TNFSF4

Summary

TNFSF4 (TNF superfamily member 4, HGNC:11934) is a protein-coding gene on chromosome 1q25.1, encoding Tumor necrosis factor ligand superfamily member 4 (P23510). Cytokine that binds to TNFRSF4.

This gene encodes a cytokine of the tumor necrosis factor (TNF) ligand family. The encoded protein functions in T cell antigen-presenting cell (APC) interactions and mediates adhesion of activated T cells to endothelial cells. Polymorphisms in this gene have been associated with Sjogren’s syndrome and systemic lupus erythematosus. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 7292 — RefSeq curated summary.

At a glance

• Gene–disease (curated): systemic lupus erythematosus (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 37
• Clinical variants (ClinVar): 20 total
• Phenotypes (HPO): 72
• Druggable target: yes
• MANE Select transcript: NM_003326

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11934
Approved symbol	TNFSF4
Name	TNF superfamily member 4
Location	1q25.1
Locus type	gene with protein product
Status	Approved
Aliases	OX-40L, gp34, CD252
Ensembl gene	ENSG00000117586
Ensembl biotype	protein_coding
OMIM	603594
Entrez	7292

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000281834, ENST00000367718, ENST00000488053, ENST00000714429, ENST00000714430, ENST00000714452, ENST00000714453, ENST00000714469, ENST00000714470, ENST00000714471, ENST00000899982, ENST00000963049

RefSeq mRNA: 2 — MANE Select: NM_003326 NM_001297562, NM_003326

CCDS: CCDS1306, CCDS72985

Canonical transcript exons

ENST00000281834 — 3 exons

Exon	Start	End
ENSE00001003107	173183731	173186865
ENSE00004023970	173207024	173207331
ENSE00004024025	173188521	173188569

Expression profiles

Bgee: expression breadth ubiquitous, 181 present calls, max score 90.15.

FANTOM5 (CAGE): breadth broad, TPM avg 5.1950 / max 526.7566, expressed in 434 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
15942	3.6922	303
15941	0.3010	111
15940	0.2577	110
15939	0.2421	101
15938	0.2312	89
15936	0.2208	103
15937	0.1389	73
15935	0.0720	31
15934	0.0391	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.15	gold quality
monocyte	CL:0000576	86.58	gold quality
mononuclear cell	CL:0000842	86.25	gold quality
leukocyte	CL:0000738	85.49	gold quality
stromal cell of endometrium	CL:0002255	80.43	gold quality
endothelial cell	CL:0000115	80.25	gold quality
mucosa of stomach	UBERON:0001199	73.62	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	72.25	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	69.37	gold quality
endometrium epithelium	UBERON:0004811	69.29	gold quality
granulocyte	CL:0000094	69.27	gold quality
blood	UBERON:0000178	67.26	gold quality
lower esophagus muscularis layer	UBERON:0035833	66.47	gold quality
lower esophagus	UBERON:0013473	66.40	gold quality
islet of Langerhans	UBERON:0000006	66.13	gold quality
vermiform appendix	UBERON:0001154	65.91	gold quality
lymph node	UBERON:0000029	65.81	gold quality
right lung	UBERON:0002167	65.77	gold quality
right adrenal gland cortex	UBERON:0035827	65.15	gold quality
cerebellar hemisphere	UBERON:0002245	64.17	gold quality
cerebellar cortex	UBERON:0002129	64.14	gold quality
rectum	UBERON:0001052	63.90	gold quality
left adrenal gland	UBERON:0001234	63.55	gold quality
right adrenal gland	UBERON:0001233	63.46	gold quality
adrenal tissue	UBERON:0018303	63.40	gold quality
spleen	UBERON:0002106	63.38	gold quality
right atrium auricular region	UBERON:0006631	63.15	gold quality
cerebellum	UBERON:0002037	62.98	gold quality
right hemisphere of cerebellum	UBERON:0014890	62.82	gold quality
tibia	UBERON:0000979	62.73	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.05

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOS, HAND2, HDAC11, IRF6, NFKB1, PITX2, SPI1, TP63, VDR

miRNA regulators (miRDB)

