY

GO Biological Process (7): positive regulation of leukocyte migration (GO:0002687), apoptotic process (GO:0006915), signal transduction (GO:0007165), positive regulation of tyrosine phosphorylation of STAT protein (GO:0042531), negative regulation of apoptotic process (GO:0043066), positive regulation of cell adhesion (GO:0045785), tumor necrosis factor-mediated signaling pathway (GO:0033209)

GO Molecular Function (2): tumor necrosis factor receptor activity (GO:0005031), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
TNFR2 non-canonical NF-kB pathway	1
Transcriptional regulation by RUNX1	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
positive regulation of immune system process	1
regulation of leukocyte migration	1
positive regulation of cell migration	1
leukocyte migration	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
tyrosine phosphorylation of STAT protein	1
regulation of tyrosine phosphorylation of STAT protein	1
positive regulation of peptidyl-tyrosine phosphorylation	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
cell adhesion	1
regulation of cell adhesion	1
positive regulation of cellular process	1
cytokine-mediated signaling pathway	1
cellular response to tumor necrosis factor	1
death receptor activity	1
tumor necrosis factor-mediated signaling pathway	1
tumor necrosis factor binding	1
binding	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1

Protein interactions and networks

STRING

1396 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNFRSF18	TNFSF18	Q9UNG2	999
TNFRSF18	TNFRSF4	P43489	945
TNFRSF18	CTLA4	P16410	928
TNFRSF18	FOXP3	Q9BZS1	912
TNFRSF18	TNFRSF9	Q07011	907
TNFRSF18	IL2RA	P01589	880
TNFRSF18	CD4	P01730	871
TNFRSF18	CD80	P33681	870
TNFRSF18	TIGIT	Q495A1	869
TNFRSF18	CD27	P26842	866
TNFRSF18	IDO1	P14902	864
TNFRSF18	CD86	P42081	841
TNFRSF18	HAVCR2	Q8TDQ0	820
TNFRSF18	TNFRSF1A	P19438	818
TNFRSF18	CD40	P25942	810

IntAct

7 interactions, top by confidence:

A	B	Type	Score
TNFSF18	TNFRSF18	psi-mi:“MI:0407”(direct interaction)	0.720
TNFRSF18	TNFSF18	psi-mi:“MI:0407”(direct interaction)	0.720
TNFSF18	TNFRSF18	psi-mi:“MI:0915”(physical association)	0.720
TNFRSF18	TNFRSF18	psi-mi:“MI:0407”(direct interaction)	0.440
MYC		psi-mi:“MI:0914”(association)	0.350
TNFRSF18	HSPA5	psi-mi:“MI:0914”(association)	0.350

BioGRID (16): TNFRSF18 (Affinity Capture-Western), UBQLN2 (Two-hybrid), TRAF1 (Affinity Capture-Western), TRAF3 (Affinity Capture-Western), TRAF2 (Affinity Capture-Western), TNFRSF18 (Affinity Capture-Western), NEDD4 (Affinity Capture-Western), TNFRSF18 (Reconstituted Complex), HSPA5 (Affinity Capture-MS), NIF3L1 (Affinity Capture-MS), IDE (Affinity Capture-MS), TRAF1 (Two-hybrid), TRAF2 (Two-hybrid), TRAF3 (Two-hybrid), TRAF2 (Affinity Capture-Western)

ESM2 similar proteins: A4FV93, A5A8Y8, B2LW77, D3ZUK3, O00468, O70534, O75074, O88204, O88839, O95407, P06579, P07204, P15306, P60882, P80370, Q09163, Q13444, Q14162, Q3SWY4, Q501P1, Q53RD9, Q5ND28, Q5VY43, Q5W7P8, Q61810, Q6AZ60, Q6GUQ1, Q6MG84, Q6UY11, Q71U07, Q75N90, Q7Z7M0, Q8K1E3, Q8K1S7, Q8K4G1, Q8NCW0, Q8ND94, Q8VIK5, Q8WUT4, Q93038

Diamond homologs: O35714, P15725, P43489, P47741, Q9Y5U5, A5D7R1, O00300, O35305, O77736, P20333, P50284, Q63199, Q9Y6Q6, O00220, O14763, O14798, P25445, P25446, Q92956, Q9BDN0, Q9BDN4, Q9BDP2, Q9TSN4, Q07011

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	65
Likely benign	19
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

708 predictions. Top by Δscore:

