TNFRSF10A

Summary

TNFRSF10A (TNF receptor superfamily member 10a, HGNC:11904) is a protein-coding gene on chromosome 8p21.3, encoding Tumor necrosis factor receptor superfamily member 10A (O00220). Receptor for the cytotoxic ligand TNFSF10/TRAIL.

The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is activated by tumor necrosis factor-related apoptosis inducing ligand (TNFSF10/TRAIL), and thus transduces cell death signal and induces cell apoptosis. Studies with FADD-deficient mice suggested that FADD, a death domain containing adaptor protein, is required for the apoptosis mediated by this protein.

Source: NCBI Gene 8797 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 101 total
• Druggable target: yes
• MANE Select transcript: NM_003844

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11904
Approved symbol	TNFRSF10A
Name	TNF receptor superfamily member 10a
Location	8p21.3
Locus type	gene with protein product
Status	Approved
Aliases	DR4, Apo2, TRAILR-1, CD261, TRAILR1
Ensembl gene	ENSG00000104689
Ensembl biotype	protein_coding
OMIM	603611
Entrez	8797

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000221132, ENST00000519862, ENST00000524158, ENST00000613472, ENST00000901503

RefSeq mRNA: 1 — MANE Select: NM_003844 NM_003844

CCDS: CCDS6039

Canonical transcript exons

ENST00000221132 — 10 exons

Exon	Start	End
ENSE00000684374	23200505	23200600
ENSE00000684381	23199266	23199448
ENSE00001217507	23190452	23192013
ENSE00001217515	23224756	23225102
ENSE00001633650	23200687	23200760
ENSE00001666256	23197132	23197204
ENSE00003496898	23201808	23201919
ENSE00003546909	23202648	23202761
ENSE00003610309	23212116	23212212
ENSE00003789187	23199886	23199917

Expression profiles

Bgee: expression breadth ubiquitous, 230 present calls, max score 94.14.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.4923 / max 135.4164, expressed in 1507 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
92290	7.5399	1421
92291	0.9524	534

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	94.14	gold quality
nipple	UBERON:0002030	90.16	gold quality
pancreatic ductal cell	CL:0002079	87.47	gold quality
tendon of biceps brachii	UBERON:0008188	86.70	gold quality
pylorus	UBERON:0001166	86.57	gold quality
oviduct epithelium	UBERON:0004804	86.10	gold quality
epithelial cell of pancreas	CL:0000083	85.46	silver quality
lymph node	UBERON:0000029	83.77	gold quality
superficial temporal artery	UBERON:0001614	83.74	gold quality
colonic epithelium	UBERON:0000397	82.98	gold quality
pharyngeal mucosa	UBERON:0000355	82.63	gold quality
nasal cavity epithelium	UBERON:0005384	82.35	silver quality
trachea	UBERON:0003126	82.24	gold quality
superior surface of tongue	UBERON:0007371	81.70	gold quality
pericardium	UBERON:0002407	81.34	gold quality
tonsil	UBERON:0002372	80.96	gold quality
oral cavity	UBERON:0000167	80.75	gold quality
mucosa of sigmoid colon	UBERON:0004993	80.72	gold quality
blood	UBERON:0000178	80.48	gold quality
caecum	UBERON:0001153	80.40	gold quality
vermiform appendix	UBERON:0001154	80.39	gold quality
visceral pleura	UBERON:0002401	80.23	gold quality
thymus	UBERON:0002370	80.02	gold quality
leukocyte	CL:0000738	79.83	gold quality
penis	UBERON:0000989	79.75	gold quality
monocyte	CL:0000576	79.72	gold quality
epithelium of nasopharynx	UBERON:0001951	79.72	gold quality
islet of Langerhans	UBERON:0000006	79.69	gold quality
esophagus mucosa	UBERON:0002469	79.27	gold quality
esophagus squamous epithelium	UBERON:0006920	79.19	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	15.75

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ETS1, GLI3, GSN, HDAC1, JUN, NFKB1, RARA, REL, RELA, TP53

miRNA regulators (miRDB)

19 targeting TNFRSF10A, 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-568	99.98	69.86	2084
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-6859-5P	98.99	68.07	2049
HSA-MIR-3149	98.77	67.13	1639
HSA-MIR-4490	98.51	68.47	943
HSA-MIR-6764-3P	98.44	67.64	1153
HSA-MIR-6824-3P	98.44	67.62	1154
HSA-MIR-4764-3P	96.81	67.94	580
HSA-MIR-4256	96.22	67.70	669
HSA-MIR-11181-5P	96.12	67.46	665