114 targeting TNFSF4, 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-8485	100.00	77.57	4731
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-96-5P	99.95	72.80	2140

Literature-anchored findings (GeneRIF, showing 40)

• Expression of CD134 and CD134 ligand in lesional and nonlesional psoriatic skin. (PMID:12624783)
• combined use of a vector driving the expression of OX40L with three other costimulatory molecules (B7-1, ICAM-1, and LFA-3) both enhances initial activation and then further potentiates sustained activation of nai;ve and effector T cells. (PMID:12798307)
• An OX40L-dependent mechanism is demonstrated in plasmacytoid dendritic cell-mediated T helper cell responses; OX40L selectively induces Th2-type immune responses by promoting CD4+ T cells to secrete IL-4, IL-5, and IL-13. (PMID:15034038)
• Elucidation of cross-talk between OX40 and OX40L could be very important in understanding interaction of cells present in inflamed airways of asthma. (PMID:15100674)
• an increasing amount of gp34/OX40L expression leads to an increasing level of up-regulation of the allogeneic CD4+ T-cell response by dendritic cells (PMID:15218969)
• Activated human natural killer (NK) cells are able to help T-cell receptor-stimulated autologous CD4+ T cells by a process that involves both OX40 ligand and B7 antigen costimulation. (PMID:15356117)
• T cell proliferation by direct cross-talk between OX40 ligand on human mast cells and OX40 on human T cells. (PMID:15470070)
• Single Nucleotide polymorphism in TNFS4 increase the risk of Arteriosclerosis (PMID:15750594)
• OX40L costimulates human antiviral memory CD8 T cell responses largely through indirect effects and can enhance anti-influenza, anti-EBV, and anti-HIV responses, particularly in combination with 4-1BBL or B7. (PMID:16272289)
• OX40L on thymic stromal lymphopoietin-activated dendritic cells triggers T helper type 2 (Th2) cell polarization in the absence of IL-12, and can switch IL-10-producing regulatory Th cell responses into TNF-alpha-producing inflammatory Th cell responses. (PMID:16275760)
• OX40 ligand (OX40L) completely inhibited the generation of IL-10-producing CD4(+) type 1 regulatory T (Tr1) cells from naive and memory CD4(+) T cells induced by the immunosuppressive drugs dexamethasone and vitamin D3. (PMID:16924108)
• the quantitation of sOX40L was correlated with the age and among these subjects, those of 70s and 80s have much higher sOX40L concentration than those of 60s (PMID:17166734)
• The demonstrate rapid infiltration of activated (OX40(+)) CD4(+) T cells into HSV-1-infected corneas and expression of OX40L on MHC Class II-negative cells, which are present in the infected corneas and required for HSK. (PMID:17185358)
• study findings indicate that functional OX40L is inducible on human activated CD4+ and CD8+ T cells, and that the expression is enhanced by TGF-beta1 (PMID:17584577)
• TSLP-induced molecule on dendritic cells that triggers inflammatory T(H)2 differentiation in the absence of IL-12. Review. (PMID:17666213)
• OX40 ligand (OX40L) is a critical in vivo mediator of TSLP-mediated Th2 responses. (PMID:18060034)
• Our present findings, if corroborated in other prospective investigations, suggest that the TNFSF4 variants tested may be useful indicators for assessing the risk of venous thromboembolism. (PMID:18356244)
• Results show that the OX40-OX40L interaction suppresses IL-17 production by PHA-stimulated human PBMC and purified CD4 and CD8 cells. (PMID:18501882)
