TNFRSF21

Summary

TNFRSF21 (TNF receptor superfamily member 21, HGNC:13469) is a protein-coding gene on chromosome 6p12.3, encoding Tumor necrosis factor receptor superfamily member 21 (O75509). Promotes apoptosis, possibly via a pathway that involves the activation of NF-kappa-B.

This gene encodes a member of the tumor necrosis factor receptor superfamily. The encoded protein activates nuclear factor kappa-B and mitogen-activated protein kinase 8 (also called c-Jun N-terminal kinase 1), and induces cell apoptosis. Through its death domain, the encoded receptor interacts with tumor necrosis factor receptor type 1-associated death domain (TRADD) protein, which is known to mediate signal transduction of tumor necrosis factor receptors. Knockout studies in mice suggest that this gene plays a role in T-helper cell activation, and may be involved in inflammation and immune regulation.

Source: NCBI Gene 27242 — RefSeq curated summary.

At a glance

• Gene–disease (curated): myopia (Limited, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 81 total
• MANE Select transcript: NM_014452

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13469
Approved symbol	TNFRSF21
Name	TNF receptor superfamily member 21
Location	6p12.3
Locus type	gene with protein product
Status	Approved
Aliases	DR6, CD358
Ensembl gene	ENSG00000146072
Ensembl biotype	protein_coding
OMIM	605732
Entrez	27242

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000296861, ENST00000877798, ENST00000911387, ENST00000952535, ENST00000952536

RefSeq mRNA: 1 — MANE Select: NM_014452 NM_014452

CCDS: CCDS4921

Canonical transcript exons

ENST00000296861 — 6 exons

Exon	Start	End
ENSE00000973751	47285944	47286595
ENSE00000973756	47234670	47234898
ENSE00001084008	47231532	47232994
ENSE00001139126	47253256	47253521
ENSE00001139134	47283938	47284432
ENSE00001226615	47309416	47309905

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 97.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.5543 / max 386.5389, expressed in 1679 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73889	20.3996	1609
73890	5.1751	1480
73888	3.3755	1156
73886	1.1158	599
73885	0.2494	88
73891	0.1345	43
73887	0.1043	36

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	97.96	gold quality
mucosa of urinary bladder	UBERON:0001259	97.82	gold quality
periodontal ligament	UBERON:0008266	97.51	gold quality
subthalamic nucleus	UBERON:0001906	97.42	gold quality
epithelium of nasopharynx	UBERON:0001951	97.42	gold quality
inferior vagus X ganglion	UBERON:0005363	97.41	gold quality
pons	UBERON:0000988	97.20	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.15	gold quality
type B pancreatic cell	CL:0000169	97.06	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.80	gold quality
epithelium of bronchus	UBERON:0002031	96.76	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.76	gold quality
bronchus	UBERON:0002185	96.71	gold quality
spinal cord	UBERON:0002240	96.66	gold quality
bronchial epithelial cell	CL:0002328	96.63	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.53	gold quality
substantia nigra pars compacta	UBERON:0001965	96.52	gold quality
colonic mucosa	UBERON:0000317	96.43	gold quality
nasal cavity epithelium	UBERON:0005384	96.25	gold quality
dorsal plus ventral thalamus	UBERON:0001897	96.23	gold quality
pharyngeal mucosa	UBERON:0000355	95.69	gold quality
medulla oblongata	UBERON:0001896	95.66	gold quality
superior vestibular nucleus	UBERON:0007227	95.53	gold quality
gingiva	UBERON:0001828	94.98	gold quality
trachea	UBERON:0003126	94.71	gold quality
gingival epithelium	UBERON:0001949	94.68	gold quality
inferior olivary complex	UBERON:0002127	94.26	gold quality
nasal cavity mucosa	UBERON:0001826	94.13	gold quality
squamous epithelium	UBERON:0006914	93.93	gold quality
ileal mucosa	UBERON:0000331	93.92	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	12.73
E-CURD-112	yes	12.18
E-MTAB-8498	yes	11.74
E-GEOD-124858	no	55.19
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): VDR

miRNA regulators (miRDB)