Literature-anchored findings (GeneRIF, showing 40)

• TNF-related apoptosis-inducing ligand (TRAIL) is not constitutively expressed in the human brain, whereas both apoptosis-mediating and apoptosis-blocking TRAIL receptors are found on neurons, astrocytes, and oligodendrocytes (PMID:11844843)
• highly expressed in metastatic gastric carcinoma and tumor-infiltrating lymphocytes (PMID:11862476)
• Human DR4 is regulated by activator protein 1 via the AP-1-binding site at -350/-344. (PMID:12082627)
• induces monocytic maturation of leukemic and normal myeloid precursors through a caspase-dependent pathway (PMID:12239152)
• Tyrosine-based sorting signal in adenovirus RID plays a role in RID’s ability to down-regulate TRAIL R1 receptor and inhibit TRAIL induced apoptosis (PMID:12388693)
• Decreased expression of DR4 may contribute to prolonged survival of eosinophils in the airways of allergic asthmatics following segmental antigen challenge. (PMID:12421985)
• Cytotoxicity and apoptosis induced by TRAIL to beta-cell lines CM were inhibited competitively by soluble TRAIL receptors, R1, R2, R3 or R4. (PMID:12488957)
• DR4 polymorphism is associated with environmental exposure and bladder cancer risk. (PMID:12649168)
• likely to be involved in chronic pancreatitis; pancreatic stellate cells may directly contribute to acinar regression by inducing apoptosis of parenchymal cells in a TRAIL-dependent manner (PMID:12808117)
• pro-inflammatory responses are mainly mediated by TRAIL receptor 1 in HaCaT keratinocytes. (PMID:12839575)
• results show that protein kinase C activation specifically inhibits the recruitment of TRAIL receptors 1 and 2 complexes, thereby modulating tumor necrosis-related apoptosis-inducing ligand(TRAIL)-induced apoptosis (PMID:12920112)
• TRAIL-induced apoptosis is enhanced by level of HBV replication in human hepatocytes, in part, by HBV-encoded X antigen-dependent upregulation of TRAIL-R1/DR4. (PMID:12927928)
• Infection of primary cells with adenoviruses carrying the relevant point mutations confirmed the crucial role of putative YXX Phi and dileucine (LL) transport motifs within Ad2 10.4-14.5 for down-regulation of Fas, TRAIL-R1, TRAIL-R2, and EGFR. (PMID:14506242)
• Fas, DR4, and DR5 are activated in drug-sensitive cells in response to anticancer drugs depending on the cytotoxic effect of each drug (PMID:14534720)
• All of mAbs to TRAIL-R1 and TRAIL-R2 induced cell death in several cancer cell lines susceptible to TRAIL but not in human umbilical vein endothelial cells in vitro (PMID:14576771)
• Malignant mesothelioma cells develop anintrinsic resistance to apoptosis induced by death receptor-4 upregulating the expression of the antiapoptotic protein c-FLIP. (PMID:15334061)
• DR4 and DR5 are differentially regulated by the signal recognition particle (PMID:15356269)
• in addition to the death domain, the C-terminal tails of DR4 and DR5 positively regulate FADD binding, caspase activation and apoptosis (PMID:15452120)
• CD95, DR4 and DR5 localization in rafts have roles in the toxicity of resveratrol and death receptor ligands in colon carcinoma cells (PMID:15480430)
• The DR4 was widespread expression on both malignant and normal cells. (PMID:15538968)
• The TRAILR1 is expressed by humans thymocytes. (PMID:15608691)
• in patients infected with cagA+/vacAs1+ H. pylori strains, expression of TRAIL and TRAIL-R1 and -R2 was down-regulated; down-regulation may limit apoptosis of gastric epithelial cells & destruction of tissue and may enable H. pylori to maintain its niche (PMID:15655781)
• RAS-MEK-ERK1/2 signaling pathway can sensitize cells to TRAIL-induced apoptosis by up-regulating DR4 and DR5 (PMID:15757891)
• Contrary to literature reports that TRAIL-induced apoptosis occurs primarily via signaling through TRAIL-R2, chronic lymphocytic leukaemia cells, in the presence of HDACi, undergo predominantly TRAIL-R1-mediated apoptosis (PMID:15861184)
• TRAIL-R1 was expressed only in acute myeloid leukemias exihibiting monocytic markers. PML/RAR-Eo is associated siwth TRAIL-R1 downmodulation. (PMID:15921376)
• There is a functional relevance of DR4 expression in ovarian neoplasms,with perhaps a substantial contribution of DR4 hyper-methylation and consequent loss of DR4 expression to ovarian cancer pathogenesis, particularly in premenopausal patients. (PMID:15972852)
• Death receptor 4 haplotype 626C-683C is associated with increased breast cancer risk (PMID:15975957)
• Thr to Arg single nucleotide polymorphism in the extracellular domain of DR4 could not be associated with the development and progression of gastric cancer. (PMID:16012731)
• TRAIL-R1 and TRAIL-R2 act as dosage-dependent tumor suppressor genes whose monoallelic deletion can impair TRAIL-induced apoptosis in B-cell lymphoma (PMID:16051735)
• TNFRSF10A is more frequent in CLL, mantle cell lymphoma, prostate cancer, bladder cancer and head and neck squamous cell carcinoma (PMID:16217763)
• TRAILR-1 apoptotic pathways plays an important role in hepatic cell death during viral infection. (PMID:16226105)
• Alpha-tocopheryl succinate activates expression of DR4/DR5 in a p53-dependent manner and re-establishes sensitivity of resistant MM cells to TRAIL-mediated apoptosis. (PMID:16529749)
• Analysis of TRAIL-R1 in patients with glioblastoma multiforme showed that age, gender, antigenic load, and % of TRAIL-R1 expression were not statistically correlated with survival however radiotherapy was significantly correlated. (PMID:16544055)
• TRAIL receptor 2 expression may be important in analysis of clinical trials involving TRAIL receptor agonists in melnoma (PMID:16778114)
• Data show that death receptor DR4 residue C336 becomes S nitrosylated and promotes apoptosis following nitrosylcobalamin treatment. (PMID:16847314)
• Death receptor 4 626C-683C may affect colorectal cancer predisposition. (PMID:17035413)
• Arsenite treatment upregulated surface levels of death receptors, TRAIL-R1 and TRAIL-R2, through increased translocation of these proteins from cytoplasm to the cell surface. (PMID:17070520)
• High DR4 expression is associated with worse disease-free and overall survival in stage III adjuvant-treated colon cancer patients. (PMID:17075118)
• initiator caspases and DR4 rather than NF-kappaB may control melanoma cell sensitivity to TRAIL (PMID:17160022)
• mutations in the TRAIL receptor DR5 inhibit TRAIL signaling through the DR4 receptor by competing for ligand binding (PMID:17666396)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	hdr	ENSDARG00000004392
danio_rerio	tnfrsfa	ENSDARG00000004451
danio_rerio	cd40	ENSDARG00000054968
danio_rerio	nradd	ENSDARG00000057143
danio_rerio	tnfrsf1b	ENSDARG00000070165
danio_rerio	tnfrsf11a	ENSDARG00000087804