• Patients with ACS show increased OX40L system (pOX40L and sOX40L) expression which may create a proinflammatory milieu for aggravating the development of atherosclerosis, and may be a valuable marker for predicting the severity of ACS. (PMID:18674525)
• human primary T cells are programmed to rapidly express functional OX40L molecules after stimulation under DNA-damaging conditions, demonstrating that the induction of OX40L by T cells is independent of cell proliferation. (PMID:18718855)
• thymic stromal lymphopoietin (TSLP) and human DCs plays an essential role in evoking inflammatory Th2 responses in allergy through OX40 ligand expression on DCs. (PMID:18832690)
• Study shows that TNFSF4 is expressed on antigen-presenting cells in human carotid atherosclerotic lesions but provides no evidence for an association of TNFSF4 gene variation with the risk for ischemic stroke. (PMID:18998106)
• 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)
• allele frequencies and genotype distributions of TNFSF4 SNPs were not substantially different between the control group and the myocardial infarction group. (PMID:19029970)
• role in systemic lupus erythematosus (Review) (PMID:19083191)
• This first replication study confirms the association of genetic variation in the upstream region of TNFSF4 with susceptibility to SLE. (PMID:19092840)
• Study confirmed the associations of BANK1 (rs3733197)and TNFSF4 (rs844648) with systemic lupus erythematosus in Hong Kong Chinese. (PMID:19357697)
• indicate a distinct CTL effector function in response to intracellular pathogens triggered via differing endogenous IL-2 production upon costimulation through CD252 (PMID:19494280)
• OX40L may play an important role in the early phase of T cell activation and proliferation (PMID:19663699)
• Polymorphisms in the TNFSF4 gene region are associated with susceptibility to systemic sclerosis and its clinical and autoantibody subsets. (PMID:19778912)
• The results showed that microbial products up regulate the expression of M3 receptor in nasal mucosal immune cells that further increases the production of OX40L in nasal DCs and drives the production of TNF-alpha in nasal mucosa. (PMID:19951374)
• Our study not only suggested that the TNFSF4 gene was associated with systemic lupus erythematosus in the Chinese Han population, but also implied that the TNFSF4 gene might also predispose multiple populations to systemic lupus erythematosus. (PMID:20012871)
• 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)
• our data provide an in vivo role for the OX40/OX40L system in the innate immune response during polymicrobial sepsis (PMID:20844189)
• Both OX40 upregulation and sOX40L increase were closely associated with Henoch-Schonlein purpura (HSP), especially HSP with nephritis. (PMID:21143648)
• The data confirm the influence of TNFSF4 polymorphisms in systemic sclerosis genetic susceptibility, especially in subsets of patients positive for lcSSc and anti-centromere antibodies. (PMID:21187296)
• These results demonstrate for the first time that HDAC11 plays an essential role in regulating OX40L expression. (PMID:21239696)
• Data show that MMP-2-conditioned dendritic cells primed naive CD4(+) T cells to differentiate into an inflammatory T(H)2 phenotype through OX40L expression and inhibition of IL-12p70 production. (PMID:21397857)
• TNFSF4 is a susceptibility gene of coronary heart disease in Chinese Han population (PMID:21402531)
• data indicate that the TNFSF4 rs45454293T-allele is associated with lower TNFSF4 expression and increased risk of myocardial infarction (PMID:21445270)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tnfsf4	ENSMUSG00000026700
rattus_norvegicus	Tnfsf4	ENSRNOG00000002968

Protein

Protein identifiers

Tumor necrosis factor ligand superfamily member 4 — P23510 (reviewed: P23510)

Alternative names: Glycoprotein Gp34, OX40 ligand, TAX transcriptionally-activated glycoprotein 1

All UniProt accessions (3): A0A024R937, A0AAQ5BI34, P23510

UniProt curated annotations — full annotation on UniProt →

Function. Cytokine that binds to TNFRSF4. Co-stimulates T-cell proliferation and cytokine production.

Subunit / interactions. Homotrimer.

Subcellular location. Membrane.

Disease relevance. Systemic lupus erythematosus (SLE) [MIM:152700] A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. Disease susceptibility is associated with variants affecting the gene represented in this entry. The upstream region of TNFSF4 contains a single risk haplotype for SLE, which is correlated with increased expression of both cell-surface TNFSF4 and TNFSF4 transcripts. Increased levels of TNFSF4 are thought to augment T-cell-APC interaction and the functional consequences of T-cell activation, thereby destabilizing peripheral tolerance.

Induction. By HTLV-1 transactivator p40-Tax.

Similarity. Belongs to the tumor necrosis factor family.

Isoforms (2)

UniProt ID	Names	Canonical?
P23510-1	1	yes
P23510-2	2

RefSeq proteins (2): NP_001284491, NP_003317* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006052	TNF_dom	Domain
IPR008983	Tumour_necrosis_fac-like_dom	Homologous_superfamily
IPR021184	TNF_CS	Conserved_site
IPR042338	TNFSF4	Family

UniProt features (19 total): strand 7, glycosylation site 4, topological domain 2, chain 1, splice variant 1, turn 1, transmembrane region 1, domain 1, disulfide bond 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2HEV	X-RAY DIFFRACTION	2.41

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P23510-F1	84.63	0.63

Functional residue map

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

Disulfide bonds (1): 97–181

Glycosylation sites (4): 90, 114, 152, 157

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 523 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, RRAGTTGT_UNKNOWN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, MODULE_255, GOBP_RESPONSE_TO_PROSTAGLANDIN_E, GOBP_INFLAMMATORY_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_LIPID

GO Biological Process (42): negative regulation of transcription by RNA polymerase II (GO:0000122), positive regulation of cytokine production (GO:0001819), defense response to nematode (GO:0002215), acute inflammatory response (GO:0002526), positive regulation of immunoglobulin production (GO:0002639), positive regulation of T cell cytokine production (GO:0002726), regulation of adaptive immune response (GO:0002819), positive regulation of type 2 immune response (GO:0002830), positive regulation of immunoglobulin mediated immune response (GO:0002891), inflammatory response (GO:0006954), immune response (GO:0006955), signal transduction (GO:0007165), positive regulation of cell population proliferation (GO:0008284), response to virus (GO:0009615), negative regulation of type II interferon production (GO:0032689), negative regulation of interleukin-17 production (GO:0032700), positive regulation of chemokine production (GO:0032722), positive regulation of type II interferon production (GO:0032729), positive regulation of interleukin-10 production (GO:0032733), positive regulation of interleukin-12 production (GO:0032735), positive regulation of interleukin-13 production (GO:0032736), positive regulation of interleukin-4 production (GO:0032753), positive regulation of interleukin-6 production (GO:0032755), memory T cell activation (GO:0035709), T-helper 2 cell activation (GO:0035712), response to nitrogen dioxide (GO:0035713), positive regulation of T cell proliferation (GO:0042102), positive regulation of CD4-positive, alpha-beta T cell differentiation (GO:0043372), positive regulation of memory T cell differentiation (GO:0043382), negative regulation of regulatory T cell differentiation (GO:0045590), negative regulation of T-helper 1 cell differentiation (GO:0045626), positive regulation of T-helper 2 cell differentiation (GO:0045630), positive regulation of alpha-beta T cell proliferation (GO:0046641), regulation of inflammatory response (GO:0050727), positive regulation of inflammatory response (GO:0050729), positive regulation of B cell activation (GO:0050871), cellular response to lipopolysaccharide (GO:0071222), cellular response to prostaglandin E stimulus (GO:0071380), positive regulation of CD4-positive, alpha-beta T cell costimulation (GO:1900281), positive regulation of interleukin-4-dependent isotype switching to IgE isotypes (GO:2000572)

GO Molecular Function (5): signaling receptor binding (GO:0005102), cytokine activity (GO:0005125), tumor necrosis factor receptor binding (GO:0005164), tumor necrosis factor receptor superfamily binding (GO:0032813), protein binding (GO:0005515)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), 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
positive regulation of cytokine production	4
defense response	2
response to other organism	2
negative regulation of cytokine production	2
type II interferon production	2
regulation of type II interferon production	2
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
cytokine production	1
regulation of cytokine production	1
positive regulation of gene expression	1
positive regulation of multicellular organismal process	1
inflammatory response	1
immunoglobulin production	1
regulation of immunoglobulin production	1
positive regulation of production of molecular mediator of immune response	1
T cell cytokine production	1
positive regulation of T cell mediated immunity	1
positive regulation of cytokine production involved in immune response	1
regulation of T cell cytokine production	1
adaptive immune response	1
regulation of immune response	1
regulation of type 2 immune response	1
type 2 immune response	1
positive regulation of immune response	1
positive regulation of B cell mediated immunity	1
regulation of immunoglobulin mediated immune response	1
immunoglobulin mediated 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
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1

Protein interactions and networks

STRING

1496 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNFSF4	TNFRSF4	P43489	999
TNFSF4	TNFRSF9	Q07011	993
TNFSF4	CD27	P26842	986
TNFSF4	CD28	P10747	981
TNFSF4	CD40LG	P29965	958
TNFSF4	ICOS	Q9Y6W8	938
TNFSF4	TNFSF9	P41273	907
TNFSF4	ICOSLG	O75144	904
TNFSF4	TNFRSF8	P28908	897
TNFSF4	TNFSF18	Q9UNG2	880
TNFSF4	CD40	P25942	873
TNFSF4	CD70	P32970	836
TNFSF4	TNFSF8	P32971	835
TNFSF4	A0A087X1L8	A0A087X1L8	831
TNFSF4	TSLP	Q969D9	818

IntAct

8 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
Tnfsf4	TNFSF4	psi-mi:“MI:0407”(direct interaction)	0.560
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (1): TNFSF4 (Affinity Capture-MS)

ESM2 similar proteins: O60939, P01134, P08887, P23510, P25291, P26012, P48030, P51641, P54900, P55259, P78380, Q07212, Q08E08, Q1A730, Q29108, Q2KHT6, Q3SXP7, Q56A07, Q58DF9, Q5H8A4, Q5M7U7, Q5SQ64, Q5ZMH6, Q62522, Q6MG56, Q7M729, Q7M730, Q7YR73, Q7Z6K3, Q864L3, Q86WI3, Q8BHK2, Q8C525, Q8IWT1, Q8R092, Q8TBF5, Q8VE33, Q95K48, Q969P5, Q96IK5

Diamond homologs: O02765, P23510, P43488, Q9Z2P3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TNFSF4	up-regulates	TNFRSF4	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	14
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

255 predictions. Top by Δscore:

Variant	Effect	Δscore
1:173186862:TATT:T	acceptor_gain	1.0000
1:173186863:ATTC:A	acceptor_loss	1.0000
1:173186864:TT:T	acceptor_gain	1.0000
1:173186865:TCTA:T	acceptor_loss	1.0000
1:173186866:C:A	acceptor_loss	1.0000
1:173186866:C:CC	acceptor_gain	1.0000
1:173186867:T:C	acceptor_loss	1.0000
1:173188516:CTT:C	donor_loss	1.0000
1:173188517:TTA:T	donor_loss	1.0000
1:173188518:TA:T	donor_loss	1.0000
1:173188519:A:AC	donor_gain	1.0000
1:173188519:AC:A	donor_gain	1.0000
1:173188520:C:CA	donor_gain	1.0000
1:173188520:CC:C	donor_gain	1.0000
1:173188520:CCG:C	donor_gain	1.0000
1:173188520:CCGGT:C	donor_gain	1.0000
1:173188568:ACCTG:A	acceptor_loss	1.0000
1:173207018:TCTTA:T	donor_loss	1.0000
1:173207019:CTTAC:C	donor_loss	1.0000
1:173207020:TTA:T	donor_loss	1.0000
1:173207021:TA:T	donor_loss	1.0000
1:173207022:A:AC	donor_gain	1.0000
1:173207022:ACC:A	donor_loss	1.0000
1:173207023:C:CC	donor_gain	1.0000
1:173477488:GACTC:G	donor_gain	1.0000
1:173477489:ACTC:A	donor_gain	1.0000
1:173477489:ACTCG:A	donor_loss	1.0000
1:173477490:CTC:C	donor_gain	1.0000
1:173477491:TC:T	donor_gain	1.0000
1:173477491:TCG:T	donor_loss	1.0000

