TNFRSF11B

Summary

TNFRSF11B (TNF receptor superfamily member 11b, HGNC:11909) is a protein-coding gene on chromosome 8q24.12, encoding Tumor necrosis factor receptor superfamily member 11B (O00300). Acts as a decoy receptor for TNFSF11/RANKL and thereby neutralizes its function in osteoclastogenesis.

The protein encoded by this gene is a member of the TNF-receptor superfamily. This protein is an osteoblast-secreted decoy receptor that functions as a negative regulator of bone resorption. This protein specifically binds to its ligand, osteoprotegerin ligand, both of which are key extracellular regulators of osteoclast development. Studies of the mouse counterpart also suggest that this protein and its ligand play a role in lymph-node organogenesis and vascular calcification. Alternatively spliced transcript variants of this gene have been reported, but their full length nature has not been determined.

Source: NCBI Gene 4982 — RefSeq curated summary.

At a glance

• Gene–disease (curated): juvenile Paget disease (Strong, GenCC)
• Clinical variants (ClinVar): 248 total — 11 pathogenic, 3 likely-pathogenic
• MANE Select transcript: NM_002546

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11909
Approved symbol	TNFRSF11B
Name	TNF receptor superfamily member 11b
Location	8q24.12
Locus type	gene with protein product
Status	Approved
Aliases	OCIF, TR1
Ensembl gene	ENSG00000164761
Ensembl biotype	protein_coding
OMIM	602643
Entrez	4982

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000297350, ENST00000517352, ENST00000521597, ENST00000903853, ENST00000915466, ENST00000966248, ENST00000966249

RefSeq mRNA: 1 — MANE Select: NM_002546 NM_002546

CCDS: CCDS6326

Canonical transcript exons

ENST00000297350 — 5 exons

Exon	Start	End
ENSE00001087245	118923557	118924762
ENSE00001196110	118951792	118951885
ENSE00001282303	118932931	118933300
ENSE00003590568	118926494	118926718
ENSE00003651201	118928738	118928929

Expression profiles

Bgee: expression breadth ubiquitous, 201 present calls, max score 99.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.7626 / max 1059.7884, expressed in 1038 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
94599	18.1970	910
94600	0.8983	230
94601	0.7420	242
94603	0.4268	190
94602	0.2895	158
205300	0.2875	136
94598	0.2689	109
94604	0.2246	107
205298	0.1949	104
94596	0.0888	45

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	99.32	gold quality
ascending aorta	UBERON:0001496	98.20	gold quality
thoracic aorta	UBERON:0001515	98.20	gold quality
right coronary artery	UBERON:0001625	98.14	gold quality
descending thoracic aorta	UBERON:0002345	97.05	gold quality
stromal cell of endometrium	CL:0002255	94.94	gold quality
calcaneal tendon	UBERON:0003701	94.54	gold quality
left coronary artery	UBERON:0001626	94.47	gold quality
aorta	UBERON:0000947	94.37	gold quality
left lobe of thyroid gland	UBERON:0001120	93.94	gold quality
coronary artery	UBERON:0001621	93.25	gold quality
right lobe of thyroid gland	UBERON:0001119	93.16	gold quality
thyroid gland	UBERON:0002046	93.01	gold quality
tendon	UBERON:0000043	92.11	gold quality
artery	UBERON:0001637	91.69	gold quality
popliteal artery	UBERON:0002250	91.62	gold quality
tibial artery	UBERON:0007610	91.59	gold quality
metanephros cortex	UBERON:0010533	90.17	gold quality
tendon of biceps brachii	UBERON:0008188	90.05	gold quality
tibia	UBERON:0000979	87.59	gold quality
blood vessel layer	UBERON:0004797	87.02	gold quality
decidua	UBERON:0002450	86.67	gold quality
synovial joint	UBERON:0002217	86.15	gold quality
islet of Langerhans	UBERON:0000006	85.45	gold quality
heart right ventricle	UBERON:0002080	85.12	gold quality
nephron tubule	UBERON:0001231	83.74	gold quality
adult mammalian kidney	UBERON:0000082	82.87	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.68	gold quality
kidney	UBERON:0002113	82.55	gold quality
right lung	UBERON:0002167	82.30	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-7381	yes	885.65
E-MTAB-8530	yes	866.67
E-GEOD-83139	yes	4.17
E-MTAB-10290	no	464.22
E-ANND-3	no	3.13

