TNFRSF11A

Chr 18ADAR

TNF receptor superfamily member 11a

Also known as: CD265, FEO, LOH18CR1, ODFR, OFE, OPTB7, OSTS, PDB2

NCBI Gene: 8792ENSG00000141655UniProt: Q9Y6Q6

The encoded protein is a TNF receptor superfamily member that serves as the receptor for RANKL and is essential for osteoclast formation and bone remodeling. Mutations cause bone disorders with both autosomal dominant and autosomal recessive inheritance patterns, including early-onset Paget disease, familial expansile osteolysis, and osteopetrosis. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.597), and the associated bone diseases can present in childhood.

Summary from RefSeq, OMIM, UniProt
Research Assistant →

Primary Disease Associations & Inheritance

{Paget disease of bone 2, early-onset}MIM #602080
AD
Osteolysis, familial expansileMIM #174810
AD
Osteopetrosis, autosomal recessive 7MIM #612301
AR
0
Active trials
31
Pubs (1 yr)
43
P/LP submissions
9%
P/LP missense
0.60
LOEUF
Multiple*
Mechanism· predicted
Clinical Summary— TNFRSF11A
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.
📋
ClinVar Variants
43 unique Pathogenic / Likely Pathogenic· 339 VUS of 600 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.60LOEUF
pLI 0.009
Z-score 3.05
OE 0.33 (0.19–0.60)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
1.29Z-score
OE missense 0.81 (0.73–0.89)
279 obs / 346.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.33 (0.19–0.60)
0≤0.351.4
Missense OE0.81 (0.73–0.89)
0≤0.61.4
Synonymous OE0.85
0≤1.21.6
LoF obs/exp: 8 / 24.2Missense obs/exp: 279 / 346.5Syn Z: 1.42
DN
0.76top 25%
GOF
0.81top 10%
LOF
0.3065th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation
DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFOur findings: i) reveal that JPD can be associated with an activating mutation within TNFRSF11A, ii) expand the range and overlap of phenotypes among the Mendelian disorders of RANK activation, and iii) call for mutation analysis to improve diagnosis, prognostication, recurrence risk assessment, andPMID:25063546

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

600 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30
Likely Pathogenic13
VUS339
Likely Benign196
Benign6
Conflicting4
30
Pathogenic
13
Likely Pathogenic
339
VUS
196
Likely Benign
6
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
0
24
0
30
Likely Pathogenic
5
4
4
0
13
VUS
9
300
28
2
339
Likely Benign
1
3
58
134
196
Benign
0
0
5
1
6
Conflicting
—4
Total21307119137588

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

TNFRSF11A · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Investigation of The Relationship of TNFRSF11A Gene Polymorphisms with Breast Cancer Development and Metastasis Risk in Patients with BRCA1 Or BRCA2 Pathogenic Variants Living in The Trakya Region of Turkey
Özdemir K et al.·Balkan J Med Genet
2021Cohort
Prognostic costimulatory molecule-related signature risk model correlates with immunotherapy response in colon cancer
Huang W et al.·Sci Rep
2023Functional
A Null Mutation of TNFRSF11A Causes Dysosteosclerosis, Not Osteopetrosis
Kırkgöz T et al.·Front Genet
2022
Retraction: "Mir-3150B-3P Inhibits the Proliferation and Invasion of Cervical Cancer Cells by Targeting Tnfrsf11A".
·J Investig Med
2025
Development of a prognostic signature of patients with esophagus adenocarcinoma by using immune-related genes
Zhang X et al.·BMC Bioinformatics
2021Cohort
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Anti-atherosclerotic role of microRNA-218-5p via regulating the TNFRSF11A/NF-κB/NLRP3/caspase-1 pyroptosis pathway.
Wei C et al.·Cytotechnology
2026
Conditional deletion of glutaminase 1 in Tnfrsf11a-expressing cells reduces bone mass and induces postnatal growth retardation in mice.
Terashita S et al.·Biochem Biophys Res Commun
2026
Duplications within exon 1 of TNFRSF11A encoding receptor activator of nuclear factor-kappa B (RANK) are associated with tendon avulsion.
Simmons JH et al.·Bone
2025
Paradoxical combination of osteosclerosis and osteopenia in an adult woman with biallelic TNFRSF11A loss-of-function variants escaping nonsense-mediated decay.
Gajewski D et al.·JBMR Plus
2025Open Access
TNFRSF11A variants contribute to systemic autoinflammatory diseases: A case series of 12 patients.
Papatheodorou V et al.·Semin Arthritis Rheum
2024Cohort
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients