TNFRSF4

Chr 1

TNF receptor superfamily member 4

Also known as: ACT35, CD134, IMD16, OX40, TXGP1L

NCBI Gene: 7293 ENSG00000186827 UniProt: P43489

The TNFRSF4 protein is a TNF receptor superfamily member that serves as a costimulatory receptor for T-cell activation and promotes T-cell survival by suppressing apoptosis through NF-kappaB signaling. Mutations cause autosomal recessive immunodeficiency 16, characterized by defective T-cell responses and impaired T cell-dependent B cell function. The gene shows low constraint against loss-of-function variants (pLI 0.0001, LOEUF 1.32), consistent with the recessive inheritance pattern requiring biallelic mutations for disease manifestation.

ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor has been shown to activate NF-kappaB through its interaction with adaptor proteins TRAF2 and TRAF5. Knockout studies in mice suggested that this receptor promotes the expression of apoptosis inhibitors BCL2 and BCL2lL1/BCL2-XL, and thus suppresses apoptosis. The knockout studies also suggested the roles of this receptor in CD4+ T cell response, as well as in T cell-dependent B cell proliferation and differentiation. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtImmunodeficiency 16

Clinical highlights

Gene–disease validity (ClinGen)

Limited · combined immunodeficiency due to OX40 deficiency · AR · ClinGen 2026

not for standalone diagnostic reporting

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.32

LOEUF

Multiple*

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?

1.32LOEUF

pLI 0.000

Z-score 0.86

OE 0.71 (0.40–1.32)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.62Z-score

OE missense 0.86 (0.75–0.99)

142 obs / 164.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.71 (0.40–1.32)

0≤0.351.4

Missense OE?0.86 (0.75–0.99)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 7 / 9.9Missense obs/exp: 142 / 164.5Syn Z: 0.16

Background carrier burden — how many people carry a rare variant somewhere in TNFRSF4?

gnomAD v4 · ~730k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 170

436 rare PASS variants

Rare truncating (LoF)

1 in 2,400

62 rare PASS variants

Rare synonymous (reference)

1 in 140

207 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TNFRSF4. 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 230	1 in 2,300
South Asian	~43k	1 in 95	1 in 6,000
Remaining (unassigned)	~30k	1 in 130	1 in 3,000
European (Finnish)	~26k	1 in 270	1 in 1,400
Admixed American	~22k	1 in 81	1 in 1,900
African / African American	~21k	1 in 92	1 in 1,500
East Asian	~20k	1 in 110	1 in 3,900
Ashkenazi Jewish	~13k	1 in 780	none seen
Middle Eastern	~2,883	1 in 86	≈ 1 in 1,400

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.