TNFSF12

Summary

TNFSF12 (TNF superfamily member 12, HGNC:11927) is a protein-coding gene on chromosome 17p13.1, encoding Tumor necrosis factor ligand superfamily member 12 (O43508). Binds to FN14 and possibly also to TNRFSF12/APO3.

The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This protein is a ligand for the FN14/TWEAKR receptor. This cytokine has overlapping signaling functions with TNF, but displays a much wider tissue distribution. This cytokine, which exists in both membrane-bound and secreted forms, can induce apoptosis via multiple pathways of cell death in a cell type-specific manner. This cytokine is also found to promote proliferation and migration of endothelial cells, and thus acts as a regulator of angiogenesis. Alternative splicing results in multiple transcript variants. Some transcripts skip the last exon of this gene and continue into the second exon of the neighboring TNFSF13 gene; such read-through transcripts are contained in GeneID 407977, TNFSF12-TNFSF13.

Source: NCBI Gene 8742 — RefSeq curated summary.

At a glance

• Gene–disease (curated): common variable immunodeficiency (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 23
• Clinical variants (ClinVar): 223 total
• Druggable target: yes
• MANE Select transcript: NM_003809

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11927
Approved symbol	TNFSF12
Name	TNF superfamily member 12
Location	17p13.1
Locus type	gene with protein product
Status	Approved
Aliases	TWEAK, DR3LG, APO3L, TNF12
Ensembl gene	ENSG00000239697
Ensembl biotype	protein_coding
OMIM	602695
Entrez	8742

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 6 protein_coding, 6 protein_coding_CDS_not_defined, 5 retained_intron, 4 nonsense_mediated_decay

ENST00000293825, ENST00000322272, ENST00000462619, ENST00000462811, ENST00000650738, ENST00000700014, ENST00000700015, ENST00000700047, ENST00000700048, ENST00000700049, ENST00000700050, ENST00000700051, ENST00000700052, ENST00000700053, ENST00000700054, ENST00000700055, ENST00000700056, ENST00000700057, ENST00000700058, ENST00000700059, ENST00000946751

RefSeq mRNA: 1 — MANE Select: NM_003809 NM_003809

CCDS: CCDS11109

Canonical transcript exons

ENST00000293825 — 7 exons

Exon	Start	End
ENSE00001263509	7549058	7549312
ENSE00003978667	7557099	7557881
ENSE00003978668	7550799	7550852
ENSE00003978670	7556778	7556902
ENSE00003978679	7550120	7550195
ENSE00003978680	7550943	7550978
ENSE00003978682	7549474	7549521

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.05.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2718 / max 5.9563, expressed in 153 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
159240	12.2548	1479
159241	1.4114	786
159237	0.5050	208
159236	0.3543	150
159242	0.2718	153
159239	0.2276	119
159238	0.0907	42

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right coronary artery	UBERON:0001625	98.05	gold quality
thoracic aorta	UBERON:0001515	97.43	gold quality
ascending aorta	UBERON:0001496	97.40	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.38	gold quality
descending thoracic aorta	UBERON:0002345	97.36	gold quality
lower esophagus	UBERON:0013473	97.34	gold quality
left coronary artery	UBERON:0001626	97.27	gold quality
popliteal artery	UBERON:0002250	97.27	gold quality
tibial artery	UBERON:0007610	97.26	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.20	gold quality
mucosa of stomach	UBERON:0001199	96.68	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.56	gold quality
apex of heart	UBERON:0002098	95.93	gold quality
left uterine tube	UBERON:0001303	95.75	gold quality
granulocyte	CL:0000094	95.73	gold quality
fundus of stomach	UBERON:0001160	95.61	gold quality
amygdala	UBERON:0001876	95.57	gold quality
temporal lobe	UBERON:0001871	95.55	gold quality
subcutaneous adipose tissue	UBERON:0002190	95.44	gold quality
adipose tissue	UBERON:0001013	95.26	gold quality
right lung	UBERON:0002167	95.22	gold quality
endocervix	UBERON:0000458	95.16	gold quality
anterior cingulate cortex	UBERON:0009835	95.16	gold quality
tibial nerve	UBERON:0001323	95.04	gold quality
omental fat pad	UBERON:0010414	95.03	gold quality
body of uterus	UBERON:0009853	94.81	gold quality
leukocyte	CL:0000738	94.69	gold quality
right frontal lobe	UBERON:0002810	94.67	gold quality
myometrium	UBERON:0001296	94.66	gold quality
monocyte	CL:0000576	94.64	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.73