Paralogs (21): FAS (ENSG00000026103), TNFRSF1B (ENSG00000028137), TNFRSF9 (ENSG00000049249), RELT (ENSG00000054967), NGFR (ENSG00000064300), TNFRSF1A (ENSG00000067182), CD40 (ENSG00000101017), LTBR (ENSG00000111321), TNFRSF10B (ENSG00000120889), TNFRSF8 (ENSG00000120949), CD27 (ENSG00000139193), TNFRSF11A (ENSG00000141655), TNFRSF21 (ENSG00000146072), TNFRSF14 (ENSG00000157873), TNFRSF11B (ENSG00000164761), TNFRSF10D (ENSG00000173530), TNFRSF10C (ENSG00000173535), TNFRSF4 (ENSG00000186827), TNFRSF18 (ENSG00000186891), TNFRSF25 (ENSG00000215788), TNFRSF6B (ENSG00000243509)

Protein

Protein identifiers

Tumor necrosis factor receptor superfamily member 10A — O00220 (reviewed: O00220)

Alternative names: Death receptor 4, TNF-related apoptosis-inducing ligand receptor 1

All UniProt accessions (3): O00220, E5RFH1, F8U8C0

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for the cytotoxic ligand TNFSF10/TRAIL. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. Promotes the activation of NF-kappa-B.