AlphaMissense

1205 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:173186559:A:G	L170P	0.996
1:173186553:A:G	L172P	0.994
1:173186773:C:A	G99W	0.994
1:173186763:A:G	L102P	0.993
1:173186640:A:G	L143P	0.990
1:173186754:A:G	L105P	0.990
1:173186772:C:T	G99E	0.990
1:173186553:A:T	L172H	0.987
1:173186773:C:G	G99R	0.985
1:173186773:C:T	G99R	0.985
1:173186790:A:T	V93D	0.985
1:173186767:A:C	Y101D	0.984
1:173186772:C:A	G99V	0.984
1:173207062:A:G	C39R	0.984
1:173186749:C:G	G107R	0.982
1:173186777:A:C	C97W	0.982
1:173186778:C:T	C97Y	0.982
1:173186758:A:G	S104P	0.981
1:173186553:A:C	L172R	0.980
1:173186718:A:G	L117P	0.980
1:173186794:A:G	S92P	0.980
1:173186622:A:T	V149D	0.979
1:173186778:C:G	C97S	0.979
1:173186779:A:G	C97R	0.979
1:173186779:A:T	C97S	0.979
1:173186559:A:T	L170Q	0.978
1:173186559:A:C	L170R	0.974
1:173186778:C:A	C97F	0.974
1:173186528:G:C	F180L	0.972
1:173186528:G:T	F180L	0.972

dbSNP variants (sampled 300 via entrez): RS1000004849 (1:173305067 T>C), RS1000012315 (1:173246786 A>C,G), RS1000023583 (1:173443049 G>A), RS1000038766 (1:173357247 T>C), RS1000049540 (1:173271060 G>A,C), RS1000050172 (1:173178821 G>A), RS1000058244 (1:173312704 G>A,T), RS1000059556 (1:173337769 T>G), RS1000075286 (1:173202744 G>A), RS1000086606 (1:173293668 A>G), RS1000091993 (1:173375210 C>A), RS1000100636 (1:173293908 A>C,T), RS1000121020 (1:173437842 C>A), RS1000128242 (1:173405735 A>C,G), RS1000132463 (1:173209092 C>T)

Disease associations

OMIM: gene MIM:603594 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
systemic lupus erythematosus	Supportive	Unknown
myocardial infarction, susceptibility to	Limited	Autosomal dominant

Mondo (2): systemic lupus erythematosus (MONDO:0007915), myocardial infarction, susceptibility to (MONDO:0012039)

Orphanet (0):

HPO phenotypes

72 total (30 of 72 shown, HPO-id order):

HPO	Term
HP:0000017	Nocturia
HP:0000093	Proteinuria
HP:0000155	Oral ulcer
HP:0000488	Retinopathy
HP:0000709	Psychosis
HP:0000711	Restlessness
HP:0000716	Depression
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000790	Hematuria
HP:0000822	Hypertension
HP:0000826	Precocious puberty
HP:0000975	Hyperhidrosis
HP:0000992	Cutaneous photosensitivity
HP:0001250	Seizure
HP:0001262	Excessive daytime somnolence
HP:0001279	Syncope
HP:0001350	Slurred speech
HP:0001369	Arthritis
HP:0001513	Obesity
HP:0001596	Alopecia
HP:0001824	Weight loss
HP:0001873	Thrombocytopenia
HP:0001878	Hemolytic anemia
HP:0001882	Decreased total leukocyte count
HP:0001945	Fever
HP:0002019	Constipation
HP:0002039	Anorexia
HP:0002072	Chorea
HP:0002076	Migraine

GWAS associations

37 associations (top):

Study	Trait	p-value
GCST000507_1	Systemic lupus erythematosus	3.000000e-32
GCST000612_38	Celiac disease	2.000000e-06
GCST000879_8	Crohn’s disease	2.000000e-15
GCST001017_18	Diabetic retinopathy	4.000000e-06
GCST001795_24	Systemic lupus erythematosus	3.000000e-12
GCST002069_8	Systemic lupus erythematosus and Systemic sclerosis	4.000000e-07
GCST002520_2	Celiac disease	8.000000e-07
GCST002793_7	Vein graft stenosis in coronary artery bypass grafting	9.000000e-06
GCST003155_38	Systemic lupus erythematosus	3.000000e-19
GCST003156_14	Systemic lupus erythematosus	4.000000e-19
GCST003156_27	Systemic lupus erythematosus	6.000000e-12
GCST003599_1	Systemic lupus erythematosus	8.000000e-09
GCST003599_5	Systemic lupus erythematosus	3.000000e-13
GCST003622_26	Systemic lupus erythematosus	2.000000e-15
GCST003622_44	Systemic lupus erythematosus	2.000000e-08
GCST003987_26	Asthma	3.000000e-08
GCST004867_41	Systemic lupus erythematosus	6.000000e-09
GCST005038_13	Allergic disease (asthma, hay fever or eczema)	1.000000e-15
GCST005539_1	Alopecia areata	7.000000e-08
GCST005752_143	Systemic lupus erythematosus	1.000000e-30
GCST005752_28	Systemic lupus erythematosus	2.000000e-07
GCST005752_52	Systemic lupus erythematosus	8.000000e-07
GCST006048_28	Rheumatoid arthritis (ACPA-positive)	3.000000e-09
GCST007797_19	Asthma onset (childhood vs adult)	1.000000e-07
GCST007798_13	Asthma	7.000000e-12
GCST007800_14	Asthma (childhood onset)	8.000000e-29
GCST007994_27	Asthma (age of onset)	5.000000e-09
GCST007995_27	Asthma (childhood onset)	2.000000e-11
GCST008568_13	IgA levels	7.000000e-09
GCST009131_3	Systemic sclerosis	5.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007051	vein graft stenosis
EFO:0004847	age at onset

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008180	Lupus Erythematosus, Systemic	C17.300.480; C20.111.590

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3712900 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, affects methylation, affects cotreatment, affects expression	6
sodium arsenite	affects expression, decreases expression, increases expression	3
Valproic Acid	affects cotreatment, decreases expression, affects expression	3
(+)-JQ1 compound	decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Cyclosporine	decreases expression, increases expression	2
Aflatoxin B1	affects expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, affects reaction, decreases reaction, increases expression	2
peracetylated N-azidoacetylmannosamine	decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
benzo(b)fluoranthene	affects cotreatment, affects expression	1
bisphenol A	decreases expression	1
gallein	affects binding, decreases reaction	1
tris(2-butoxyethyl) phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
di-n-butylphosphoric acid	affects expression	1
usnic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
incobotulinumtoxinA	decreases expression	1
NSC 689534	increases expression	1
Leflunomide	increases expression	1
Acetylcysteine	decreases reaction, increases expression	1

