TNFRSF4

Summary

TNFRSF4 (TNF receptor superfamily member 4, HGNC:11918) is a protein-coding gene on chromosome 1p36.33, encoding Tumor necrosis factor receptor superfamily member 4 (P43489). Receptor for TNFSF4/OX40L/GP34.

The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor has been shown to activate NF-kappaB through its interaction with adaptor proteins TRAF2 and TRAF5. Knockout studies in mice suggested that this receptor promotes the expression of apoptosis inhibitors BCL2 and BCL2lL1/BCL2-XL, and thus suppresses apoptosis. The knockout studies also suggested the roles of this receptor in CD4+ T cell response, as well as in T cell-dependent B cell proliferation and differentiation.

Source: NCBI Gene 7293 — RefSeq curated summary.

At a glance

• Gene–disease (curated): combined immunodeficiency due to OX40 deficiency (Supportive, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 362 total
• Phenotypes (HPO): 7
• Druggable target: yes
• MANE Select transcript: NM_003327

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11918
Approved symbol	TNFRSF4
Name	TNF receptor superfamily member 4
Location	1p36.33
Locus type	gene with protein product
Status	Approved
Aliases	ACT35, OX40, CD134
Ensembl gene	ENSG00000186827
Ensembl biotype	protein_coding
OMIM	600315
Entrez	7293

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 7 protein_coding, 3 non_stop_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000379236, ENST00000453580, ENST00000497869, ENST00000699969, ENST00000699970, ENST00000699971, ENST00000699972, ENST00000699973, ENST00000699974, ENST00000699975, ENST00000699976, ENST00000699977, ENST00000699978, ENST00000699979

RefSeq mRNA: 2 — MANE Select: NM_003327 NM_001410709, NM_003327

CCDS: CCDS11, CCDS90838

Canonical transcript exons

ENST00000379236 — 7 exons

Exon	Start	End
ENSE00001333051	1211704	1211832
ENSE00001333068	1213663	1213785
ENSE00001832731	1213983	1214153
ENSE00003649215	1211942	1212138
ENSE00003978390	1212638	1212704
ENSE00003978399	1212992	1213093
ENSE00003978400	1211340	1211625

Expression profiles

Bgee: expression breadth ubiquitous, 160 present calls, max score 82.81.

FANTOM5 (CAGE): breadth broad, TPM avg 4.7920 / max 395.6722, expressed in 413 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
9723	3.4471	276
9721	0.5168	169
9722	0.4607	95
9720	0.3674	154

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	82.81	gold quality
granulocyte	CL:0000094	82.16	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.05	silver quality
spleen	UBERON:0002106	80.23	gold quality
omental fat pad	UBERON:0010414	79.43	gold quality
peritoneum	UBERON:0002358	79.33	gold quality
adipose tissue of abdominal region	UBERON:0007808	77.52	gold quality
lymph node	UBERON:0000029	76.50	gold quality
cartilage tissue	UBERON:0002418	75.33	gold quality
mucosa of transverse colon	UBERON:0004991	74.64	gold quality
endometrium epithelium	UBERON:0004811	74.53	gold quality
upper lobe of left lung	UBERON:0008952	74.09	gold quality
blood	UBERON:0000178	72.98	gold quality
vermiform appendix	UBERON:0001154	72.92	gold quality
heart left ventricle	UBERON:0002084	71.69	gold quality
subcutaneous adipose tissue	UBERON:0002190	71.52	gold quality
right lung	UBERON:0002167	71.29	gold quality
upper lobe of lung	UBERON:0008948	71.28	gold quality
small intestine Peyer’s patch	UBERON:0003454	71.17	gold quality
cardiac ventricle	UBERON:0002082	70.66	gold quality
right lobe of thyroid gland	UBERON:0001119	70.61	gold quality
hindlimb stylopod muscle	UBERON:0004252	70.40	gold quality
left lobe of thyroid gland	UBERON:0001120	70.05	gold quality
adipose tissue	UBERON:0001013	69.70	gold quality
transverse colon	UBERON:0001157	69.60	gold quality
gastrocnemius	UBERON:0001388	69.20	gold quality
connective tissue	UBERON:0002384	68.66	gold quality
body of stomach	UBERON:0001161	68.39	gold quality
thyroid gland	UBERON:0002046	68.39	gold quality
small intestine	UBERON:0002108	68.14	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-GEOD-139324	yes	2499.36
E-HCAD-8	yes	2001.89
E-CURD-95	yes	1451.04
E-CURD-120	yes	935.40
E-MTAB-8410	yes	29.98
E-CURD-46	yes	25.64
E-HCAD-11	yes	17.48
E-HCAD-1	yes	14.89
E-CURD-122	yes	9.25
E-MTAB-6701	yes	8.89
E-ANND-3	yes	3.59