137 targeting TNFRSF21, 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-3163	100.00	77.23	8605
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489

Literature-anchored findings (GeneRIF, showing 26)

• DR6 mediates T cell proliferation and differentiation in mice. (PMID:11485735)
• DR6 knockout mice are viable and fertile, and show hyperproliferation of T cells when stimulated. (PMID:11714751)
• androgen signaling pathway might cross talk with apoptosis signaling pathway through the interaction between ARA267-alpha and DR6 (PMID:15623156)
• MMP-14 and DR6 are part of a mechanism tumor cells can employ to actively escape detection by the immune system by affecting the generation of antigen presenting cells (PMID:17962943)
• N-glycosylation of the extracellular part might participate in directing DR6 into lipid raft membrane microdomains. (PMID:19654028)
• The model is used to provide a satisfying structural and energetic interpretation of DR6-growth factor-like domain of NAPP binding and to suggest the possibility of and a mechanism for spontaneous apoptosis. (PMID:21337622)
• findings show that DR6 expression is significantly but transiently upregulated only in activated both CD4+ and CD8+ T cells in NF-kappaB and NF-AT dependent manner with a contribution of PI3K-dependent signaling (PMID:21501873)
• SAXS measurements on the ectodomain suggested that a dimer defines the minimal physical unit of an unliganded DR6 molecule in solution. (PMID:22525750)
• DR6 serum protein may be a tool to aid in the diagnosis of some sarcomatous tumors to improve treatment planning. (PMID:22567163)
• DR6-induced apoptosis occurs through a new pathway that is different from the type I and type II pathways through interacting with Bax. (PMID:22761420)
• The present findings suggested that DR6 is involved in the pathogenesis of endometriosis by creating the proliferative and anti-apoptotic characteristics of endometriosis. (PMID:24028773)
• our findings provide new insight into a novel mechanism by which DR6 induces downstream signaling in response to an agonist antibody. (PMID:24374337)
• Circulating levels of DR6 and Gpm6B correlate with breast cancer tumor grade. (PMID:24696529)
• Our results support the view that DR6 functions with APP to modulate synaptic density in the adult CNS (PMID:24806669)
• These results provide direct support for the model that APP and DR6 function cell autonomously and in the same pathway to control pruning (PMID:24806670)
• Increase in the expression levels of mRNA and protein for the death receptor 6 is associated with various types of gynaecological malignancy. (PMID:25113253)
• Knockdown death receptor 6 by shRNA in human pDCs cell line GEN2.2 significantly diminished the CpG-ODN induced IFN-regulatory factor 7 nuclear localization and IFN-I production. (PMID:26906057)
• data identify a new mechanism underlying tumour cell extravasation and metastasis, and suggest endothelial DR6-mediated necroptotic signalling pathways as targets for anti-metastatic therapies (PMID:27487218)
• Hepatitis C virus modulates DR6 signaling pathway for viral propagation.DR6 is not involved in the entry, replication, and translation steps of the HCV life cycle.Hepatitis C virus NS5A protein specifically interacts with DR6. (PMID:28743875)
• MiR20a5p functioned as an oncogene in HNSCC by downregulating TNFRSF21. (PMID:29901115)
• Variants in TNFRSF21 cause non-syndromic high myopia in Chinese population. (PMID:31189563)
• Proapoptotic Mitochondrial Carrier Homolog Protein PSAP Mediates Death Receptor 6 Induced Apoptosis. (PMID:32144986)
• circTNFRSF21, a newly identified circular RNA promotes endometrial carcinoma pathogenesis through regulating miR-1227-MAPK13/ATF2 axis. (PMID:32299063)
• Long Noncoding RNAs Testis Development Related Gene 1 Aggravates Transforming Growth Factor-beta1-Induced Fibrogenesis and Inflammatory Response of Cardiac Fibroblasts Via miR-605-3p/Tumor Necrosis Factor Receptor Superfamily-21 Axis. (PMID:34775426)
• Death Receptor 6 as a Prognostic Marker in Low-grade Glioma. (PMID:35220214)
• Gene-based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma. (PMID:37944567)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tnfrsf21	ENSDARG00000001807
mus_musculus	Tnfrsf21	ENSMUSG00000023915
rattus_norvegicus	Tnfrsf21	ENSRNOG00000011517