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

122 targeting TNFRSF11B, 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-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775

Literature-anchored findings (GeneRIF, showing 40)

• Stimulation of osteoprotegerin (OPG) gene expression by transforming growth factor-beta (TGF-beta). Mapping of the OPG promoter region that mediates TGF-beta effects (PMID:11451955)
• Osteoprotegerin (OPG) is a survival factor for human prostate cancer cells. (PMID:11912131)
• The altered state of bone turnover during glucocorticoid treatment of patients with chronic glomerulonephritis is related to acute suppression of OPG. (PMID:12052453)
• single nucleotide polymorphism is related to vascular morphology and function. (PMID:12054556)
• differentially regulates protease expression in osteoclast cultures (PMID:12054560)
• secretion from prostate cancer is stimulated by cytokines, in vitro (PMID:12054622)
• osteoprotegerin expression is a novel PPAR gamma target gene in vascular smooth muscle cells. It is downregulated by PPAR gamma activation (PMID:12056809)
• PDGF induces osteoprotegerin expression in vascular smooth muscle cells by multiple signal pathways. (PMID:12067713)
• investigation of the genetic influence of Sp1 polymorphism on bone density in Irish women (PMID:12073153)
• Polymorphisms in the osteoprotegerin gene are associated with osteoporotic fractures (PMID:12096838)
• Juvenile Paget’s disease can result from osteoprotegerin deficiency caused by homozygous deletion of TNFRSF11B. (PMID:12124406)
• regulation of synthesis by isoflavones during osteoblast cell differentiation via an estrogen-receptor-dependent pathway (PMID:12150965)
• demonstrate that androgens specifically inhibit OPG mRNA levels and protein secretion by osteoblastic cells (PMID:12153751)
• analysis of OPG involvement in the etiology of osteoporosis using both linkage and association analyses (PMID:12181640)
• polymorphism and the risk of osteoporosis and vascular disease (PMID:12213849)
• Sequence variations in the promoter in patients with postmenopausal osteoporosis (PMID:12213850)
• bound, internalized, and degraded by multiple myeloma cells (PMID:12351414)
• inhibition of expression by parathyroid hormone via protein kinase A activation of cAMP-response element-binding protein (PMID:12364326)
• observations suggest that in postmenopausal women, circulating levels of OPG may reflect OPG activity in bone and are related to circulating endogenous levels of estradiol (PMID:12364420)
• Effects of 17beta-E2 and progesterone on the expression of osteoprotegerin in normal human osteoblast-like cells. (PMID:12398237)
• The novel finding of elevated serum OPG may reflect a compensatory reaction to enhanced osteoclast activity, despite the normal OCN level in Wilson disease (PMID:12412803)
• compared the gene expression of RANKL and osteoprogerin (OPG), a decoy receptor of RANKL, between moderate and advanced periodontitis, and healthy subjects (PMID:12469211)
• REVIEW: role of these molecules in immunology and skeletal remodelling and assess their involvement in diseases of bones and joints, including rheumatoid arthritis, Paget’s disease, post-menopausal osteoporosis and malignant bone diseases (PMID:12564836)
• Osteoprotegerin plays a major role in the development of transplantation osteoporosis. (PMID:12584041)
• examination as indices of bone turnover in different bone diseases (PMID:12619938)
• Osteoprotegerin has a role in inhibiting proliferation of myeloid progenitor cells (PMID:12662434)
• increased levels of OPG in plasma from diabetic patients with microvascular complications indicates that OPG may be involved in the development of vascular dysfunction in diabetes. (PMID:12824864)
• osteoprotegerin (OPG)inhibits HTLV-I infection of various cell lines via binding to heparan sulfate (PMID:12857926)
• osteoprotegerin and RANK ligand have roles in breast cancer bone metastasis (PMID:12923331)
• OPG expression may not be a major pathway of glioma cell resistance to future Apo2L/TRAIL-based therapeutic approaches. (PMID:14504888)
• Single nucleotide polymorphisms in OPG are not related to bone density or fracture in elderly women. (PMID:14508625)
• Correlations between OPG, IGF system components, and some markers of bone metabolism may indicate the role of OPG/RANKL system in the pathogenesis of bone metabolism disturbances following renal transplantation. (PMID:14529897)
• Mutations in TNFRSF11B account for the majority of, but not all, cases of idiopathic hyperphosphatasia, and there are distinct genotype-phenotype relationships. (PMID:14672344)
• RANKL-OPG pathway may regulate valvular calcification in calcific aortic stenosis (PMID:14734048)
• Results describe a negative association between serum osteoprotegerin (OPG) and bone mass with increased fracture odds ratios, and an influence of the OPG promoter mutation on bone mass and fracture status independent of serum OPG level. (PMID:14999524)
• Osteoprotegerin blocks endothelial cell apoptosis through binding TRAIL and preventing its interaction with death-inducing TRAIL-receptors. (PMID:15064358)
• The presence of the T allele of the osteoprotegerin (OPG) gene appears to be associated with low bone mineral density in children with juvenile idiopathic arthritis. (PMID:15124262)
• In vitro studies demonstrated that milk OPG is biologically active and suggested that it may contribute to the antiresorptive activity of milk on bone. (PMID:15155868)
• polymorphism in the promoter region of OPG is associated with vascular morphology in hypertensive subjects (PMID:15223723)
• These findings suggest that the TRAIL/OPG system is involved in the pathophysiology of endometriosis, possibly affecting the apoptosis of endometriotic cells. (PMID:15242994)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tnfrsf11b	ENSMUSG00000063727
rattus_norvegicus	Tnfrsf11b	ENSRNOG00000008336

