TNFRSF11B

Chr 8

TNF receptor superfamily member 11b

Also known as: OCIF, OPG, PDB5, TR1

NCBI Gene: 4982 ENSG00000164761 UniProt: O00300

The protein functions as a decoy receptor that inhibits bone resorption by binding to osteoprotegerin ligand and neutralizing osteoclast activation, serving as a key negative regulator of bone homeostasis. Mutations cause autosomal recessive juvenile-onset Paget disease of bone 5, characterized by early-onset abnormal bone remodeling. The gene is moderately constrained against loss-of-function variants (LOEUF 0.548), indicating some intolerance to complete protein loss.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

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. [provided by RefSeq, Jul 2008]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtPaget disease of bone 5, juvenile-onset

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.55

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — TNFRSF11B

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.55LOEUF

pLI 0.162

Z-score 3.00

OE 0.26 (0.14–0.55)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.84Z-score

OE missense 0.84 (0.74–0.95)

184 obs / 219.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.26 (0.14–0.55)

0≤0.351.4

Missense OE?0.84 (0.74–0.95)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 5 / 19.2Missense obs/exp: 184 / 219.0Syn Z: 0.57

Background carrier burden — how many people carry a rare variant somewhere in TNFRSF11B?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

478 rare PASS variants

Rare truncating (LoF)

1 in 5,300

43 rare PASS variants

Rare synonymous (reference)

1 in 130

195 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TNFRSF11B. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 110	1 in 5,800
South Asian	~43k	1 in 140	none seen
Remaining (unassigned)	~30k	1 in 130	≈ 1 in 30,000
European (Finnish)	~27k	1 in 480	none seen
Admixed American	~22k	1 in 98	1 in 2,300
African / African American	~21k	1 in 150	≈ 1 in 4,600
East Asian	~20k	1 in 81	≈ 1 in 9,900
Ashkenazi Jewish	~13k	1 in 570	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 260	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 5 coding exons well covered in gnomAD exomes and genomes.? see exons ↓