Paralogs (21): FAS (ENSG00000026103), TNFRSF1B (ENSG00000028137), TNFRSF9 (ENSG00000049249), RELT (ENSG00000054967), NGFR (ENSG00000064300), TNFRSF1A (ENSG00000067182), CD40 (ENSG00000101017), TNFRSF10A (ENSG00000104689), LTBR (ENSG00000111321), TNFRSF10B (ENSG00000120889), TNFRSF8 (ENSG00000120949), CD27 (ENSG00000139193), TNFRSF11A (ENSG00000141655), 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 21 — O75509 (reviewed: O75509)

Alternative names: Death receptor 6

All UniProt accessions (1): O75509

UniProt curated annotations — full annotation on UniProt →

Function. Promotes apoptosis, possibly via a pathway that involves the activation of NF-kappa-B. Can also promote apoptosis mediated by BAX and by the release of cytochrome c from the mitochondria into the cytoplasm. Trophic-factor deprivation triggers the cleavage of surface APP by beta-secretase to release sAPP-beta which is further cleaved to release an N-terminal fragment of APP (N-APP). Negatively regulates oligodendrocyte survival, maturation and myelination. Plays a role in signaling cascades triggered by stimulation of T-cell receptors, in the adaptive immune response and in the regulation of T-cell differentiation and proliferation. Negatively regulates T-cell responses and the release of cytokines such as IL4, IL5, IL10, IL13 and IFNG by Th2 cells. Negatively regulates the production of IgG, IgM and IgM in response to antigens. May inhibit the activation of JNK in response to T-cell stimulation. Also acts as a regulator of pyroptosis: recruits CASP8 in response to reactive oxygen species (ROS) and subsequent oxidation, leading to activation of GSDMC.

Subunit / interactions. Associates with TRADD. Interacts with NGFR. Interacts with CASP8. (Microbial infection) Interacts with hepatitis C virus (HCV) non-structural protein 5A; this interaction allows the modulation by the virus of JNK, p38 MAPK, STAT3, and Akt signaling pathways in a DR6-dependent manner.

Subcellular location. Cell membrane.

Tissue specificity. Detected in fetal spinal cord and in brain neurons, with higher levels in brain from Alzheimer disease patients (at protein level). Highly expressed in heart, brain, placenta, pancreas, lymph node, thymus and prostate. Detected at lower levels in lung, skeletal muscle, kidney, testis, uterus, small intestine, colon, spleen, bone marrow and fetal liver. Very low levels were found in adult liver and peripheral blood leukocytes.

Post-translational modifications. Oxidized in response to reactive oxygen species (ROS), leading to endocytosis.

Induction. Up-regulated by TNF.

RefSeq proteins (1): NP_055267* (*=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
IPR022330	TNFR_21	Family
IPR034034	TNFRSF21_N	Domain
IPR034037	TNFRSF21_death	Domain

Pfam: PF00020, PF00531

UniProt features (63 total): strand 18, disulfide bond 9, mutagenesis site 7, helix 7, glycosylation site 6, repeat 4, region of interest 2, compositionally biased region 2, topological domain 2, signal peptide 1, chain 1, lipid moiety-binding region 1, transmembrane region 1, turn 1, domain 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
3U3P	X-RAY DIFFRACTION	2.09
3QO4	X-RAY DIFFRACTION	2.2
3U3Q	X-RAY DIFFRACTION	2.7
3U3S	X-RAY DIFFRACTION	2.7
3U3V	X-RAY DIFFRACTION	2.96
3U3T	X-RAY DIFFRACTION	3.21
2DBH	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75509-F1	68.57	0.34