Subunit / interactions. Monomer. Homooligomers and heterooligomers with TNFRSF10B. Three TNFRSF10A molecules interact with the TNFSF10 homotrimer. Can interact with TRADD and RIPK1. Interacts with ARAP1. In the absence of stimulation, interacts with BIRC2, DDX3X and GSK3B. The interaction with BIRC2 and DDX3X is further enhanced upon receptor stimulation and accompanied by DDX3X and BIRC2 cleavage. Interacts with ZDHHC3. Interacts with PTPN6; this interaction enables the inhibition of T-cell receptor signaling via LCK. (Microbial infection) Interacts with HCMV protein UL141; this interaction prevents TNFRSF10A cell surface expression.

Subcellular location. Cell membrane. Membrane raft. Cytoplasm. Cytosol.

Tissue specificity. Widely expressed. High levels are found in spleen, peripheral blood leukocytes, small intestine and thymus, but also in K-562 erythroleukemia cells, MCF-7 breast carcinoma cells and activated T-cells.

Post-translational modifications. Palmitoylated. Palmitoylation of TNFRSF10A is required for its association with lipid rafts, oligomerization and function in TRAIL-induced cell death. Palmitoylated by ZDHHC3.

RefSeq proteins (1): NP_003835* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000488	Death_dom	Domain
IPR001368	TNFR/NGFR_Cys_rich_reg	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR020465	TNFR_10	Family
IPR034024	TNFRSF10_N	Domain
IPR034029	TNFRSF10A/B_death	Domain
IPR052491	TNFRSF10	Family

Pfam: PF00020, PF00531

UniProt features (47 total): sequence variant 8, disulfide bond 7, strand 7, mutagenesis site 6, modified residue 4, repeat 3, compositionally biased region 2, topological domain 2, signal peptide 1, chain 1, glycosylation site 1, transmembrane region 1, sequence conflict 1, turn 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5CIR	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00220-F1	66.91	0.33

Functional residue map

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

Post-translational modifications (4): 52, 424, 463, 466

Disulfide bonds (7): 132–145, 148–164, 167–180, 170–188, 190–204, 207–221, 211–229

Glycosylation sites (1): 156

Mutagenesis-validated functional residues (6):

Position	Phenotype
261	no effect on palmitoylation. loss of palmitoylation, decreased association with membranes, decreased oligomerization, de
262	no effect on palmitoylation. loss of palmitoylation, decreased association with membranes, decreased oligomerization, de
263	no effect on palmitoylation. loss of palmitoylation, decreased association with membranes, decreased oligomerization, de
268	no effect on palmitoylation.
274	no effect on palmitoylation.
279	no effect on palmitoylation.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-140534	Caspase activation via Death Receptors in the presence of ligand
R-HSA-202733	Cell surface interactions at the vascular wall
R-HSA-3371378	Regulation by c-FLIP
R-HSA-5213460	RIPK1-mediated regulated necrosis
R-HSA-5218900	CASP8 activity is inhibited
R-HSA-6803211	TP53 Regulates Transcription of Death Receptors and Ligands
R-HSA-69416	Dimerization of procaspase-8
R-HSA-75158	TRAIL signaling

MSigDB gene sets: 130 (showing top): GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_CELLULAR_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_ACTIVATION_OF_NF_KAPPAB_INDUCING_KINASE_ACTIVITY, GOCC_CELL_SURFACE, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, MODULE_528, MODULE_308, BILD_HRAS_ONCOGENIC_SIGNATURE, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, KOKKINAKIS_METHIONINE_DEPRIVATION_96HR_UP, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, chr8p21, GOBP_APOPTOTIC_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_PHOSPHORUS_METABOLIC_PROCESS

GO Biological Process (8): apoptotic process (GO:0006915), signal transduction (GO:0007165), activation of NF-kappaB-inducing kinase activity (GO:0007250), extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625), TRAIL-activated apoptotic signaling pathway (GO:0036462), positive regulation of apoptotic process (GO:0043065), cellular response to mechanical stimulus (GO:0071260), extrinsic apoptotic signaling pathway (GO:0097191)

GO Molecular Function (6): protease binding (GO:0002020), death receptor activity (GO:0005035), signaling receptor activity (GO:0038023), identical protein binding (GO:0042802), TRAIL binding (GO:0045569), protein binding (GO:0005515)