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFATC2, NFKB

miRNA regulators (miRDB)

45 targeting TNFSF12, 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-4668-3P	100.00	68.74	2635
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-6877-3P	98.98	65.83	560
HSA-MIR-6819-3P	98.95	65.57	572
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-4742-3P	98.73	69.82	1803
HSA-MIR-6880-5P	98.08	65.59	1282
HSA-MIR-33B-3P	97.92	67.39	529
HSA-MIR-515-3P	97.92	67.98	506
HSA-MIR-519E-3P	97.92	68.25	508
HSA-MIR-299-3P	97.73	66.67	773

Literature-anchored findings (GeneRIF, showing 40)

• TWEAK induces multiple pathways of cell death, including both caspase-dependent apoptosis and cathepsin B-dependent necrosis, in a cell type-specific manner via TWEAK receptor(s) distinct from death receptor 3. (PMID:11777967)
• TWEAK may differentially regulate microvascular growth, remodeling and/or maintenance in vivo, depending upon the angiogenic context. (PMID:11839778)
• T cells from systemic lupus erythematosus patients kill autologous monocytes through apoptotic pathways involving the ligand TWEAK. (PMID:12421989)
• These results indicated that TWEAK could induce pro-inflammatory reactions via fibroblast growth factor-inducible 14 (Fn14)on human umbilical vein endothelial cells. (PMID:12445828)
• TWEAK-induced apoptotic cell death has been extensively characterized in fibroblast growth factor-inducible 14 (Fn14)transfectants. (PMID:12496418)
• TWEAK is involved in atherosclerosis by inducing pro-inflammatory cytokines and extracellular matrix degrading enzymes, which reduce plaque stability. (PMID:15056843)
• TWEAK acts on human keratinocytes as an inducer of RANTES via Fn14. (PMID:15140220)
• TWEAK/TWEAK receptor interactions have roles in the pathogenesis of inflammatory and systemic autoimmune diseases [review] (PMID:15353286)
• TWEAK-overexpressing cells do not have a growth advantage in vitro, they form larger and more highly vascularized tumors in athymic mice when compared with control, vector-transfected cells. (PMID:15604260)
• TWEAK-stimulated glioma cells had increased cellular resistance to cytotoxic therapy-induced apoptosis (PMID:15611130)
• TWEAK may play an important role in ischemia-induced brain injury (PMID:15681834)
• our results suggest that the Tweak/Fn14 pathway may be protumorigenic in human breast cancer. (PMID:15735761)
• Expression of TWEAK in subcutaneous adipose tissue from obese patients. (PMID:16503147)
• the TWEAK-Fn14 interaction is highly dependent on multiple Fn14 residues located in both CRD modules (PMID:16526941)
• TWEAK is a novel arthritogenic mediator that may contribute to rheumatoid pathogenesis by multiple mechanisms. (PMID:16888023)
• Activation of Fn14 signaling by the ligand TNF-like weak inducer of apoptosis (TWEAK) stimulates migration and up-regulates expression of Fn14; this TWEAK effect requires Rac1 and nuclear factor-kappaB (NF-kappaB) activity. (PMID:17018610)
• These results indicate that the TWEAK/Fn14 pathway is a novel regulator of skeletal muscle precursor cells and illustrate an important mechanism by which inflammatory cytokines influence tissue regeneration and repair. (PMID:17124496)
• TWEAK may be a novel regulator for wound contraction in keloids (PMID:17178215)
• the role of Fn14 during myogenic differentiation could be independent of TWEAK cytokine (PMID:17383968)
• CD163 either acts as a TWEAK scavenger in pathological conditions or serves as an alternate receptor for TWEAK in cells lacking Fn14/TweakR. (PMID:17548657)
• TWEAK may be involved in pathogenesis of hemophagocytic lymphohistiocytosis and is useful as a clinical marker. (PMID:17918252)
• TWEAK is a new player in kidney injury both at the glomerular and tubulointerstitial levels [review] (PMID:17981571)
• Serum levels of TWEAK were significantly elevated in patients with RA, and reflected disease activity and short-term response to etanercept treatment. (PMID:18465450)
• Lysosomal degradation of cIAP1-TRAF2 by TWEAK/FN14 therefore critically alters the balance of life/death signals emanating from TNF-R1 in immortalized cells. (PMID:18606850)
• The soluble form of TWEAK is detectable in serum and CSF of patients, and TWEAK concentrations were not statistically different between the disease groups. (PMID:18945822)
• Concurrent presence of elevated sTWEAK plasma concentrations and an inflammatory environment have additive effects on mortality in hemodialysis patients. (PMID:18945991)
• Transient overexpression of human TWEAK in murine salivary glands leads to a general proliferation of epithelial cells vs a selective stimulation of a salivary progenitor cell. (PMID:18992019)
• TWEAK expression is related to the metastatic ability of breast cancer. (PMID:19000449)
• Taken together, these findings indicate that the TWEAK/Fn14 pathway contributes to inflammation and tissue injury and is, therefore, a potential therapeutic target in MS. (PMID:19018248)
• TWEAK may play an important pathogenic role in the development of glomerulonephritis by promoting a local inflammatory environment and inducing kidney cell proliferation (PMID:19233685)
• TWEAK/Fn14 may be important in regulating myocardial structural remodeling and function and may play a role in the pathogenesis of dilated cardiomyopathy. (PMID:19349318)
• TWEAK-Fn14 functions, in part, through the NF-kappaB signaling pathway to up-regulate VEGF expression to foster ovarian cancer cell metastasis. (PMID:19398263)
• The CD163-expressing macrophages recognize and internalize TWEAK: potential consequences in atherosclerosis. (PMID:19473660)
• The available evidence suggests that TWEAK might be a target for therapeutic intervention in renal and vascular injury and its role in different forms of tissue damage should be further explored. (PMID:19482507)
• Data show that The measurement of serum sTWEAK concentrations improves the prediction of CAD based on existing biomarkers. (PMID:19505454)
• TWEAK levels were increased in patients with systemic sclerosis, and associated with a lower frequency of pulmonary fibrosis in patients with systemic sclerosis (PMID:19531747)
• our study further supports a role for TWEAK in the pathogenesis of lupus nephritis (PMID:19785730)
• TWEAK and its receptor Fn14 are novel potential mediators of adipogenesis in immature and mature adipocytes and may have potential application in the control of human adiposity. (PMID:19828625)
• possible role in implantation (PMID:19854517)
• TWEAK/fibroblast growth factor-inducible 14 interaction may have proinflammatory effects in retinal pigment epithelial cells. TWEAK increased the production of IL-8 and MCP-1 via Fn14. TGF-beta(1) augmented TWEAK-induced production of these chemokines. (PMID:19895311)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tnfsf12	ENSMUSG00000097328
rattus_norvegicus	Tnfsf12	ENSRNOG00000045670

Paralogs (2): TNFSF13B (ENSG00000102524), TNFSF13 (ENSG00000161955)

Protein

Protein identifiers

Tumor necrosis factor ligand superfamily member 12 — O43508 (reviewed: O43508)

Alternative names: APO3 ligand, TNF-related weak inducer of apoptosis

All UniProt accessions (10): A0A0U5J5F5, A0A8V8TP82, A0A8V8TPL4, A0A8V8TPS2, A0A8V8TQJ4, A0A8V8TQK2, A0A8V8TQX4, C0H5Y4, O43508, Q4ACW9

UniProt curated annotations — full annotation on UniProt →

Function. Binds to FN14 and possibly also to TNRFSF12/APO3. Weak inducer of apoptosis in some cell types. Mediates NF-kappa-B activation. Promotes angiogenesis and the proliferation of endothelial cells. Also involved in induction of inflammatory cytokines. Promotes IL8 secretion.

Subunit / interactions. Homotrimer. Interacts with the angiogenic factor AGGF1/VG5Q.

Subcellular location. Cell membrane Secreted Cell membrane.

Tissue specificity. Highly expressed in adult heart, pancreas, skeletal muscle, brain, colon, small intestine, lung, ovary, prostate, spleen, lymph node, appendix and peripheral blood lymphocytes. Low expression in kidney, testis, liver, placenta, thymus and bone marrow. Also detected in fetal kidney, liver, lung and brain.

Post-translational modifications. The soluble form derives from the membrane form by proteolytic processing.

Miscellaneous. Based on a readthrough transcript which may produce a TWE-PRIL (TNFSF12-TNFSF13) fusion protein. Expressed at protein level in primary T-lymphocytes and monocytic cell lines.

Similarity. Belongs to the tumor necrosis factor family.

Isoforms (2)

UniProt ID	Names	Canonical?
O43508-1	1	yes
O43508-2	TWE-PRIL, TNFSF12-TNFSF13

RefSeq proteins (1): NP_003800* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006052	TNF_dom	Domain
IPR008983	Tumour_necrosis_fac-like_dom	Homologous_superfamily
IPR051748	TNF_Ligand_Superfamily	Family

Pfam: PF00229

UniProt features (24 total): strand 10, chain 2, turn 2, topological domain 2, disulfide bond 1, splice variant 1, transmembrane region 1, domain 1, region of interest 1, compositionally biased region 1, site 1, glycosylation site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4HT1	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43508-F1	77.96	0.50

Antibody-complex structures (SAbDab): 1 — 4HT1

Functional residue map

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

Catalytic / active sites (1): 93–94 (cleavage)

Disulfide bonds (1): 191–210

Glycosylation sites (1): 139

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5668541	TNFR2 non-canonical NF-kB pathway
R-HSA-5676594	TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway

MSigDB gene sets: 162 (showing top): RNGTGGGC_UNKNOWN, MODULE_516, ACTACCT_MIR196A_MIR196B, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, TGCACTT_MIR519C_MIR519B_MIR519A, MODULE_64, GTCTACC_MIR379, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, MODULE_75, GOBP_APOPTOTIC_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS

GO Biological Process (11): angiogenesis (GO:0001525), positive regulation of endothelial cell proliferation (GO:0001938), apoptotic process (GO:0006915), immune response (GO:0006955), signal transduction (GO:0007165), cell differentiation (GO:0030154), endothelial cell migration (GO:0043542), positive regulation of protein catabolic process (GO:0045732), positive regulation of angiogenesis (GO:0045766), extrinsic apoptotic signaling pathway (GO:0097191), positive regulation of extrinsic apoptotic signaling pathway (GO:2001238)

GO Molecular Function (4): signaling receptor binding (GO:0005102), cytokine activity (GO:0005125), tumor necrosis factor receptor binding (GO:0005164), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), perinuclear region of cytoplasm (GO:0048471), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Cytokine Signaling in Immune system	1
TNFR2 non-canonical NF-kB pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
apoptotic signaling pathway	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
endothelial cell proliferation	1
regulation of endothelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
programmed cell death	1
execution phase of apoptosis	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
cellular developmental process	1
cell migration	1
positive regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
cell surface receptor signaling pathway	1
extrinsic apoptotic signaling pathway	1
positive regulation of apoptotic signaling pathway	1
regulation of extrinsic apoptotic signaling pathway	1
protein binding	1
receptor ligand activity	1
tumor necrosis factor receptor superfamily binding	1
binding	1
membrane	1
cell periphery	1
cytoplasm	1

Protein interactions and networks

STRING

1442 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNFSF12	TNFRSF12A	Q9NP84	999
TNFSF12	TNFRSF25	P78507	994
TNFSF12	TNFRSF10B	O14763	890
TNFSF12	TNFRSF1A	P19438	847
TNFSF12	TNF	P01375	846
TNFSF12	TNFSF13	O75888	841
TNFSF12	TNFSF13B	Q9Y275	835
TNFSF12	TNFRSF10A	O00220	821
TNFSF12	FGF20	Q9NP95	781
TNFSF12	FGF22	Q9HCT0	781
TNFSF12	FGF6	P10767	781
TNFSF12	FGF16	O43320	781
TNFSF12	FGF18	O76093	780
TNFSF12	FGF17	O60258	780
TNFSF12	FGF5	P12034	780