Variant	Effect	Δscore
1:1206381:TTAC:T	donor_loss	1.0000
1:1206382:TA:T	donor_loss	1.0000
1:1206383:A:AC	donor_gain	1.0000
1:1206383:A:AT	donor_loss	1.0000
1:1206383:AC:A	donor_gain	1.0000
1:1206383:ACC:A	donor_gain	1.0000
1:1206384:C:CA	donor_gain	1.0000
1:1206384:CC:C	donor_gain	1.0000
1:1206384:CCC:C	donor_gain	1.0000
1:1206384:CCCG:C	donor_gain	1.0000
1:1206384:CCCGG:C	donor_gain	1.0000
1:1204053:A:AC	donor_gain	0.9900
1:1204053:ACT:A	donor_gain	0.9900
1:1204054:C:CC	donor_gain	0.9900
1:1204054:CTC:C	donor_gain	0.9900
1:1204061:G:C	donor_gain	0.9900
1:1206379:ACTT:A	donor_loss	0.9800
1:1204397:A:AC	donor_gain	0.9700
1:1204398:C:CC	donor_gain	0.9700
1:1204398:CT:C	donor_gain	0.9700
1:1204497:G:C	acceptor_gain	0.9600
1:1204054:CT:C	donor_gain	0.9500
1:1204054:CTCCT:C	donor_gain	0.9400
1:1204060:AGCTG:A	donor_gain	0.9300
1:1204202:C:CT	acceptor_gain	0.9200
1:1204202:C:T	acceptor_gain	0.9200
1:1204056:C:CA	donor_gain	0.9100
1:1203967:CT:C	acceptor_gain	0.8900
1:1203969:C:CC	acceptor_gain	0.8900
1:1204055:T:TA	donor_gain	0.8900

AlphaMissense

1547 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:1204437:G:C	F120L	0.995
1:1204437:G:T	F120L	0.995
1:1204439:A:G	F120L	0.995
1:1204467:G:C	F110L	0.988
1:1204467:G:T	F110L	0.988
1:1204469:A:G	F110L	0.988
1:1204468:A:C	F110C	0.987
1:1205443:G:C	F79L	0.981
1:1205443:G:T	F79L	0.981
1:1205445:A:G	F79L	0.981
1:1204462:C:G	C112S	0.979
1:1204463:A:T	C112S	0.979
1:1204438:A:C	F120C	0.976
1:1204414:C:G	C128S	0.973
1:1204415:A:T	C128S	0.973
1:1204453:C:G	C115S	0.970
1:1204454:A:T	C115S	0.970
1:1204404:C:A	W131C	0.969
1:1204404:C:G	W131C	0.969
1:1205391:C:A	G97C	0.967
1:1204177:C:G	C153S	0.966
1:1204178:A:T	C153S	0.966
1:1204201:C:A	G145V	0.965
1:1204202:C:A	G145W	0.963
1:1205390:C:A	G97V	0.963
1:1204453:C:T	C115Y	0.960
1:1204198:T:A	N146I	0.959
1:1204452:A:C	C115W	0.959
1:1204463:A:G	C112R	0.958
1:1204201:C:T	G145E	0.957

dbSNP variants (sampled 300 via entrez): RS1000378662 (1:1206395 G>A,T), RS1000679655 (1:1205282 G>A,C), RS1001151157 (1:1203694 C>A,G,T), RS1001434242 (1:1203034 C>A), RS1001588619 (1:1206653 G>A,C), RS1001870117 (1:1206258 G>A,C), RS1001923926 (1:1206056 G>A,C), RS1002198652 (1:1208187 C>T), RS1002355105 (1:1204423 T>C), RS1002388305 (1:1204582 G>A), RS1002512986 (1:1207437 G>C), RS1003588441 (1:1205128 C>T), RS1003819160 (1:1208458 G>A), RS1004047178 (1:1204939 C>T), RS1004049463 (1:1206272 C>A,G,T)

Disease associations

OMIM: gene MIM:603905 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001725_30	Inflammatory bowel disease	8.000000e-13

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3712995 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — Tumour necrosis factor (TNF) receptor family

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, increases methylation	2
aristolochic acid I	increases expression	1
propionaldehyde	decreases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	increases expression, affects cotreatment, increases abundance	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
bisphenol S	affects cotreatment, decreases methylation	1
NSC 689534	affects binding, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Arsenic Trioxide	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	increases expression, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Cisplatin	increases expression	1
Copper	affects binding, decreases expression	1
Drugs, Chinese Herbal	increases expression	1
Fluorouracil	increases expression	1
Lipopolysaccharides	affects cotreatment, increases expression, affects response to substance	1
Manganese	increases abundance, increases expression, affects cotreatment	1
Naphthoquinones	increases expression	1
Silicon Dioxide	increases expression	1
Smoke	increases expression, increases abundance	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	increases expression	1
Valproic Acid	increases methylation	1
Cyclosporine	decreases methylation	1

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8R4	Abcam HCT 116 TNFRSF18 KO	Cancer cell line	Male
CVCL_B9TI	Abcam A-549 TNFRSF18 KO	Cancer cell line	Male
CVCL_D2HG	Abcam MCF-7 TNFRSF18 KO	Cancer cell line	Female
CVCL_KA39	CHO-K1/GITR	Spontaneously immortalized cell line	Female
CVCL_LH48	Jurkat 1F2-hGITR	Cancer cell line	Male
CVCL_UE32	HT1080 human GITR	Cancer cell line	Male

Clinical trials (associated diseases)

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