TNFSF11

Chr 13

TNF superfamily member 11

Also known as: CD254, ODF, OPGL, OPTB2, RANKL, TNLG6B, TRANCE, hRANKL2

NCBI Gene: 8600 ENSG00000120659 UniProt: O14788

The protein functions as a cytokine that binds to osteoprotegerin and RANK receptor, serving as a key factor for osteoclast differentiation and activation, and also regulates T-cell dependent immune responses and dendritic cell survival. Mutations cause autosomal recessive osteopetrosis type 2, characterized by defective bone resorption due to absent or dysfunctional osteoclasts, leading to dense but brittle bones and potential complications including bone marrow failure and cranial nerve compression. This gene shows low constraint against loss-of-function variants (pLI 0.005), consistent with the recessive inheritance pattern where heterozygous carriers are typically unaffected.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the tumor necrosis factor (TNF) cytokine family which is a ligand for osteoprotegerin and functions as a key factor for osteoclast differentiation and activation. This protein was shown to be a dendritic cell survival factor and is involved in the regulation of T cell-dependent immune response. T cell activation was reported to induce expression of this gene and lead to an increase of osteoclastogenesis and bone loss. This protein was shown to activate antiapoptotic kinase AKT/PKB through a signaling complex involving SRC kinase and tumor necrosis factor receptor-associated factor (TRAF) 6, which indicated this protein may have a role in the regulation of cell apoptosis. Targeted disruption of the related gene in mice led to severe osteopetrosis and a lack of osteoclasts. The deficient mice exhibited defects in early differentiation of T and B lymphocytes, and failed to form lobulo-alveolar mammary structures during pregnancy. [provided by RefSeq, Mar 2026]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtOsteopetrosis, autosomal recessive 2

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · autosomal recessive osteopetrosis 2 · AR · ClinGen 2024

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.85

LOEUF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.85LOEUF

pLI 0.005

Z-score 1.96

OE 0.43 (0.24–0.85)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.93Z-score

OE missense 0.80 (0.70–0.92)

139 obs / 173.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.24–0.85)

0≤0.351.4

Missense OE?0.80 (0.70–0.92)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 6 / 13.9Missense obs/exp: 139 / 173.4Syn Z: -1.02

Background carrier burden — how many people carry a rare variant somewhere in TNFSF11?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 98

361 rare PASS variants

Rare truncating (LoF)

1 in 2,300

52 rare PASS variants

Rare synonymous (reference)

1 in 190

176 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TNFSF11. 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 170	1 in 4,300
South Asian	~43k	1 in 180	1 in 270
Remaining (unassigned)	~30k	1 in 110	1 in 3,000
European (Finnish)	~27k	1 in 260	1 in 5,000
Admixed American	~22k	1 in 140	≈ 1 in 4,700
African / African American	~21k	1 in 180	1 in 2,100
East Asian	~20k	1 in 160	≈ 1 in 6,100
Ashkenazi Jewish	~13k	1 in 2,200	none seen
Middle Eastern	~2,884	1 in 190	≈ 1 in 1,100

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 ↓