Paralogs (21): FAS (ENSG00000026103), TNFRSF1B (ENSG00000028137), TNFRSF9 (ENSG00000049249), RELT (ENSG00000054967), NGFR (ENSG00000064300), TNFRSF1A (ENSG00000067182), CD40 (ENSG00000101017), TNFRSF10A (ENSG00000104689), LTBR (ENSG00000111321), TNFRSF10B (ENSG00000120889), TNFRSF8 (ENSG00000120949), CD27 (ENSG00000139193), TNFRSF11A (ENSG00000141655), TNFRSF21 (ENSG00000146072), TNFRSF14 (ENSG00000157873), TNFRSF10D (ENSG00000173530), TNFRSF10C (ENSG00000173535), TNFRSF4 (ENSG00000186827), TNFRSF18 (ENSG00000186891), TNFRSF25 (ENSG00000215788), TNFRSF6B (ENSG00000243509)

Protein

Protein identifiers

Tumor necrosis factor receptor superfamily member 11B — O00300 (reviewed: O00300)

Alternative names: Osteoclastogenesis inhibitory factor, Osteoprotegerin

All UniProt accessions (2): E5RFV7, O00300

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a decoy receptor for TNFSF11/RANKL and thereby neutralizes its function in osteoclastogenesis. Inhibits the activation of osteoclasts and promotes osteoclast apoptosis in vitro. Bone homeostasis seems to depend on the local ratio between TNFSF11 and TNFRSF11B. May also play a role in preventing arterial calcification. May act as decoy receptor for TNFSF10/TRAIL and protect against apoptosis. TNFSF10/TRAIL binding blocks the inhibition of osteoclastogenesis.