Cellosaurus cell lines

2 cell lines: 1 spontaneously immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_KA42	CHO-K1/OX-40L	Spontaneously immortalized cell line	Female
CVCL_UE45	293T human OX40L	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00120887	PHASE4	COMPLETED	Lupus Atherosclerosis Prevention Study
NCT00125307	PHASE4	COMPLETED	Tacrolimus for the Treatment of Systemic Lupus Erythematosus With Membranous Nephritis
NCT00188188	PHASE4	UNKNOWN	Study of Endothelial Dysfunction in Systemic Lupus and Its Role in Heart Disease
NCT00371501	PHASE4	COMPLETED	Aspirin and Statins for Prevention of Atherosclerosis and Arterial Thromboembolism in Systemic Lupus Erythematosus
NCT00392093	PHASE4	COMPLETED	Effect of Hormone Replacement Therapy on Lupus Activity
NCT00413361	PHASE4	COMPLETED	The Reduction of Systemic Lupus Erythematosus Flares :Study PLUS
NCT00508898	PHASE4	WITHDRAWN	The Efficacy and Safety of Calcitriol for the Treatment of Lupus Nephritis and Persistent Proteinuria
NCT00668330	PHASE4	COMPLETED	Steroid Induced Osteoporosis in Patients With Systemic Lupus Erythematosus
NCT00739050	PHASE4	TERMINATED	Effect of Simvastatin on Endothelial Function in Premenopausal Women With Systemic Lupus Erythematosus (0733-271)(TERMINATED)
NCT00815282	PHASE4	COMPLETED	Immune Response After Human Papillomavirus Vaccination in Patients With Autoimmune Disease
NCT00828178	PHASE4	COMPLETED	Efficacy of Fish Oil in Lupus Patients
NCT00866229	PHASE4	UNKNOWN	Efficacy and Adverse Effect of Simvastatin Compare to Rosuvastatin in Systemic Lupus Erythematosus (SLE) Patients With Corticosteroid Therapy and High Low-Density Lipoprotein (LDL) Cholesterol Level
NCT00911521	PHASE4	COMPLETED	Immunogenicity and Safety of a Quadrivalent Human Papillomavirus (HPV) Vaccine in Patients With SLE: a Controlled Study
NCT01101802	PHASE4	COMPLETED	Mycophenolate Mofetil in Systemic Lupus Erythematosus (MISSILE)
NCT01112215	PHASE4	COMPLETED	Enteric-coated Mycophenolate Sodium Versus Azathioprine for the Extra-renal Lupus Manifestations
NCT01151644	PHASE4	UNKNOWN	Safety and Efficacy of Anti-Pandemic H1N1 Vaccination in Rheumatic Diseases
NCT01276782	PHASE4	WITHDRAWN	Levothyroxine in Pregnant SLE Patients
NCT01322308	PHASE4	COMPLETED	Effect of Pioglitazone on Endothelial Function in Premenopausal Women With Uncomplicated Systemic Lupus Erythematosus
NCT01359826	PHASE4	WITHDRAWN	The Effect of Milnacipran on Fatigue and Quality of Life in Lupus Patients
NCT01597492	PHASE4	COMPLETED	A Study to Evaluate the Effect of Belimumab on Vaccine Responses in Subjects With Systemic Lupus Erythematosus (SLE)
NCT01632241	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in Black Race Patients With Systemic Lupus Erythematosus (SLE)
NCT01705977	PHASE4	COMPLETED	Belimumab Assessment of Safety in SLE
NCT01753401	PHASE4	COMPLETED	Acthar for the Treatment of Systemic Lupus Erythematosus (SLE) in Patients With a History of Persistently Active Disease
NCT02270970	PHASE4	UNKNOWN	Evaluation of Belimumab Impact on a BLyS Activity Signature Test in the Absence of Confounding Polypharmacy
NCT02477150	PHASE4	COMPLETED	Safety and Immunogenicity of a Zoster Vaccine in SLE
NCT02741960	PHASE4	COMPLETED	The Effect of Metformin on Reducing Lupus Flares
NCT02779153	PHASE4	WITHDRAWN	Acthar SLE (Systemic Lupus Erythematosus)
NCT02953821	PHASE4	COMPLETED	Acthar Gel for Active Systemic Lupus Erythematosus (SLE)
NCT03042260	PHASE4	UNKNOWN	Prophylactic Trimethoprim/Sulfamethoxazole to Prevent Severe Infections in Patients With Lupus Erythematous
NCT03098823	PHASE4	COMPLETED	A Crossover Study to Compare RAYOS to IR Prednisone to Improve Fatigue and Morning Symptoms for SLE
NCT03122431	PHASE4	COMPLETED	Relevance of Monitoring Blood and Salivar Levels of Drugs Used in Rheumatic Autoimmune Diseases
NCT03543839	PHASE4	RECRUITING	Trial of Belimumab in Early Lupus
NCT04447053	PHASE4	UNKNOWN	Sequential Belimumab and T-cell Based Therapy in SLE
NCT04515719	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in SLE Patients
NCT04893161	PHASE4	UNKNOWN	A Model About the Response of Belimumab in SLE
NCT04908865	PHASE4	COMPLETED	Open-label Study of Belimumab Plus Standard Therapy in Chinese Pediatric Participants With Active Systemic Lupus Erythematosus (SLE)
NCT04956484	PHASE4	COMPLETED	Belimumab In Early Systemic Lupus Erythematosus
NCT05559671	PHASE4	RECRUITING	Safety of the Herpes Zoster Subunit Vaccine in Lupus
NCT05666336	PHASE4	UNKNOWN	Multi-omics Studies on the Efficacy of Telitacicept in Chinese SLE Patients
NCT05748925	PHASE4	COMPLETED	Cardio Renal Effects of SGLT2 Inhibitors Among Lupus Nephritis Patients