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB1, NFKB, RELA, SP3, YY1

Literature-anchored findings (GeneRIF, showing 40)

• Pimecrolimus inhibits up-regulation of OX40 and synthesis of inflammatory cytokines upon secondary T cell activation by allogeneic dendritic cells. (PMID:12296857)
• Expression of CD134 and CD134 ligand in lesional and nonlesional psoriatic skin. (PMID:12624783)
• CD134 positive cells are identified within inflammatory lesions of active multiple sclerosis (MS), acute MS and chronic active MS as well as in acute disseminated leukoencephalitis patients. (PMID:14644025)
• T cell proliferation by direct cross-talk between OX40 ligand on human mast cells and OX40 on human T cells. (PMID:15470070)
• Mutagenesis showed that Asp60 and Asp62 are required for interaction with FIV, and modeling studies localized these two residues to the outer edge of domain 1 (PMID:15592478)
• The expression of CD134 was markedly higher, compared to CD137, both on the day of the surgery and ten days after colorectal cancer surgery. (PMID:15638367)
• Deficiencies in OX40 and CD30 signals were additive, secondary Ab responses were ablated.OX40/CD30 double-knockout OTII transgenic T cells fail to survive compared with normal T cells when cocultured with CD4(+)CD3(-) cells in vitro. (PMID:15778343)
• Decrease in OX40 expression posttransplant includes the defective reconstitution of Treg cells, and the active inhibition of gene transcription by cyclosporine. (PMID:15808546)
• stimulation of OX40/4-1BB rendered cells sensitive to apoptosis induced by TNF-alpha and reduced activation of NF-kappaB. OX40/4-1BB stimulation repressed the mitogen response in activated CD25+CD4+ T cells and preactivated CD8+ T cells (PMID:15941918)
• CD3+ T lymphocytes co-expressing CD134 and CD137 antigens on peripheral blood revealed an increased percentages of OX-40/CD137 positive cells in patients with Graves’ disease (p<0.025) compared to the controls. (PMID:16232366)
• The relevance of these findings is supported by the vital functions fulfilled by OX40 in mammals as reflected by the high level of evolutionary conservation. (PMID:16329997)
• The coexpression of CD25 and the costimulatory molecule CD134 on memory T-cells provides a novel marker for type 1 diabetes-associated T-cell immunity. (PMID:16380476)
• OX40 ligation on CD4(+) T cells represents a potentially novel immunotherapeutic strategy that should be investigated to treat and prevent persistent virus infections, such as HIV-1 infection. (PMID:16456009)
• OX40 is induced transiently on CD8(+) T cells upon activation and its signals contribute to both clonal expansion and functional reinforcement (PMID:16750861)
• In the present study we found that costimulation via OX40 and TNF-R in OX40-expressing HIV-1-infected T cell lines leads to a marked reduction of HIV-1 production associated with rapid cell death. (PMID:18327975)
• The expression of OX40 on CD4+ T cells in sentinel lymph nodes draining primary melanomas decreased withe more advanced tumor features, suggesting an immunosuppressive effect. (PMID:18374895)
• Activity of OX40 ligand is enhanced by oligomerization and cell surface immobilization. (PMID:18397322)
• the frequency of the most frequent haplotype, C-C-A-A, was significantly lower and that of the second most frequent, C-T-G-A, was significantly higher in hypertensive subjects than in controls. This difference was observed only in female patients (PMID:18398332)