GO Cellular Component (8): Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), cell surface (GO:0009986), plasma membrane raft (GO:0044853), membrane raft (GO:0045121), cytoplasm (GO:0005737), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Caspase activation via Death Receptors in the presence of ligand	2
Caspase activation via extrinsic apoptotic signalling pathway	1
Hemostasis	1
Regulated Necrosis	1
Regulation of necroptotic cell death	1
TP53 Regulates Transcription of Cell Death Genes	1
Death Receptor Signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
programmed cell death	2
apoptotic signaling pathway	2
protein binding	2
cytoplasm	2
execution phase of apoptosis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
activation of protein kinase activity	1
non-canonical NF-kappaB signal transduction	1
extrinsic apoptotic signaling pathway	1
extrinsic apoptotic signaling pathway via death domain receptors	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
response to mechanical stimulus	1
cellular response to abiotic stimulus	1
cellular response to external stimulus	1
cell surface receptor signaling pathway	1
enzyme binding	1
transmembrane signaling receptor activity	1
molecular transducer activity	1
binding	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
plasma membrane	1
membrane raft	1
plasma membrane region	1
membrane microdomain	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1943 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNFRSF10A	TNFSF10	P50591	999
TNFRSF10A	TNFRSF25	P78507	998
TNFRSF10A	FADD	Q13158	998
TNFRSF10A	TNF	P01375	997
TNFRSF10A	FASLG	P48023	997
TNFRSF10A	Q5Y7H0	Q5Y7H0	952
TNFRSF10A	CASP8	Q14790	944
TNFRSF10A	TRADD	Q15628	939
TNFRSF10A	FAS	P25445	931
TNFRSF10A	TNFRSF10B	O14763	919
TNFRSF10A	TNFRSF1A	P19438	918
TNFRSF10A	CFLAR	O15519	913
TNFRSF10A	TOR1A	O14656	878
TNFRSF10A	HLA-DRB1	P01911	868
TNFRSF10A	TNFRSF21	O75509	850
TNFRSF10A	CHI3L1	P30923	850

IntAct

41 interactions, top by confidence:

A	B	Type	Score
TNFRSF10A	CASP8	psi-mi:“MI:0403”(colocalization)	0.820
CASP8	TNFRSF10A	psi-mi:“MI:0403”(colocalization)	0.820
TNFRSF10A	CASP8	psi-mi:“MI:0915”(physical association)	0.820
CASP8	TNFRSF10A	psi-mi:“MI:0914”(association)	0.820
TNFSF10	TNFRSF10A	psi-mi:“MI:0914”(association)	0.800
TNFRSF10A	TNFSF10	psi-mi:“MI:0407”(direct interaction)	0.800
FADD	TNFRSF10A	psi-mi:“MI:0914”(association)	0.730
TNFRSF10A	ARAP1	psi-mi:“MI:0915”(physical association)	0.540
TNFRSF10A	ARAP1	psi-mi:“MI:0403”(colocalization)	0.540
TNFRSF10A	TNFRSF10B	psi-mi:“MI:0914”(association)	0.530
LGALS3BP	TNFRSF10A	psi-mi:“MI:0915”(physical association)	0.500
PARK7	TNFRSF10A	psi-mi:“MI:0915”(physical association)	0.400
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
TNFRSF10A	NAP1L4	psi-mi:“MI:0914”(association)	0.350
TNFRSF10A	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.350
NS3	C15orf61	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
	TNFRSF10A	psi-mi:“MI:0914”(association)	0.350

BioGRID (183): CFLAR (Affinity Capture-Western), FADD (Affinity Capture-Western), CASP8 (Affinity Capture-Western), CASP8 (Affinity Capture-MS), ALDH3B1 (Affinity Capture-MS), FADD (Affinity Capture-MS), FGFR4 (Affinity Capture-MS), LSS (Affinity Capture-MS), ACVR1 (Affinity Capture-MS), UGCG (Affinity Capture-MS), IFNAR1 (Affinity Capture-MS), TNFRSF10B (Affinity Capture-MS), KCNT2 (Affinity Capture-MS), KIAA0195 (Affinity Capture-MS), FBXO11 (Affinity Capture-MS)