IntAct

24 interactions, top by confidence:

A	B	Type	Score
TNFRSF12A	TNFSF12	psi-mi:“MI:0915”(physical association)	0.760
TNFSF12	TNFRSF12A	psi-mi:“MI:0915”(physical association)	0.760
TNFSF12	TNFRSF12A	psi-mi:“MI:0407”(direct interaction)	0.760
TNFRSF12A	TNFSF12	psi-mi:“MI:0407”(direct interaction)	0.760
TNFSF12	DDIT3	psi-mi:“MI:0915”(physical association)	0.560
TNFSF12	SGTA	psi-mi:“MI:0915”(physical association)	0.560
CDK1	TNFSF12	psi-mi:“MI:0915”(physical association)	0.560
TNFSF12	APP	psi-mi:“MI:0915”(physical association)	0.560
TNFSF12	tnfrsf12a.L	psi-mi:“MI:0407”(direct interaction)	0.560
tnfrsf12a.L	TNFSF12	psi-mi:“MI:0407”(direct interaction)	0.560
DICER1	TNFSF12	psi-mi:“MI:0915”(physical association)	0.540
TNFSF12	DICER1	psi-mi:“MI:0403”(colocalization)	0.540
TNFSF12	TRAF2	psi-mi:“MI:0914”(association)	0.350
TNFSF12	SGTA	psi-mi:“MI:0915”(physical association)	0.000
TNFSF12	DDIT3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (30): TNFSF12 (Two-hybrid), TNFSF12 (Two-hybrid), TNFSF12 (Two-hybrid), TNFSF12 (Two-hybrid), CLCN3 (Affinity Capture-MS), RRP1 (Affinity Capture-MS), VTI1B (Affinity Capture-MS), KLHDC3 (Affinity Capture-MS), TRPM3 (Affinity Capture-MS), DNAJC14 (Affinity Capture-MS), RRP1 (Affinity Capture-MS), TTI2 (Affinity Capture-MS), KIF14 (Affinity Capture-MS), SLC30A1 (Affinity Capture-MS), CCDC71L (Affinity Capture-MS)

ESM2 similar proteins: A1L515, A2A9Q0, D3YZZ2, D4A2Q0, E1BDF2, E7ERA6, F2Z333, H3BV60, O43508, O46547, O54907, P0C6B2, P0DH78, P41155, P51172, P70225, Q01113, Q13477, Q14626, Q29RT8, Q5RF19, Q5SZI1, Q5T7M4, Q5U4P2, Q63148, Q64385, Q6AZ51, Q6BAA4, Q6UWL6, Q6UXT9, Q6ZMC9, Q86UR1, Q86YD3, Q8BH06, Q8N1F8, Q8NFR9, Q96G42, Q99640, Q99M75, Q99MF4

Diamond homologs: O43508, O54907

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TNFSF12	“down-regulates quantity by destabilization”	MYH3	polyubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	124
Likely benign	88
Benign	9

Top pathogenic / likely-pathogenic (0)

SpliceAI

979 predictions. Top by Δscore:

Variant	Effect	Δscore
17:7549309:CCAG:C	donor_loss	1.0000
17:7549311:AG:A	donor_loss	1.0000
17:7549312:GGTG:G	donor_loss	1.0000
17:7550116:CTAGG:C	acceptor_loss	1.0000
17:7550117:TAG:T	acceptor_loss	1.0000
17:7550193:GTG:G	donor_gain	1.0000
17:7550797:A:AG	acceptor_gain	1.0000
17:7550798:G:GA	acceptor_gain	1.0000
17:7550798:GC:G	acceptor_gain	1.0000
17:7550798:GCA:G	acceptor_gain	1.0000
17:7550798:GCAC:G	acceptor_gain	1.0000
17:7550850:AAG:A	donor_loss	1.0000
17:7550852:GGT:G	donor_loss	1.0000
17:7550852:GGTG:G	donor_loss	1.0000
17:7550853:G:GC	donor_loss	1.0000
17:7550854:T:G	donor_loss	1.0000
17:7550941:A:AG	acceptor_gain	1.0000
17:7550942:G:GT	acceptor_gain	1.0000
17:7550942:GTTC:G	acceptor_gain	1.0000
17:7556773:TTCA:T	acceptor_loss	1.0000
17:7556774:TCA:T	acceptor_loss	1.0000
17:7556775:CAG:C	acceptor_loss	1.0000
17:7556899:TCAGG:T	donor_loss	1.0000
17:7556901:AGG:A	donor_loss	1.0000
17:7556903:G:T	donor_loss	1.0000
17:7549310:CAG:C	donor_loss	0.9900
17:7549311:AGG:A	donor_loss	0.9900
17:7549469:A:AG	acceptor_gain	0.9900
17:7549470:G:GG	acceptor_gain	0.9900
17:7549470:G:GT	acceptor_gain	0.9900

AlphaMissense

1554 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:7556803:G:C	W133C	0.999
17:7556803:G:T	W133C	0.999
17:7556801:T:A	W133R	0.998
17:7556801:T:C	W133R	0.998
17:7556862:T:C	F153S	0.998
17:7556802:G:C	W133S	0.995
17:7556861:T:C	F153L	0.995
17:7556863:T:A	F153L	0.995
17:7556863:T:G	F153L	0.995
17:7557171:T:C	C191R	0.994
17:7557337:T:C	F246S	0.994
17:7556862:T:G	F153C	0.993
17:7556868:T:A	V155D	0.993
17:7557105:T:C	F169L	0.993
17:7557107:T:A	F169L	0.993
17:7557107:T:G	F169L	0.993
17:7557173:C:G	C191W	0.993
17:7557336:T:C	F246L	0.993
17:7557338:C:A	F246L	0.993
17:7557338:C:G	F246L	0.993
17:7557136:T:C	L179P	0.992
17:7557331:G:A	G244E	0.991
17:7557334:T:C	L245P	0.991
17:7557228:T:C	C210R	0.990
17:7557229:G:A	C210Y	0.990
17:7557337:T:G	F246C	0.990
17:7557134:G:C	K178N	0.989
17:7557134:G:T	K178N	0.989
17:7557183:T:C	F195L	0.989
17:7557185:C:A	F195L	0.989

dbSNP variants (sampled 300 via entrez): RS1000265250 (17:7557960 C>T), RS1000403047 (17:7557654 G>A), RS1000442012 (17:7549768 T>C), RS1000612281 (17:7556607 T>C), RS1000715734 (17:7556625 C>T), RS1001131133 (17:7552049 G>A,C), RS1001162258 (17:7552377 G>C), RS1001379399 (17:7548015 A>G), RS1001410491 (17:7548470 C>A,G,T), RS1001592195 (17:7555435 A>G), RS1002190500 (17:7553627 G>A,C), RS1002731158 (17:7553184 A>G), RS1003055172 (17:7549292 C>A,G,T), RS1003335001 (17:7551799 AT>A,ATT), RS1003805170 (17:7548142 T>C)

Disease associations

OMIM: gene MIM:602695 | disease phenotypes: MIM:607594

GenCC curated gene-disease

Disease	Classification	Inheritance
common variable immunodeficiency	Supportive	Autosomal dominant
inborn error of immunity	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
common variable immunodeficiency	Limited	AD

Mondo (2): common variable immunodeficiency (MONDO:0015517), inborn error of immunity (MONDO:0003778)

Orphanet (1): OBSOLETE: Common variable immunodeficiency (Orphanet:1572)