• Results show that the OX40-OX40L interaction suppresses IL-17 production by PHA-stimulated human PBMC and purified CD4 and CD8 cells. (PMID:18501882)
• These data offer a novel approach for UCB Treg expansion using aAPCs, including those coexpressing OX40L or 4-1BBL. (PMID:18645038)
• Targeting the OX40 costimulation is therapeutically important in the induction of transplant tolerance. (PMID:18660703)
• 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)
• OX40 antigen levels were significantly elevated in Systemic sclerosis patients compared with Systemic Lupus patients and controls; elevated levels were assoicated with early-onset disease (PMID:18843780)
• Lack of OX40 signals in transgenic mice significantly reduces the number and proportion of killer cell lectin-like receptor G1 (KLRG1)-defective memory precursor effector T cells. (PMID:18941188)
• Dendritic cells matured in the presence of PGE(2) induced the expression of OX40, OX40L, and CD70 on T cells facilitating T-cell/T-cell interaction that warrant long-lasting costimulation. (PMID:19029446)
• Compared with control group, the expression of OX40 and Bcl-2 was significantly higher in allergic rhinitis. (PMID:19253527)
• the mechanisms regulating OX40 expression on activated T cells (Review) (PMID:19538134)
• OX40/OX40L expression is increased in the bronchial submucosa in mild asthma, but not in moderate-to-severe disease, and is related to the degree of tissue eosinophilia and IL-4 expression. (PMID:20139223)
• Data suggest the role of Perforin + cytotoxic T lymphocytes and CD134+ cells in the pathogenesis of autoimmunity of SLE. (PMID:20306696)
• The rs2298212G/A polymorphism in OX40 gene may be associated with the severity of coronary atherosclerotic disease. (PMID:20376799)
• This study has shown that activation of OX40 induces CCL20 expression in the presence of antigen stimulation. (PMID:20400327)
• High OX40 expression may be associated with malignant transformation, progression, invasion and metastasis in breast cancer biology. (PMID:20634005)
• Possible proinflammatory effects of OX40L on the pathogenesis of atherosclerois. (PMID:21086790)
• PAPP-A level was significantly related to soluble and membrane-bound OX40L in patients with ACS. (PMID:21111564)
• Both OX40 upregulation and sOX40L increase were closely associated with Henoch-Schonlein purpura (HSP), especially HSP with nephritis. (PMID:21143648)
• Transgenic OX40 forms a signaling complex in T cells that contains phosphoinositide 3-kinase (PI3K) and protein kinase B (PKB). (PMID:21289304)
• OX40 gene polymorphism may be associated with a risk of ACS in the Han Chinese population, although the association between OX40L polymorphisms and ACS requires further investigation (PMID:21476935)
• For the first time, we have shown that short ragweed pollen initiates TLR4-dependent TSLP/OX40L/OX40 signaling, which triggers T(H)2-dominant allergic inflammation (PMID:21820713)
• Head and neck cancer patients have decreased levels of alternative co-stimulatory receptors OX40 and 4-1BB. (PMID:22204816)
• We show that the inflammatory and cytotoxic function of CD4(+)CD28(null) T cells can be inhibited by blocking OX40 and 4-1BB costimulatory receptors. (PMID:22282196)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	hdr	ENSDARG00000004392
danio_rerio	tnfrsfa	ENSDARG00000004451
danio_rerio	cd40	ENSDARG00000054968
danio_rerio	tnfrsf1b	ENSDARG00000070165
danio_rerio	tnfrsf11a	ENSDARG00000087804
mus_musculus	Tnfrsf4	ENSMUSG00000029075
rattus_norvegicus	Tnfrsf4	ENSRNOG00000020106