ESM2 similar proteins: A0A0U1RR11, A0A0U1RRI6, A6NCS6, A6NJG2, B0BN44, D3YXK1, E9PY61, E9Q0B3, F5H4A9, O00220, O00221, P09038, P0DPI3, P22083, P98077, Q08AU9, Q2M2W7, Q2M3V2, Q2TBI2, Q5F267, Q5FW56, Q5IS69, Q5R866, Q5T4W7, Q5TM52, Q5U4P2, Q5VTJ3, Q659K9, Q673H1, Q69ZB3, Q6AYE8, Q6IPT2, Q6PJ61, Q7RTU4, Q7TSX9, Q7YR31, Q80SU3, Q86SH2, Q86Y97, Q8NBR0

Diamond homologs: O00220, O14763, O14798, P15725, P47741, P83626, Q9QZM4, Q9UBN6, O19131, P19438, P50555, Q80WM9, O00300, O77736, O35305, P43489, P50284, Q92956, Q9Y6Q6, A5D7R1, P25119, P36941, P68636, P68637, Q80WY6, Q8SQ34, O35714, P25445, P25446, Q63199, Q9BDN0, Q9BDN4, Q9BDP2, Q9TSN4, Q9Y5U5, O08712, O08727, P25943, P29825, Q9ER62

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
TNFSF10	up-regulates	TNFRSF10A	binding
RIPK1	up-regulates	TNFRSF10A
MARCHF8	“down-regulates quantity”	TNFRSF10A	ubiquitination
TNFRSF10A	up-regulates	FADD	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 26 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
RIPK1-mediated regulated necrosis	5	152.3×	8e-09

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	66
Likely benign	11
Benign	10

Top pathogenic / likely-pathogenic (0)

SpliceAI

1408 predictions. Top by Δscore:

Variant	Effect	Δscore
8:23191992:T:C	acceptor_gain	1.0000
8:23197130:A:AC	donor_gain	1.0000
8:23197131:C:CC	donor_gain	1.0000
8:23197131:CT:C	donor_gain	1.0000
8:23197131:CTCT:C	donor_gain	1.0000
8:23201752:T:TA	donor_gain	1.0000
8:23201806:AC:A	donor_gain	1.0000
8:23201807:CC:C	donor_gain	1.0000
8:23201807:CCCT:C	donor_gain	1.0000
8:23201821:T:TA	donor_gain	1.0000
8:23224751:CTCA:C	donor_loss	1.0000
8:23224752:TCA:T	donor_loss	1.0000
8:23224753:CA:C	donor_loss	1.0000
8:23224754:A:AT	donor_loss	1.0000
8:23192009:CAGAG:C	acceptor_gain	0.9900
8:23192010:AGAG:A	acceptor_gain	0.9900
8:23192011:GAG:G	acceptor_gain	0.9900
8:23192011:GAGC:G	acceptor_loss	0.9900
8:23192012:AG:A	acceptor_gain	0.9900
8:23192013:GCTGG:G	acceptor_loss	0.9900
8:23192014:C:CC	acceptor_gain	0.9900
8:23192014:C:T	acceptor_loss	0.9900
8:23192015:T:C	acceptor_loss	0.9900
8:23197124:ACACT:A	donor_loss	0.9900
8:23197125:CACT:C	donor_loss	0.9900
8:23197126:ACTT:A	donor_loss	0.9900
8:23197127:CTTAC:C	donor_loss	0.9900
8:23197128:T:TC	donor_loss	0.9900
8:23197129:T:TG	donor_loss	0.9900
8:23197130:AC:A	donor_loss	0.9900

AlphaMissense

3032 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:23201852:G:C	F195L	0.995
8:23201852:G:T	F195L	0.995
8:23201854:A:G	F195L	0.995
8:23201868:C:G	C190S	0.980
8:23201869:A:T	C190S	0.980
8:23191739:G:C	F454L	0.979
8:23191739:G:T	F454L	0.979
8:23191741:A:G	F454L	0.979
8:23191858:A:G	W415R	0.977
8:23191858:A:T	W415R	0.977
8:23201853:A:C	F195C	0.974
8:23191856:C:A	W415C	0.973
8:23191856:C:G	W415C	0.973
8:23191961:C:A	W380C	0.973
8:23191961:C:G	W380C	0.973
8:23200704:C:G	C229S	0.970
8:23200705:A:T	C229S	0.970
8:23191963:A:G	W380R	0.966
8:23191963:A:T	W380R	0.966
8:23200728:C:G	C221S	0.965
8:23200729:A:T	C221S	0.965
8:23201826:C:G	C204S	0.963
8:23201827:A:T	C204S	0.963
8:23200758:C:G	C211S	0.962
8:23200759:A:T	C211S	0.962
8:23201869:A:G	C190R	0.960
8:23201898:C:G	C180S	0.960
8:23201899:A:T	C180S	0.960
8:23200727:A:C	C221W	0.957
8:23200729:A:G	C221R	0.955