Subunit / interactions. Homodimer. Interacts with TNFSF10 and TNFSF11.

Subcellular location. Secreted.

Tissue specificity. Highly expressed in adult lung, heart, kidney, liver, spleen, thymus, prostate, ovary, small intestine, thyroid, lymph node, trachea, adrenal gland, testis, and bone marrow. Detected at very low levels in brain, placenta and skeletal muscle. Highly expressed in fetal kidney, liver and lung.

Post-translational modifications. N-glycosylated. Contains sialic acid residues. The N-terminus is blocked.

Disease relevance. Paget disease of bone 5, juvenile-onset (PDB5) [MIM:239000] An autosomal recessive, juvenile-onset form of Paget disease, a disorder of bone remodeling characterized by increased bone turnover affecting one or more sites throughout the skeleton, primarily the axial skeleton. Osteoclastic overactivity followed by compensatory osteoblastic activity leads to a structurally disorganized mosaic of bone (woven bone), which is mechanically weaker, larger, less compact, more vascular, and more susceptible to fracture than normal adult lamellar bone. PDB5 clinical manifestations include short stature, progressive long bone deformities, fractures, vertebral collapse, skull enlargement, and hyperostosis with progressive deafness. The disease is caused by variants affecting the gene represented in this entry.

Induction. Up-regulated by increasing calcium-concentration in the medium and estrogens. Down-regulated by glucocorticoids.

RefSeq proteins (1): NP_002537* (*=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
IPR017371	TNFR_11B	Family
IPR022323	TNFR_11	Family
IPR052459	TNFRSF_decoy_receptor	Family
IPR057633	Death_TNF11B	Domain

Pfam: PF00020, PF23630

UniProt features (47 total): strand 16, disulfide bond 9, glycosylation site 5, repeat 4, mutagenesis site 4, sequence variant 3, domain 2, signal peptide 1, chain 1, sequence conflict 1, site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3URF	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00300-F1	86.79	0.57

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): 400 (involved in dimerization)

Disulfide bonds (9): 41–54, 44–62, 65–80, 83–97, 87–105, 107–118, 124–142, 145–160, 166–185

Glycosylation sites (5): 152, 165, 178, 289, 98

Mutagenesis-validated functional residues (4):

Position	Phenotype
78–79	decreases inhibition of osteoclast differentiation.
116	reduces affinity for tnfsf11. decreases inhibition of osteoclast differentiation.
400–401	abolishes dimerization.
400	abolishes dimerization.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 407 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, FUNG_IL2_SIGNALING_2, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, MODULE_64, GOZGIT_ESR1_TARGETS_DN, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_TUMOR_NECROSIS_FACTOR_MEDIATED_SIGNALING_PATHWAY, NAGASHIMA_NRG1_SIGNALING_UP, HERNANDEZ_ABERRANT_MITOSIS_BY_DOCETACEL_4NM_UP, HERNANDEZ_MITOTIC_ARREST_BY_DOCETAXEL_1_UP, GOBP_REGULATION_OF_LEUKOCYTE_DIFFERENTIATION

GO Biological Process (7): skeletal system development (GO:0001501), apoptotic process (GO:0006915), signal transduction (GO:0007165), negative regulation of tumor necrosis factor-mediated signaling pathway (GO:0010804), extracellular matrix organization (GO:0030198), negative regulation of odontogenesis of dentin-containing tooth (GO:0042489), negative regulation of osteoclast differentiation (GO:0045671)

GO Molecular Function (4): cytokine activity (GO:0005125), signaling receptor activity (GO:0038023), heparan sulfate binding (GO:1904399), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), extracellular matrix (GO:0031012), signaling receptor complex (GO:0043235)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
TNFR2 non-canonical NF-kB pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
system development	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
negative regulation of cytokine-mediated signaling pathway	1
regulation of tumor necrosis factor-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
extracellular structure organization	1
external encapsulating structure organization	1
odontogenesis of dentin-containing tooth	1
negative regulation of odontogenesis	1
regulation of odontogenesis of dentin-containing tooth	1
negative regulation of myeloid leukocyte differentiation	1
osteoclast differentiation	1
regulation of osteoclast differentiation	1
receptor ligand activity	1
molecular transducer activity	1
glycosaminoglycan binding	1
carboxylic acid binding	1
sulfur compound binding	1
binding	1
cellular anatomical structure	1
membrane	1
cell periphery	1
external encapsulating structure	1
protein-containing complex	1

Protein interactions and networks

STRING

1514 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNFRSF11B	TNFSF11	O14788	997
TNFRSF11B	TNFSF10	P50591	919
TNFRSF11B	ACP5	P13686	771
TNFRSF11B	SP7	Q8TDD2	735
TNFRSF11B	RUNX2	Q13950	730
TNFRSF11B	COL1A1	P02452	710
TNFRSF11B	TBXAS1	P24557	683
TNFRSF11B	SOST	Q9BQB4	677
TNFRSF11B	LRP5	O75197	669
TNFRSF11B	BGLAP	P02818	663
TNFRSF11B	IL6	P05231	637
TNFRSF11B	IL17RC	Q8NAC3	623
TNFRSF11B	CTSK	P43235	615
TNFRSF11B	TNFRSF11A	Q9Y6Q6	610
TNFRSF11B	ALPL	P05186	609

IntAct

22 interactions, top by confidence:

A	B	Type	Score
TNFRSF11B	TNFSF11	psi-mi:“MI:0407”(direct interaction)	0.620
TNFSF11	TNFRSF11B	psi-mi:“MI:0407”(direct interaction)	0.620
TNFRSF11B	PSEN1	psi-mi:“MI:0915”(physical association)	0.560
TNFRSF11B	HTT	psi-mi:“MI:0915”(physical association)	0.560
TNFRSF11A	TNFRSF11B	psi-mi:“MI:0915”(physical association)	0.540
TNFRSF11A	TNFRSF11B	psi-mi:“MI:0407”(direct interaction)	0.540
HAPLN1	TNFRSF11B	psi-mi:“MI:0915”(physical association)	0.400
SIGLEC7	TNFRSF11B	psi-mi:“MI:0915”(physical association)	0.400
SIGLEC9	TNFRSF11B	psi-mi:“MI:0915”(physical association)	0.400
LTF	TNFRSF11B	psi-mi:“MI:0915”(physical association)	0.400
TNFRSF11B	SCRN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): TNFSF11 (Reconstituted Complex), TNFRSF11B (Affinity Capture-MS), TNFRSF11B (Reconstituted Complex), KPRP (Affinity Capture-MS), SCRN1 (Affinity Capture-MS), TNFRSF11B (Proximity Label-MS)

ESM2 similar proteins: A5D7R1, D3ZF92, F1LW30, O00300, O08712, O08727, O14763, O62802, O70458, O70535, O75509, O77736, O95256, P01590, P20334, P20352, P22934, P25118, P25445, P25446, P26897, P30836, P41690, P42703, P51867, P83626, Q07011, Q13478, Q5M9I1, Q61098, Q63199, Q65Z14, Q6UXZ4, Q6X782, Q6X784, Q6X786, Q764M8, Q8K1S2, Q8K5B1, Q90VY2

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, O00220, O14763, O14798, O77736, P15725, P47741, Q9QZM4

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
TNFSF11	up-regulates	TNFRSF11B	binding
CREB5	“down-regulates quantity by repression”	TNFRSF11B	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	3
Uncertain significance	140
Likely benign	51
Benign	19

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1076352	NC_000008.10:g.(?119936613)(119964060_?)del	Pathogenic
1454756	NM_002546.4(TNFRSF11B):c.1205A>T (p.Ter402Leu)	Pathogenic
208808	NC_000008.11:g.(118690580_118696647)_(118950613_118950848)del	Pathogenic
208809	NM_002546.4(TNFRSF11B):c.226A>C (p.Thr76Pro)	Pathogenic
2136706	NM_002546.4(TNFRSF11B):c.25_28dup (p.Val10fs)	Pathogenic
2870826	NM_002546.4(TNFRSF11B):c.412C>T (p.Arg138Ter)	Pathogenic
3674589	NM_002546.4(TNFRSF11B):c.577C>T (p.Gln193Ter)	Pathogenic
6969	NM_002546.4(TNFRSF11B):c.544_546del (p.Asp182del)	Pathogenic
6970	NM_002546.4(TNFRSF11B):c.260G>A (p.Cys87Tyr)	Pathogenic
6972	NM_002546.4(TNFRSF11B):c.966_969delinsCTT (p.Asp323fs)	Pathogenic
802437	NM_002546.4(TNFRSF11B):c.997C>T (p.Arg333Ter)	Pathogenic
191231	NM_002546.4(TNFRSF11B):c.194G>T (p.Cys65Phe)	Likely pathogenic
191343	Single allele	Likely pathogenic
3062042	NM_002546.4(TNFRSF11B):c.419_420del (p.Thr140fs)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

2677 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:118928896:C:G	C145S	0.992
8:118928897:A:T	C145S	0.992
8:118933011:C:G	C107S	0.991
8:118933012:A:T	C107S	0.991
8:118926707:A:G	C202R	0.990
8:118928851:C:G	C160S	0.990
8:118928852:A:T	C160S	0.990
8:118928897:A:G	C145R	0.990
8:118926542:A:G	W257R	0.989
8:118926542:A:T	W257R	0.989
8:118924582:C:G	R333P	0.988
8:118926706:C:G	C202S	0.988
8:118926706:C:T	C202Y	0.988
8:118926707:A:T	C202S	0.988
8:118933200:C:G	C44S	0.988
8:118933201:A:T	C44S	0.988
8:118924586:A:G	W332R	0.987
8:118924586:A:T	W332R	0.987
8:118928852:A:G	C160R	0.987
8:118932977:G:C	C118W	0.987
8:118932978:C:G	C118S	0.987
8:118932979:A:G	C118R	0.987
8:118932979:A:T	C118S	0.987
8:118933071:C:G	C87S	0.987
8:118933072:A:T	C87S	0.987
8:118926540:C:A	W257C	0.986
8:118926540:C:G	W257C	0.986
8:118932961:A:G	C124R	0.986
8:118933017:C:G	C105S	0.986
8:118933018:A:T	C105S	0.986

dbSNP variants (sampled 300 via entrez): RS1000110214 (8:118939262 T>A), RS1000266869 (8:118927904 C>T), RS1000293562 (8:118940751 G>A), RS1000368175 (8:118952619 G>A,C,T), RS1000619403 (8:118939203 G>T), RS1000671713 (8:118951751 C>T), RS1000902416 (8:118938957 A>G), RS1000983153 (8:118946394 T>G), RS1001019340 (8:118952634 A>G), RS1001091695 (8:118926142 T>G), RS1001159493 (8:118952793 G>A), RS1001173056 (8:118932802 C>A,T), RS1001248512 (8:118946125 G>A), RS1001251248 (8:118952348 C>T), RS1001296212 (8:118942546 T>C)

Disease associations

OMIM: gene MIM:602643 | disease phenotypes: MIM:239000

GenCC curated gene-disease

Disease	Classification	Inheritance
juvenile Paget disease	Strong	Autosomal recessive

Mondo (2): juvenile Paget disease (MONDO:0009394), connective tissue disorder (MONDO:0003900)

Orphanet (1): Juvenile Paget disease (Orphanet:2801)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003240	Connective Tissue Diseases	C17.300
C537701	Hyperostosis corticalis deformans juvenilis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2073618	Toxicity	3	anastrozole;letrozole	Breast Neoplasms