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), TNFRSF18 (ENSG00000186891), TNFRSF25 (ENSG00000215788), TNFRSF6B (ENSG00000243509)

Protein

Protein identifiers

Tumor necrosis factor receptor superfamily member 4 — P43489 (reviewed: P43489)

Alternative names: ACT35 antigen, OX40L receptor, TAX transcriptionally-activated glycoprotein 1 receptor

All UniProt accessions (11): A0A8V8TP52, A0A8V8TP56, A0A8V8TPH3, A0A8V8TPH7, A0A8V8TPN6, A0A8V8TPP1, A0A8V8TQH5, A0A8V8TQH9, A0A8V8TQV3, A0A8V8TQV7, P43489

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for TNFSF4/OX40L/GP34. Is a costimulatory molecule implicated in long-term T-cell immunity. (Microbial infection) Acts as a receptor for human herpesvirus 6B/HHV-6B.

Subunit / interactions. Interacts with TRAF2, TRAF3 and TRAF5. (Microbial infection) Interacts with Human herpesvirus 6B/HHV-6B gQ1:gQ2 proteins.

Subcellular location. Membrane.

Disease relevance. Immunodeficiency 16 (IMD16) [MIM:615593] An autosomal recessive primary immunodeficiency associated with classic Kaposi sarcoma of childhood and poor T-cell recall immune responses due to complete functional OX40 deficiency. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (2): NP_001397638, NP_003318* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001368	TNFR/NGFR_Cys_rich_reg	Domain
IPR020445	TNFR_4	Family
IPR034022	TNFRSF4_N	Domain

Pfam: PF00020

UniProt features (42 total): strand 16, disulfide bond 9, repeat 4, region of interest 2, glycosylation site 2, topological domain 2, sequence variant 2, signal peptide 1, chain 1, transmembrane region 1, helix 1, turn 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
1D0A	X-RAY DIFFRACTION	2
2HEY	X-RAY DIFFRACTION	2
6OKM	X-RAY DIFFRACTION	2.1
2HEV	X-RAY DIFFRACTION	2.41
7YK4	X-RAY DIFFRACTION	2.7
6OGX	X-RAY DIFFRACTION	2.77
6OKN	X-RAY DIFFRACTION	3.25
8AG1	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43489-F1	77.32	0.52

Antibody-complex structures (SAbDab): 5 — 6OGX, 6OKM, 6OKN, 7YK4, 8AG1

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 (9): 31–42, 43–56, 46–64, 67–81, 84–99, 87–107, 109–125, 128–141, 147–166

Glycosylation sites (2): 146, 160

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5669034	TNFs bind their physiological receptors

MSigDB gene sets: 305 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_B_CELL_ACTIVATION, GOCC_CELL_SURFACE, GOBP_B_CELL_PROLIFERATION, GOBP_POSITIVE_REGULATION_OF_B_CELL_PROLIFERATION, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_REGULATION_OF_IMMUNOGLOBULIN_PRODUCTION, GOBP_LEUKOCYTE_PROLIFERATION, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, GOBP_IMMUNOGLOBULIN_PRODUCTION, RUTELLA_RESPONSE_TO_HGF_VS_CSF2RB_AND_IL4_DN

GO Biological Process (8): negative regulation of transcription by RNA polymerase II (GO:0000122), positive regulation of immunoglobulin production (GO:0002639), inflammatory response (GO:0006954), immune response (GO:0006955), positive regulation of B cell proliferation (GO:0030890), T cell proliferation (GO:0042098), tumor necrosis factor-mediated signaling pathway (GO:0033209), symbiont entry into host cell (GO:0046718)

GO Molecular Function (3): virus receptor activity (GO:0001618), tumor necrosis factor receptor activity (GO:0005031), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
TNFR2 non-canonical NF-kB pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
immunoglobulin production	1
regulation of immunoglobulin production	1
positive regulation of production of molecular mediator of immune response	1
defense response	1
immune system process	1
response to stimulus	1
regulation of B cell proliferation	1
B cell proliferation	1
positive regulation of lymphocyte proliferation	1
positive regulation of B cell activation	1
T cell activation	1
lymphocyte proliferation	1
cytokine-mediated signaling pathway	1
cellular response to tumor necrosis factor	1
viral life cycle	1
symbiont entry into host	1
symbiont entry into host cell	1
exogenous protein binding	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

1760 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNFRSF4	TNFSF4	P23510	999
TNFRSF4	TNFSF9	P41273	997
TNFRSF4	CD80	P33681	994
TNFRSF4	CD70	P32970	994
TNFRSF4	ICOSLG	O75144	993
TNFRSF4	CD86	P42081	990
TNFRSF4	A0A087X1L8	A0A087X1L8	985
TNFRSF4	TNFRSF18	Q9Y5U5	945
TNFRSF4	CD40	P25942	939
TNFRSF4	CD40LG	P29965	936
TNFRSF4	TNFRSF8	P28908	935
TNFRSF4	CD27	P26842	929
TNFRSF4	TNFSF8	P32971	926
TNFRSF4	CD28	P10747	924
TNFRSF4	ICOS	Q9Y6W8	898

IntAct

6 interactions, top by confidence:

A	B	Type	Score
TNFSF4	TNFRSF4	psi-mi:“MI:0407”(direct interaction)	0.760
TNFSF4	TNFRSF4	psi-mi:“MI:0915”(physical association)	0.760
TNFRSF4	TNFRSF4	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (13): RC3H1 (Protein-RNA), NUFIP2 (Protein-RNA), TRAF5 (Affinity Capture-Western), TRAF5 (Reconstituted Complex), TRAF2 (Two-hybrid), TNFRSF4 (Affinity Capture-Western), TNFRSF4 (Affinity Capture-Western), TNFRSF9 (Affinity Capture-Western), TNFRSF4 (Affinity Capture-Western), TNFRSF4 (Affinity Capture-Western), TNFRSF4 (Affinity Capture-Western), TNFRSF4 (Affinity Capture-Western), TNFRSF4 (Affinity Capture-Western)