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 (1): 368

Disulfide bonds (9): 67–80, 70–88, 91–106, 109–123, 113–131, 133–144, 150–168, 171–186, 192–211

Glycosylation sites (6): 82, 141, 252, 257, 278, 289

Mutagenesis-validated functional residues (7):

Position	Phenotype
82	abolishes one glycosylation site and reduces total n-glycosylation; when associated with q-252; q-278 and q-289.
141	abolishes one glycosylation site and reduces total n-glycosylation; when associated with q-82; q-252; q-278 and q-289.
252	abolishes one glycosylation site and reduces total n-glycosylation; when associated with q-278 and q-289.
257	abolishes one glycosylation site and reduces total n-glycosylation; when associated with q-82; q-141; q-252; q-278 and q
278	abolishes one glycosylation site and reduces total n-glycosylation. abolishes one glycosylation site and reduces total n
289	abolishes one glycosylation site and reduces total n-glycosylation; when associated with q-278.
368	abolishes palmitoylation.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-1989781	PPARA activates gene expression
R-HSA-3371453	Regulation of HSF1-mediated heat shock response
R-HSA-3371511	HSF1 activation
R-HSA-3371568	Attenuation phase
R-HSA-3371571	HSF1-dependent transactivation

MSigDB gene sets: 432 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_NEURON_RECOGNITION, MCLACHLAN_DENTAL_CARIES_UP, GOBP_RESPONSE_TO_PEPTIDE, GOBP_B_CELL_ACTIVATION, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GCANCTGNY_MYOD_Q6, MODULE_64, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_B_CELL_ACTIVATION, GOBP_NEGATIVE_REGULATION_OF_NERVOUS_SYSTEM_PROCESS

GO Biological Process (19): B cell apoptotic process (GO:0001783), adaptive immune response (GO:0002250), apoptotic process (GO:0006915), humoral immune response (GO:0006959), axonal fasciculation (GO:0007413), negative regulation of B cell proliferation (GO:0030889), negative regulation of myelination (GO:0031642), negative regulation of interleukin-10 production (GO:0032693), negative regulation of interleukin-13 production (GO:0032696), negative regulation of interleukin-5 production (GO:0032714), negative regulation of T cell proliferation (GO:0042130), myelination (GO:0042552), regulation of oligodendrocyte differentiation (GO:0048713), T cell receptor signaling pathway (GO:0050852), neuron apoptotic process (GO:0051402), cellular response to tumor necrosis factor (GO:0071356), oligodendrocyte apoptotic process (GO:0097252), immune system process (GO:0002376), signal transduction (GO:0007165)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Cellular response to heat stress	3
Regulation of lipid metabolism by PPARalpha	1
HSF1-dependent transactivation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of cytokine production	3
immune response	2
negative regulation of lymphocyte proliferation	2
lymphocyte apoptotic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
neuron recognition	1
axon development	1
neuron projection fasciculation	1
regulation of B cell proliferation	1
B cell proliferation	1
negative regulation of B cell activation	1
regulation of myelination	1
negative regulation of nervous system process	1
myelination	1
negative regulation of cellular process	1
interleukin-10 production	1
regulation of interleukin-10 production	1
interleukin-13 production	1
regulation of interleukin-13 production	1
interleukin-5 production	1
regulation of interleukin-5 production	1
T cell proliferation	1
regulation of T cell proliferation	1
negative regulation of T cell activation	1
axon ensheathment	1
regulation of glial cell differentiation	1
oligodendrocyte differentiation	1
antigen receptor-mediated signaling pathway	1
apoptotic process	1
response to tumor necrosis factor	1
cellular response to cytokine stimulus	1
glial cell apoptotic process	1
biological_process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1