PharmGKB variants

7 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1485286	TNFRSF11B		0.00	0
rs1485288	TNFRSF11B		0.00	0
rs2073618	COLEC10, TNFRSF11B	3	6.25	1	anastrozole;letrozole
rs3102724	TNFRSF11B		0.00	0
rs3102728	TNFRSF11B		0.00	0
rs3134068	COLEC10, TNFRSF11B		0.00	0
rs11573856	TNFRSF11B		0.00	0

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

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, decreases expression, decreases reaction, affects expression, increases expression (+1 more)	10
Zoledronic Acid	increases expression, increases secretion, affects expression, decreases expression, decreases reaction	6
Valproic Acid	affects expression, decreases expression, increases expression	6
Raloxifene Hydrochloride	affects cotreatment, decreases expression, increases expression, increases secretion	6
bisphenol A	affects cotreatment, increases methylation, decreases secretion, increases reaction, decreases expression (+1 more)	5
Tetrachlorodibenzodioxin	increases expression, affects expression, decreases expression, affects cotreatment	5
Fulvestrant	affects cotreatment, increases methylation, decreases reaction, increases expression, decreases expression	4
Dexamethasone	increases reaction, decreases secretion, decreases reaction, affects cotreatment, increases expression (+1 more)	4
Particulate Matter	decreases expression, increases abundance	4
trichostatin A	increases expression, affects cotreatment	3
Acetaminophen	decreases expression	3
cobaltiprotoporphyrin	decreases reaction, decreases secretion, increases expression, increases reaction	2
sodium arsenite	decreases expression	2
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	2
butylbenzyl phthalate	affects cotreatment, decreases secretion, increases reaction, increases expression	2
perfluorooctane sulfonic acid	affects expression, decreases expression	2
SB 203580	affects cotreatment, increases reaction, decreases expression, decreases reaction	2
(+)-JQ1 compound	decreases expression	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Ascorbic Acid	affects cotreatment, increases expression, decreases expression, decreases reaction	2
Benzo(a)pyrene	increases expression, increases methylation	2
Cannabidiol	decreases reaction, increases expression, decreases expression	2
Doxorubicin	decreases expression, increases expression	2
Hydrogen Peroxide	affects expression, increases expression	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Progesterone	increases reaction, affects cotreatment, decreases expression, decreases reaction	2
Silicon Dioxide	decreases expression	2
Tamoxifen	affects cotreatment, decreases expression, increases expression, increases secretion	2