ESM2 similar proteins: A4D2P6, A5PJC7, O14836, O19131, P07174, P08138, P15725, P18519, P19438, P20333, P22273, P22934, P25118, P26842, P32927, P41272, P42701, P43489, P47741, P49796, P50555, P52734, P98174, Q01114, Q07303, Q08351, Q13477, Q14162, Q3U4N7, Q3UV31, Q60943, Q60953, Q6AZ51, Q6UWJ8, Q6WN34, Q8BH06, Q8BUM9, Q8BX43, Q8K5A9, Q8NAC3

Diamond homologs: A5D7R1, D3ZF92, O00300, O08712, O08727, O35305, O75509, O95407, P0DTN0, P20333, P25119, P25942, P25943, P27512, P29825, P36941, P43489, P83626, Q28203, Q3LRP1, Q3ZTK5, Q63199, Q7YRL5, Q8SQ34, Q9EPU5, Q9Y6Q6, O73559, P0DSV7, P0DSV8, P68636, P68637, P07174, P08138, P15725, P20334, P47741, P50284, Q07011, Q9Z0W1, O35714

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TNFSF4	up-regulates	TNFRSF4	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	186
Likely benign	143
Benign	17

Top pathogenic / likely-pathogenic (0)

SpliceAI

830 predictions. Top by Δscore:

Variant	Effect	Δscore
1:1211622:CCCC:C	acceptor_gain	1.0000
1:1211623:CCC:C	acceptor_gain	1.0000
1:1211623:CCCC:C	acceptor_gain	1.0000
1:1211624:CCC:C	acceptor_gain	1.0000
1:1211624:CCCTG:C	acceptor_loss	1.0000
1:1211626:CT:C	acceptor_loss	1.0000
1:1211627:T:A	acceptor_loss	1.0000
1:1211699:CTCA:C	donor_loss	1.0000
1:1211700:TCA:T	donor_loss	1.0000
1:1211701:CAC:C	donor_loss	1.0000
1:1211702:A:AC	donor_gain	1.0000
1:1211702:ACCAG:A	donor_loss	1.0000
1:1211703:C:CC	donor_gain	1.0000
1:1211703:C:G	donor_loss	1.0000
1:1211829:CGGC:C	acceptor_gain	1.0000
1:1212636:A:AC	donor_gain	1.0000
1:1212637:C:CC	donor_gain	1.0000
1:1213090:CTTC:C	acceptor_gain	1.0000
1:1213661:A:AC	donor_gain	1.0000
1:1213662:C:CC	donor_gain	1.0000
1:1213980:CACCT:C	donor_loss	1.0000
1:1213981:A:AC	donor_gain	1.0000
1:1213981:ACCTG:A	donor_loss	1.0000
1:1213982:C:CC	donor_gain	1.0000
1:1213982:CCTGG:C	donor_gain	1.0000
1:1211621:TCCCC:T	acceptor_gain	0.9900
1:1211622:CCCCC:C	acceptor_gain	0.9900
1:1211624:CC:C	acceptor_gain	0.9900
1:1211625:CC:C	acceptor_gain	0.9900
1:1211626:C:CC	acceptor_gain	0.9900

AlphaMissense

1770 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:1213671:C:G	C87S	0.997
1:1213672:A:T	C87S	0.997
1:1213983:C:A	G49C	0.997
1:1212676:G:C	F133L	0.996
1:1212676:G:T	F133L	0.996
1:1212678:A:G	F133L	0.996
1:1212643:C:A	W144C	0.995
1:1212643:C:G	W144C	0.995
1:1213036:C:G	C109S	0.995
1:1213037:A:T	C109S	0.995
1:1212701:C:G	C125S	0.994
1:1212702:A:T	C125S	0.994
1:1213042:C:G	C107S	0.994
1:1213043:A:T	C107S	0.994
1:1213785:C:A	G49V	0.994
1:1212653:C:G	C141S	0.993
1:1212654:A:T	C141S	0.993
1:1213051:T:A	D104V	0.993
1:1213066:C:G	C99S	0.993
1:1213067:A:T	C99S	0.993
1:1212677:A:C	F133C	0.992
1:1212700:A:C	C125W	0.992
1:1212701:C:T	C125Y	0.992
1:1213052:C:G	D104H	0.992
1:1212692:C:G	C128S	0.991
1:1212693:A:T	C128S	0.991
1:1213035:G:C	C109W	0.989
1:1213037:A:G	C109R	0.989
1:1213671:C:T	C87Y	0.989
1:1213731:C:T	C67Y	0.989