HPO phenotypes

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

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST003989_34	Chin dimples	1.000000e-11
GCST003997_1	Myopia	8.000000e-15
GCST006061_191	Atrial fibrillation	1.000000e-11
GCST006190_4	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	3.000000e-10
GCST006190_54	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	3.000000e-08
GCST006192_52	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	8.000000e-11
GCST006192_75	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	2.000000e-12
GCST006193_37	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	9.000000e-11
GCST006193_75	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	9.000000e-09
GCST006195_19	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	3.000000e-11
GCST006195_69	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	1.000000e-12
GCST006291_1	Spherical equivalent or myopia (age of diagnosis)	9.000000e-09
GCST006414_33	Atrial fibrillation	2.000000e-09
GCST007328_70	Alcohol consumption (drinks per week)	5.000000e-09
GCST009308_9	Emotional recognition	3.000000e-06
GCST010002_119	Refractive error	3.000000e-22
GCST010241_94	Apolipoprotein A1 levels	8.000000e-13
GCST010242_408	HDL cholesterol levels	8.000000e-20
GCST010244_165	Triglyceride levels	3.000000e-11
GCST010703_158	Brain morphology (MOSTest)	3.000000e-09
GCST90002400_202	Plateletcrit	7.000000e-17
GCST90020029_825	Waist circumference adjusted for body mass index	2.000000e-10
GCST90020029_826	Waist circumference adjusted for body mass index	2.000000e-11

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0006527	smoking status measurement
EFO:0006335	systolic blood pressure
EFO:0004847	age at onset
EFO:0008354	cognitive function measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0004346	neuroimaging measurement
EFO:0007985	platelet crit
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D017074	Common Variable Immunodeficiency	C20.673.330
D007153	Immunologic Deficiency Syndromes	C20.673