Protein interactions and networks

STRING

990 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNFRSF21	APP	P05067	993
TNFRSF21	TRADD	Q15628	959
TNFRSF21	TNFRSF10B	O14763	889
TNFRSF21	CASP6	P55212	865
TNFRSF21	TNFRSF10A	O00220	850
TNFRSF21	FASLG	P48023	786
TNFRSF21	TNFRSF25	P78507	785
TNFRSF21	TNFSF10	P50591	784
TNFRSF21	TNFSF15	O95150	766
TNFRSF21	TNFRSF1A	P19438	759
TNFRSF21	APLP2	Q06481	730
TNFRSF21	TNF	P01375	708
TNFRSF21	NGFR	P08138	678
TNFRSF21	CASP8	Q14790	671
TNFRSF21	FADD	Q13158	669

IntAct

34 interactions, top by confidence:

A	B	Type	Score
APP	TNFRSF21	psi-mi:“MI:0407”(direct interaction)	0.620
TNFRSF21	APP	psi-mi:“MI:0407”(direct interaction)	0.620
TNFRSF21	PI16	psi-mi:“MI:0407”(direct interaction)	0.600
PI16	TNFRSF21	psi-mi:“MI:0407”(direct interaction)	0.600
TNFRSF21	PI16	psi-mi:“MI:0403”(colocalization)	0.600
SGTA	TNFRSF21	psi-mi:“MI:0915”(physical association)	0.560
NGFR	TNFRSF21	psi-mi:“MI:0915”(physical association)	0.540
NGFR	TNFRSF21	psi-mi:“MI:0407”(direct interaction)	0.540
TNFRSF21	TNFRSF21	psi-mi:“MI:0407”(direct interaction)	0.440
TNFRSF21	SDC1	psi-mi:“MI:0407”(direct interaction)	0.440
TNFRSF21	SMC1A	psi-mi:“MI:0915”(physical association)	0.400
TNFRSF21	DNAJC8	psi-mi:“MI:0915”(physical association)	0.400
TNFRSF21	MPIG6B	psi-mi:“MI:0915”(physical association)	0.400
TRADD	TNFRSF21	psi-mi:“MI:0915”(physical association)	0.400
TNFRSF21		psi-mi:“MI:0915”(physical association)	0.370
MATR3	TNFRSF21	psi-mi:“MI:0915”(physical association)	0.370
STX11	TNFRSF21	psi-mi:“MI:0915”(physical association)	0.370
TNFRSF21	WASH2P	psi-mi:“MI:0915”(physical association)	0.370
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
CACNA1C	IGLL5	psi-mi:“MI:0914”(association)	0.350
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350
SLC37A1	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC4A1	UPK3BL1	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350

BioGRID (36): TNFRSF21 (Affinity Capture-RNA), TNFRSF21 (Affinity Capture-MS), PSMD4 (Affinity Capture-Western), TNFRSF21 (Two-hybrid), TNFRSF21 (Affinity Capture-MS), TNFRSF21 (Affinity Capture-MS), TNFRSF21 (Affinity Capture-MS), TNFRSF21 (Affinity Capture-MS), DNAJC8 (Proximity Label-MS), SMC1A (Proximity Label-MS), TRADD (Affinity Capture-Western), TNFRSF21 (Affinity Capture-MS), TNFRSF21 (Affinity Capture-MS), TNFRSF21 (Affinity Capture-MS), TNFRSF21 (Affinity Capture-MS)

ESM2 similar proteins: A2AR95, A4IHY6, B7ZWI3, D3ZF92, O15165, O43278, O75509, O88204, P98153, P98154, Q0VBF2, Q1L8G6, Q29RU0, Q4KMG9, Q566M8, Q5DTZ6, Q5HZW5, Q5R662, Q5R8E0, Q5RD34, Q5RF74, Q5VUB5, Q61003, Q68FU0, Q6AXS2, Q6NRX0, Q6UWW9, Q6ZPS6, Q6ZUJ8, Q7TQH7, Q86YD5, Q8BGN6, Q8BLD6, Q8BUJ9, Q8R182, Q8TEB7, Q8WUU8, Q91ZV2, Q91ZV3, Q96PD2