dbSNP variants (sampled 300 via entrez): RS1000059108 (1:1211211 C>T), RS1000159274 (1:1215698 G>A), RS1000499339 (1:1214573 G>C), RS1000536204 (1:1210977 A>C), RS1000558686 (1:1212808 T>A,C), RS1000571448 (1:1214307 C>T), RS1000965986 (1:1212545 C>G,T), RS1002173564 (1:1213619 G>A), RS1002993181 (1:1212458 G>T), RS1004643861 (1:1213806 A>G), RS1005055301 (1:1212863 C>G,T), RS1005199120 (1:1213912 G>A,T), RS1005570841 (1:1210910 C>A,T), RS1006323015 (1:1211746 G>A), RS1006416831 (1:1216070 A>T)

Disease associations

OMIM: gene MIM:600315 | disease phenotypes: MIM:615593, MIM:615120

GenCC curated gene-disease

Disease	Classification	Inheritance
combined immunodeficiency due to OX40 deficiency	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
combined immunodeficiency due to OX40 deficiency	Limited	AR

Mondo (2): combined immunodeficiency due to OX40 deficiency (MONDO:0014268), congenital myasthenic syndrome 8 (MONDO:0014052)

Orphanet (2): Combined immunodeficiency due to OX40 deficiency (Orphanet:431149), Congenital myasthenic syndrome (Orphanet:590)

HPO phenotypes

7 total (7 of 7 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001744	Splenomegaly
HP:0001876	Pancytopenia
HP:0002721	Immunodeficiency
HP:0003621	Juvenile onset
HP:0004844	Coombs-positive hemolytic anemia
HP:0100726	Kaposi’s sarcoma

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): CHEMBL3989383 (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

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 1 [PMID: 24930776]	Binding	5.92	pIC50

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, decreases expression	2
Progesterone	affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
Asian ginseng	increases expression, decreases reaction	1
triphenyl phosphate	affects expression	1
gallein	affects binding, decreases reaction	1
pimecrolimus	decreases expression	1
abrine	increases expression	1
bisphenol S	affects cotreatment, increases methylation	1
(+)-JQ1 compound	decreases expression	1
Arsenic Trioxide	increases expression	1
Fulvestrant	affects cotreatment, increases methylation, decreases methylation	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Diethylhexyl Phthalate	decreases reaction, increases expression	1
Erythrosine	decreases reaction, affects binding	1
Latex	increases expression	1
Menthol	decreases expression	1
Mevalonic Acid	decreases reaction, increases expression	1
Nickel	increases expression	1
Oxygen	increases expression	1
Ozone	decreases expression, increases abundance	1
Perfume	increases expression	1
Eosine I Bluish	affects binding, decreases reaction	1
Rose Bengal	affects binding, decreases reaction	1
Tretinoin	decreases expression	1
Valproic Acid	increases methylation	1
Sodium Selenite	increases expression	1
Simvastatin	decreases reaction, increases expression, decreases expression	1
Soot	increases abundance, decreases expression	1

Cellosaurus cell lines

10 cell lines: 5 cancer cell line, 3 transformed cell line, 2 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A8AC	Raji-hOX40	Cancer cell line	Male
CVCL_B8R5	Abcam HCT 116 TNFRSF4 KO	Cancer cell line	Male
CVCL_B9TJ	Abcam A-549 TNFRSF4 KO	Cancer cell line	Male
CVCL_D2HH	Abcam MCF-7 TNFRSF4 KO	Cancer cell line	Female
CVCL_E3FR	HEK293-OX40	Transformed cell line	Female
CVCL_E6S5	Genomeditech CHO-K1 H_TNFRSF4(CD134)	Spontaneously immortalized cell line	Female
CVCL_E8DF	BPS Bioscience HEK293 OX40+NF-kappaB-driven luciferase reporter	Transformed cell line	Female
CVCL_KA41	CHO-K1/OX-40	Spontaneously immortalized cell line	Female
CVCL_UE31	HT1080 human OX40	Cancer cell line	Male
CVCL_UE44	293T human OX40	Transformed cell line	Female

Clinical trials (associated diseases)

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