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3713023 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	affects cotreatment, decreases expression, increases expression	3
sodium arsenite	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, increases expression	1
tungsten carbide	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases expression	1
hydroquinone	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
Am 580	decreases expression	1
arctigenin	increases secretion, affects cotreatment, affects reaction, decreases expression, decreases reaction (+1 more)	1
3-nitrobenzanthrone	decreases expression	1
abrine	decreases expression	1
MRK 003	decreases expression	1
bisphenol S	affects cotreatment, increases expression	1
jinfukang	increases expression	1
brevetoxin 2	increases expression	1
(+)-JQ1 compound	decreases expression	1
Aripiprazole	affects cotreatment, decreases expression	1
Rosiglitazone	decreases expression	1
Temozolomide	increases expression	1
Air Pollutants	increases abundance, decreases expression	1
Allergens	increases expression, affects cotreatment	1
Arsenic	affects expression	1
Vehicle Emissions	affects cotreatment, increases expression	1
Benzo(a)pyrene	decreases expression	1
Cobalt	affects cotreatment, decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00520494	PHASE4	COMPLETED	Efficacy and Safety of Vivaglobin® in Previously Untreated Patients With Primary Immunodeficiency
NCT01289847	PHASE4	COMPLETED	A Study to Find Out How Safe and Effective Gammaplex® is in Young People With Primary Immunodeficiency
NCT01946906	PHASE4	COMPLETED	The Rifaximin Study in CVID
NCT05193552	PHASE4	RECRUITING	Usage of Spirometry in Managing IgG Therapy in CVID With Airway Disease
NCT03677557	PHASE4	UNKNOWN	Safety, Tolerability, Patient Satisfaction and Cost of 16.5% Subcutaneous Immunoglobulin (Cutaquig®) Treatment
NCT00168012	PHASE3	COMPLETED	Efficacy and Safety of Intravenous Immunoglobulin IVIG-F10 in Patients With Primary Immunodeficiencies (PID)
NCT00168025	PHASE3	COMPLETED	Efficacy and Safety of Intravenous Immunoglobulin IgPro10 in Patients With Primary Immunodeficiencies (PID)
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT00322556	PHASE3	COMPLETED	Safety and Efficacy of Intravenous Immunoglobulin IgPro10 in Patients With Primary Immunodeficiencies (PID)
NCT00542997	PHASE3	COMPLETED	Study of Subcutaneous Immune Globulin in Patients Requiring IgG Replacement Therapy
NCT01884311	PHASE3	COMPLETED	Pharmacokinetics (PK) and Safety of Subgam-VF in Primary Immunodeficiency Diseases
NCT01963143	PHASE3	COMPLETED	Bioequivalence Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Gammaplex® 10 and Gammaplex® 5% in Primary Immunodeficiency Diseases
NCT02247141	PHASE3	COMPLETED	A Multi-centre Open Study to Assess the Safety and Efficacy of Subgam®
NCT00001646	PHASE3	COMPLETED	Voriconazole vs. Amphotericin B in the Treatment of Invasive Aspergillosis
NCT00468273	PHASE3	COMPLETED	A Clinical Study of Intravenous Immunoglobulin
NCT00811174	PHASE3	TERMINATED	Efficacy, Safety and Kinetics Study of Octagam 10% in Primary Immunodeficiency Diseases