Diamond homologs: A5D7R1, D3ZF92, O00300, O08712, O08727, O35305, O75509, O95407, P0DTN0, P20333, P25119, P25942, P25943, P27512, P29825, P36941, P43489, P83626, Q28203, Q3LRP1, Q3ZTK5, Q63199, Q7YRL5, Q8SQ34, Q9EPU5, Q9Y6Q6, Q80WM9, O73559, P0DSV7, P0DSV8, P68636, P68637, P28908, Q80WY6, Q8BX43, Q92956, Q969Z4, Q9N092, P08138, P50284

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
TNFRSF21	up-regulates	TRADD	binding
TNFRSF21	down-regulates	ROS
TNFRSF21	down-regulates	Demyelination
TNF	up-regulates	TNFRSF21	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	68
Likely benign	5
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1133 predictions. Top by Δscore:

Variant	Effect	Δscore
6:47232990:CTTTT:C	acceptor_gain	1.0000
6:47232991:TTTT:T	acceptor_gain	1.0000
6:47232992:TTT:T	acceptor_gain	1.0000
6:47232993:TT:T	acceptor_gain	1.0000
6:47232995:C:A	acceptor_loss	1.0000
6:47232995:C:CC	acceptor_gain	1.0000
6:47232996:T:C	acceptor_loss	1.0000
6:47232998:C:CT	acceptor_gain	1.0000
6:47234894:TCCAG:T	acceptor_gain	1.0000
6:47234895:CCAG:C	acceptor_gain	1.0000
6:47234895:CCAGC:C	acceptor_gain	1.0000
6:47234896:CAG:C	acceptor_gain	1.0000
6:47234896:CAGC:C	acceptor_gain	1.0000
6:47234899:C:CC	acceptor_gain	1.0000
6:47253251:ATTAC:A	donor_loss	1.0000
6:47253252:TTAC:T	donor_loss	1.0000
6:47253253:TACC:T	donor_loss	1.0000
6:47253254:A:T	donor_loss	1.0000
6:47253255:C:CG	donor_loss	1.0000
6:47253522:C:CC	acceptor_gain	1.0000
6:47253523:T:A	acceptor_loss	1.0000
6:47253528:C:CT	acceptor_gain	1.0000
6:47253529:A:T	acceptor_gain	1.0000
6:47286469:AGGTT:A	donor_gain	1.0000
6:47232999:A:T	acceptor_gain	0.9900
6:47234664:CCGTA:C	donor_loss	0.9900
6:47234665:CGTAC:C	donor_loss	0.9900
6:47234666:GTACC:G	donor_loss	0.9900
6:47234667:TACCT:T	donor_loss	0.9900
6:47234668:A:T	donor_loss	0.9900

AlphaMissense

4313 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:47253477:A:G	W430R	1.000
6:47253477:A:T	W430R	1.000
6:47232793:A:T	V647D	0.999
6:47232805:A:G	L643P	0.999
6:47253320:A:G	L482P	0.999
6:47253332:A:G	L478P	0.999
6:47253369:A:G	W466R	0.999
6:47253369:A:T	W466R	0.999
6:47253377:A:G	L463P	0.999
6:47253380:G:T	A462D	0.999
6:47283962:A:G	W407R	0.999
6:47283962:A:T	W407R	0.999
6:47232772:A:G	L654P	0.998
6:47232797:A:G	S646P	0.998
6:47232850:A:G	L628P	0.998
6:47232859:A:G	L625P	0.998
6:47232979:A:T	V585E	0.998
6:47232987:C:A	K582N	0.998
6:47232987:C:G	K582N	0.998
6:47253389:G:T	A459D	0.998
6:47253498:C:G	A423P	0.998
6:47286483:C:G	C70S	0.998
6:47286484:A:T	C70S	0.998
6:47232781:A:G	L651P	0.997
6:47232802:A:G	L644P	0.997
6:47232813:G:C	S640R	0.997
6:47232813:G:T	S640R	0.997
6:47232815:T:G	S640R	0.997
6:47232973:C:G	R587P	0.997
6:47253497:G:T	A423E	0.997