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C9IN	KSCBi002-B-2	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04197050	PHASE4	UNKNOWN	Effect of Sacubitril/Valsartan on Reduced Right Ventricular Ejection Fraction in Patients With CTD
NCT04928586	PHASE4	UNKNOWN	Immunosuppressant Combined With Pirfenidone in CTD-ILD
NCT05440240	PHASE4	RECRUITING	Percutaneous Needle Fasciotomy +/- Corticosteroid Injection for Dupuytren’s Contracture
NCT05505409	PHASE4	UNKNOWN	Efficacy and Safety of Pirfenidone in CTD-ILD
NCT06499233	PHASE4	RECRUITING	Efficacy and Safety of Prophylactic Treatment for Pneumocystis Jirovecii Pneumonia in Patients With Autoimmune Inflammatory Rheumatic Disease
NCT00864201	PHASE3	UNKNOWN	A Study to Evaluate the Use of Bosentan in Patients With Exercise Induced Pulmonary Arterial Hypertension Associated With Connective Tissue Disease
NCT01196091	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01205438	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01488708	PHASE3	TERMINATED	On Open-Label Study in Participants With Systemic Lupus Erythematosus
NCT03626688	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients
NCT03683186	PHASE3	ENROLLING_BY_INVITATION	A Study Evaluating the Long-Term Efficacy and Safety of Ralinepag in Subjects With PAH Via an Open-Label Extension
NCT04084678	PHASE3	TERMINATED	A Study of Ralinepag to Evaluate Effects on Exercise Capacity by CPET in Subjects With WHO Group 1 PH
NCT06716606	PHASE3	RECRUITING	A Study to Investigate the Long-term Safety and Efficacy of Belimumab in Adults With Interstitial Lung Disease (ILD) Associated With Systemic Sclerosis (SSc) and Other Connective Tissue Diseases (CTD) (BLISSconneCTD-OLE)
NCT06917690	PHASE3	RECRUITING	A Study to Learn About the Safety and Efficacy of the Drug Oleogel-S10 in Japanese Patients With Epidermolysis Bullosa
NCT00004357	PHASE2	COMPLETED	Absorption of Corticosteroids in Children With Juvenile Dermatomyositis
NCT00005675	PHASE2	COMPLETED	Oral Type I Collagen for Relieving Scleroderma
NCT01808196	PHASE2	COMPLETED	Testing Effectiveness of Losartan in Patients With EoE With or Without a CTD
NCT02682511	PHASE2	ACTIVE_NOT_RECRUITING	Oral Ifetroban to Treat Diffuse Cutaneous Systemic Sclerosis (SSc) or SSc-associated Pulmonary Arterial Hypertension
NCT04993885	PHASE2	RECRUITING	Avatrombopag in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies
NCT05516758	PHASE2	TERMINATED	A Study of Peresolimab (LY3462817) in Participants With Moderately-to-Severely Active Rheumatoid Arthritis
NCT05998759	PHASE2	RECRUITING	Telitacicept for the Treatment of Connective Tissue Disease-associated Thrombocytopenia
NCT06104228	PHASE2	RECRUITING	129 Xenon MRI as a Biomarker for Diagnosis and Response to Therapy in Pulmonary Arterial Hypertension (PAH)
NCT01093911	PHASE1	COMPLETED	Safety Study of CDP7657 in Healthy Volunteers and Patients With Systemic Lupus Erythematosus (SLE)
NCT01764594	PHASE1	COMPLETED	Safety Study of CDP7657 in Patients With Systemic Lupus Erythematosus
NCT02392130	PHASE1	COMPLETED	A Clinical Trial to Assess the Potential of LEO 130852A Gel to Reduce Steroid Induced Skin Atrophy on Healthy Skin
NCT03337165	PHASE1	COMPLETED	Autologous Tolerogenic Dendritic Cells for Treatment of Patients With Rheumatoid Arthritis
NCT03929120	PHASE1	COMPLETED	Allogeneic Bone Marrow Mesenchymal Stem Cells for Patients With Interstitial Lung Disease (ILD) & Connective Tissue Disorders (CTD)
NCT01424033	PHASE2/PHASE3	TERMINATED	A Clinical Trial for CTD-ILD Treatment
NCT04915482	PHASE2/PHASE3	UNKNOWN	TPO-RAs Combined With Anti-CD20 Antibody in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies
NCT06574581	PHASE1/PHASE2	RECRUITING	ADSCs Therapy in Patients With CTD-ILD
NCT00001330	Not specified	COMPLETED	Study of Silicone-Associated Connective Tissue Diseases
NCT00001641	Not specified	COMPLETED	Study of Heritable Connective Tissue Disorders
NCT00001978	Not specified	TERMINATED	Determination of Kidney Function
NCT00076830	Not specified	COMPLETED	Evaluation and Treatment of Patients With Connective Tissue Disease
NCT00341679	Not specified	COMPLETED	Studies of the Natural History and Pathogenesis of Autoimmune/Connective Tissue Diseases
NCT00470327	Not specified	RECRUITING	A Study of the Natural Progression of Interstitial Lung Disease (ILD)
NCT00491309	Not specified	UNKNOWN	Exercise and Respiratory Therapy in Patients With Rheumatoid Arthritis / Collagenosis and Pulmonary Hypertension