NCT01012323	PHASE3	COMPLETED	A Study of NewGam, Human Immunoglobulin 10%, in Patients With Primary Immunodeficiency Diseases
NCT01313507	PHASE3	COMPLETED	High Infusion Rate Study of Immunoglobulin Intravenous (Human) 10% (NewGam)
NCT01406470	PHASE3	COMPLETED	Phase 3 Study of Immune Globulin Intravenous (Human)IVIG-SN™ in Subjects With Primary Immunodeficiency
NCT02783482	PHASE3	COMPLETED	Study of Immune Globulin Intravenous (Human) GC5107 in Subjects With Primary Humoral Immunodeficiency
NCT02810444	PHASE3	COMPLETED	Study to Investigate Efficacy, Safety and Pharmacokinetics of BT595 in Subjects With PID
NCT03961009	PHASE3	COMPLETED	Clinical Assessment of Pharmacokinetics, Efficacy, and Safety of 10% IVIg in PID Patients
NCT04842643	PHASE3	COMPLETED	An Extension Study of TAK-664 for Japanese People With Primary Immunodeficiency Disease
NCT04944979	PHASE3	ACTIVE_NOT_RECRUITING	Clinical Assessment of Pharmacokinetics, Efficacy, and Safety of 10% IVIg in Pediatric PID Patients (KIDCARES10)
NCT06089122	PHASE3	UNKNOWN	Efficacy, Safety, and Pharmacokinetics of Shu Yang IVIG
NCT06150833	PHASE3	UNKNOWN	Efficacy and Safety and Pharmacokinetics of Boya IVIG
NCT07346859	PHASE3	RECRUITING	Study of BP-SCIG 20% in Patients With Primary Immunodeficiency (PID)
NCT01489618	PHASE2	TERMINATED	Prime Boost Vaccination Strategy Combining Conjugated Anti- Pneumococcal Vaccine (s0) and Polysaccharide Anti- Pneumococcal Vaccine (s4) Compared to Polysaccharide Anti- Pneumococcal Vaccine Alone (s4) In Patients With Common Variable Immunodeficiency
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT02579967	PHASE2	RECRUITING	Pilot Trial of Allogeneic Blood or Marrow Transplantation for Primary Immunodeficiencies
NCT03663933	PHASE2	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Cell Transplantation for Disorders of T-cell Proliferation and/or Dysregulation
NCT04339777	PHASE2	RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Inborn Errors of Immunity
NCT04925375	PHASE2	RECRUITING	Abatacept for the Treatment of Common Variable Immunodeficiency With Interstitial Lung Disease
NCT05593588	PHASE2	ENROLLING_BY_INVITATION	Senolytics Treatment of Interstitial Lung Disease in Common Variable Immunodeficiency
NCT06897358	PHASE2	ACTIVE_NOT_RECRUITING	Leniolisib for Immune Dysregulation in CVID
NCT07284641	PHASE2	RECRUITING	Hematopoietic Stem Cell Transplantation (HSCT) for Common Variable Immunodeficiency (CVID) and Other Autoimmune Manifestations of Primary Immune Regulatory Disorders (PIRD)
NCT00001438	PHASE2	COMPLETED	A Pilot Study of the Combination of Retinoic Acid and Interferon-Alpha2a for the Treatment of Lymphoproliferative Disorders in Children With Immunodeficiency Syndromes
NCT00176865	PHASE2	COMPLETED	Stem Cell Transplant for Immunologic or Histiocytic Disorders
NCT00389324	PHASE2	COMPLETED	A Trial of the Pharmacokinetics, Safety, and Tolerability of Subcutaneous Gamunex® in Primary Immunodeficiency
NCT00598481	PHASE2	COMPLETED	ADA Gene Transfer Into Hematopoietic Stem/Progenitor Cells for the Treatment of ADA-SCID