dbSNP variants (sampled 300 via entrez): RS1000006354 (6:47245969 C>T), RS1000036567 (6:47260895 T>A), RS1000088474 (6:47261098 C>G,T), RS1000104077 (6:47301148 T>A,C), RS1000161358 (6:47243200 C>G), RS1000258974 (6:47235990 C>T), RS1000288421 (6:47236218 G>A), RS1000333151 (6:47278108 C>A), RS1000426604 (6:47267199 A>G), RS1000515550 (6:47303046 C>G), RS1000589202 (6:47264954 C>T), RS1000615787 (6:47296992 G>A), RS1000675462 (6:47243452 G>A), RS1000748644 (6:47270600 A>C), RS1000755387 (6:47290734 G>A,C)

Disease associations

OMIM: gene MIM:605732 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
myopia	Limited	Autosomal dominant

Mondo (1): myopia (MONDO:0001384)

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000320_3	Panic disorder	5.000000e-06
GCST006206_2	Thiopurine-induced alopecia in inflammatory bowel disease	2.000000e-07

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009216	Myopia	C11.744.636

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects binding, decreases expression, affects cotreatment, increases expression	8
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression, increases methylation	6
methylmercuric chloride	increases expression, affects cotreatment	4
Benzo(a)pyrene	affects methylation, increases expression	4
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, affects expression, increases expression	4
trichostatin A	affects cotreatment, increases expression	3
Progesterone	increases expression, affects cotreatment, decreases expression	3
Cyclosporine	affects expression, decreases expression	3
sodium arsenite	decreases expression, affects response to substance	2
cobaltous chloride	decreases expression, increases expression	2
Zoledronic Acid	increases expression, decreases expression	2
Arsenic Trioxide	affects expression, affects cotreatment, increases expression	2
Acetaminophen	affects expression, increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Hydrogen Peroxide	affects expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Fenofibrate	increases expression	2
Tunicamycin	decreases expression	2
Aflatoxin B1	increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
FR900359	increases phosphorylation	1
peracetylated N-azidoacetylmannosamine	decreases expression	1
dicrotophos	increases expression	1
biochanin A	decreases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	increases expression	1
VX-agent	decreases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
cinnamaldehyde	increases expression	1
methylparaben	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00347204	PHASE4	COMPLETED	Comparison of Acular LS Versus Nevanac for Pain Control in Eyes Undergoing PRK
NCT00349843	PHASE4	COMPLETED	Investigation of Multi-Purpose Solution-Based Corneal Staining and Ocular Comfort
NCT00349882	PHASE4	COMPLETED	Effects of Contact Lens Care Regimens on the Corneal Epithelium
NCT00350246	PHASE4	COMPLETED	Long-term Effects of Laser Refractive Surgery
NCT00404105	PHASE4	COMPLETED	A Comparison of PRK and LASIK for Correction of Myopia
NCT00455455	PHASE4	COMPLETED	Corneal and Conjunctival Sensitivity and Staining Study
NCT00541177	PHASE4	UNKNOWN	Study of Myopia Prevention in Children With Low Concentration of Atropine
NCT00627302	PHASE4	COMPLETED	Efficacy of PEG-400 and Systane Artificial Tears (Alcon) on Quality of Vision
NCT00640341	PHASE4	COMPLETED	Comparative Performance of PureVision, Acuvue Oasys and O2Optix
NCT00770094	PHASE4	UNKNOWN	Multi Laser Platform Comparison Study for LASIK