dbSNP variants (sampled 300 via entrez): RS1000028712 (8:23219280 T>C), RS1000059808 (8:23219074 C>T), RS1000127404 (8:23190633 G>A,C), RS1000143940 (8:23210446 C>G), RS1000166115 (8:23225282 G>A,T), RS1000256730 (8:23214052 AG>A,AGG), RS1000294 (8:23222622 G>A,T), RS1000339563 (8:23193715 C>A,T), RS1000401382 (8:23224758 G>C), RS1000442144 (8:23199449 C>G,T), RS1000487155 (8:23212053 G>A,T), RS1000562719 (8:23223777 G>A), RS1000730666 (8:23215690 A>C), RS1000736135 (8:23225870 C>A), RS1000751801 (8:23205937 C>A,G,T)

Disease associations

OMIM: gene MIM:603611 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST000751_1	Attention deficit hyperactivity disorder	3.000000e-06
GCST001232_1	Age-related macular degeneration	1.000000e-12
GCST001884_17	Age-related macular degeneration	3.000000e-15
GCST003219_49	Advanced age-related macular degeneration	5.000000e-11
GCST009653_1	Central serous retinopathy	1.000000e-13
GCST009653_3	Central serous retinopathy	1.000000e-09
GCST010723_4	Early age-related macular degeneration	2.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:1001492	atrophic macular degeneration
EFO:0009784	central serous retinopathy

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3551 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs20575	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Arthritis

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs20575	TNFRSF10A	3	4.75	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors
rs20576	TNFRSF10A		0.00	0
rs2230229	TNFRSF10A		0.00	0

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
SC-67655	Agonist	7.3	pIC50

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.10	IC50	80	nM	CHEMBL1253325
6.12	IC50	755	nM	CHEMBL2373021
5.46	IC50	3500	nM	CHEMBL2373027

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, affects methylation, affects cotreatment, increases expression	9
Bortezomib	affects expression, affects cotreatment, increases expression, decreases expression, increases localization (+4 more)	8
Resveratrol	affects reaction, decreases reaction, increases reaction, increases localization, affects cotreatment (+1 more)	8
Aflatoxin B1	increases expression, increases methylation, affects expression	6
Cisplatin	increases expression, increases localization, decreases response to substance	4
Doxorubicin	increases expression, affects reaction, increases activity, affects response to substance	4
Fluorouracil	increases expression, affects cotreatment, decreases expression, decreases response to substance	4
Acetylcysteine	decreases reaction, increases expression	3
Estradiol	increases expression	3
Plant Extracts	decreases reaction, increases expression, affects response to substance	3
Quercetin	decreases reaction, increases reaction, increases expression, affects localization	3
Cyclosporine	increases expression, affects cotreatment	3
bisphenol A	decreases expression, increases expression	2
trichostatin A	affects expression, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	increases expression, increases reaction	2
entinostat	increases expression, affects cotreatment	2
(+)-JQ1 compound	affects cotreatment, increases expression, decreases expression	2
Temozolomide	affects cotreatment, decreases expression, decreases response to substance, increases expression	2
Zoledronic Acid	affects cotreatment, increases expression	2
Vorinostat	increases expression, increases reaction	2
Capsaicin	increases expression	2
Curcumin	increases reaction, decreases reaction, increases expression	2
Methotrexate	increases expression	2
Ozone	increases expression, increases oxidation	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Tobacco Smoke Pollution	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Paclitaxel	decreases reaction, increases expression, affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1250029	Binding	Binding affinity to human TNF-related apoptosis-inducing ligand receptor 1 by surface plasmon resonance method	C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L. — Nat Chem Biol

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2J1	Abcam HeLa TNFRSF10A KO	Cancer cell line	Female

Clinical trials (associated diseases)

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