NCT00821236	PHASE4	COMPLETED	Contralateral Comparison of Three Excimer Laser Systems in Performing LASIK
NCT00889941	PHASE4	COMPLETED	Effect of Preoperative Pupil Size on Quality of Vision After Wavefront-Guided LASIK
NCT00937105	PHASE4	COMPLETED	Daily Wear Corneal Infiltrative Event Study
NCT01173198	PHASE4	COMPLETED	An Evaluation of Outcomes Following Wavefront Optimized or Wavefront Guided Lasik Procedure in Low to Moderate Myopic Patients
NCT01250925	PHASE4	COMPLETED	Effect of Contact Lens Wear on Immune Cell Density and Morphology of the Ocular Surface
NCT01387360	PHASE4	COMPLETED	Presbyopic Supracor Treatment for Near Myopic/Hyperopic Pseudophakic Eyes
NCT01454843	PHASE4	COMPLETED	LASIK Using the Alcon Allegretto Wavefront-Guided Excimer Laser vs AMO Visx Wavefront-Guided Excimer Laser
NCT01693939	PHASE4	COMPLETED	Evaluation of the Post-LASIK Flap Thickness of the FS200 Femtosecond Laser Flap
NCT01706237	PHASE4	WITHDRAWN	Visual Outcomes And Contrast Sensitivity After Myopic Wavefront-Optimized Lasik With Nexisvision Shield Or Bandage Contact Lens
NCT01746589	PHASE4	COMPLETED	Visual Outcomes and Contrast Sensitivity After Myopic LASIK
NCT01977807	PHASE4	UNKNOWN	A Prospective Safety and Effectiveness Study of the 500 Hz Technolas Perfect Vision Excimer Laser in Asian Eyes Using LASIK
NCT02071576	PHASE4	UNKNOWN	A Prospective Safety and Effectiveness Study of the 500 Hz Technolas Perfect Vision Excimer Laser Using LASIK
NCT02112968	PHASE4	UNKNOWN	A Prospective Safety and Effectiveness Study of a New High Repetition Rate Excimer Laser Using LASIK for the Correction of Ammetropia and Presbyopia
NCT02186184	PHASE4	COMPLETED	Effect of Orthokeratology Versus Spectacles on Myopia Progression in Chinese Children: A Crossover Trial
NCT02544529	PHASE4	WITHDRAWN	Echothiophate Iodide for the Prevention of Progression of Myopia
NCT03001401	PHASE4	UNKNOWN	Comparison of Next Generation Laser Techniques of Myopia Correction: iDesign vs. SMILE
NCT03158142	PHASE4	COMPLETED	The Influence of Atropine on Choroidal Thickness
NCT03544827	PHASE4	COMPLETED	The Effects of Low Dose Atropine on Choroidal Thickness
NCT03881670	PHASE4	COMPLETED	On-Eye Optical Quality of Lotrafilcon B Lenses Over 12 Hours
NCT03949101	PHASE4	UNKNOWN	Atropine for Children and Adolescent Myopia Progression Study
NCT04208750	PHASE4	COMPLETED	Clinical Investigation of the Vision-R800 Device.
NCT04283331	PHASE4	UNKNOWN	Anesthetic Impregnated Bandage Soft Contact Lens (BSCL) in Pain Management After Photorefractive Keratectomy (PRK)
NCT05357326	PHASE4	UNKNOWN	Myopia Intervention in Children and Adolescents and Establishment of a Precise Intervention Model
NCT05448989	PHASE4	UNKNOWN	Efficacy and Safety of 1% Atropine 5+3 Regimen in Children and Adolescents Controlling Myopia
NCT05449015	PHASE4	UNKNOWN	Study on the Effect of Two Ways of Cycloplegia on Biological Parameters of Ciliary Muscle
NCT05733741	PHASE4	COMPLETED	Preservative-free Topical Anesthetics for Post-PRK Pain
NCT05803863	PHASE4	UNKNOWN	Efficacy Comparison of 2 Low-dose Atropine Eye Drops in Vietnamese Children Myopia Management
NCT06431841	PHASE4	ACTIVE_NOT_RECRUITING	Atropine and Spectacle Combination Treatment (ASPECT): 12-month Results of a Randomized Clinical Trial for Myopia Control
NCT06450132	PHASE4	ACTIVE_NOT_RECRUITING	Changes in Eye Shape With Myopia Management Interventions
NCT06553404	PHASE4	ACTIVE_NOT_RECRUITING	Myoslow Lens Study to Control Myopia in Children